Conditions: Hepatitis C Virus Infection
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 106
Healthy volunteers: no

Brief summary:
This study will have two parts as follows:

The PK Lead-in Phase of the study will evaluate the steady state pharmacokinetics (PK) and confirm the dose of sofosbuvir (SOF) in hepatitis C virus (HCV)-infected pediatric participants. The PK Lead-in Phase will also evaluate the safety and tolerability of 7 days of dosing of SOF+ribavirin (RBV) in HCV-infected pediatric participants.

The Treatment Phase will be initiated by age cohort after confirmation of age-appropriate SOF dosage levels. Participants from the PK Lead-in Phase will immediately rollover into the Treatment Phase with no interruption of study drug administration. The Treatment Phase will evaluate the antiviral efficacy, safety, and tolerability of SOF+RBV for 12 or 24 weeks in pediatric participants with genotype 2 or 3 HCV infection, respectively.

Detailed description:

Arms:
arm 1: Participants between 12 to \< 18 years of age with genotype (GT) 2 HCV infection weighing ≥ 45 kg will receive SOF (1 x 400 mg tablet, 4 x 100 mg tablets, or 8 x 50 mg oral granules based on swallowability assessment during screening) plus RBV (up to 1400 mg) for 12 weeks. arm 2: Participants between 12 to \< 18 years of age with genotype 3 HCV infection weighing ≥ 45 kg will receive SOF (1 x 400 mg tablet, 4 x 100 mg tablets, or 8 x 50 mg oral granules based on swallowability assessment during screening) plus RBV (up to 1400 mg) for 24 weeks. arm 3: Participants between 6 to \< 12 years of age with genotype 2 HCV infection weighing ≥ 17 kg and \< 45 kg will receive SOF (2 x 100 mg tablets or 4 x 50 mg oral granules based on swallowability assessment during screening) plus RBV (up to 1400 mg) for 12 weeks. arm 4: Participants between 6 to \< 12 years of age with genotype 3 HCV infection weighing ≥ 17 kg and \< 45 kg will receive SOF (2 x 100 mg tablets or 4 x 50 mg oral granules based on swallowability assessment during screening) plus RBV (up to 1400 mg) for 24 weeks. arm 5: Participants between 3 to \< 6 years of age with genotype 2 HCV infection weighing ≥ 17kg will receive SOF (4 x 50 mg oral granules) plus RBV (up to 1400 mg) for 12 weeks and those weighing \< 17 kg will receive SOF (3 x 50 mg oral granules) + RBV (up to 1400 mg) for 12 weeks. arm 6: Participants between 3 to \< 6 years of age with genotype 2 HCV infection weighing ≥ 17kg will receive SOF (4 x 50 mg oral granules) plus RBV (up to 1400 mg) for 24 weeks and those weighing \< 17 kg will receive SOF (3 x 50 mg oral granules) + RBV (up to 1400 mg) for 24 weeks.

Interventions: intervention 1: SOF intervention 2: RBV
Intervention descriptions: intervention 1: SOF administered orally once daily intervention 2: RBV oral solution or capsules will be administered orally in a divided daily dose based on weight

Protocol document:
Prot_003.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Arm 
Study to Investigate the Safety and Efficacy of 
Sofosbuvir + Ribavirin in Adolescents and Children with 
Genotype 2 or 3 Chronic HCV Infection
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive 
Foster City, CA 94404, USA
IND No.:
EudraCT Number:
106739
2014-002283-32
Indication:
Hepatitis C Virus Infection 
Protocol ID:
GS-US-334-1112
Gilead Sciences Medical 
Monitor:
Name:
Bittoo Kanwar, MD, 
Telephone:
Mobile:
Fax:
E-mail:
Protocol Version/Date:
Original:
20 December 2013
Amendment 1:
10 February 2014
Amendment 2:
14 March 2014
Amendment 3:
10 October 2014
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....................................................................16
1.
INTRODUCTION ..............................................................................................................................................19
1.1.
Background ............................................................................................................................................19
1.2.
Sofosbuvir ..............................................................................................................................................20
1.2.1.
Summary of Additional Clinical Experience with Sofosbuvir .............................................20
1.3.
Ribavirin (RBV).....................................................................................................................................22
1.4.
Rationale for the Current Study .............................................................................................................22
1.5.
Rationale for Dose Selection of SOF .....................................................................................................23
1.6.
Overall Risk/Benefit Assessment...........................................................................................................23
2.
OBJECTIVES.....................................................................................................................................................25
3.
STUDY DESIGN................................................................................................................................................26
3.1.
Treatment Plan and Regimen .................................................................................................................26
3.1.1.
PK Lead-in ...........................................................................................................................26
3.1.2.
Treatment Phase ...................................................................................................................26
3.2.
Visit Schedule ........................................................................................................................................28
3.2.1.
PK Lead-in ...........................................................................................................................28
3.2.2.
Treatment Phase ...................................................................................................................29
3.3.
Virologic Response-Based Stopping Criteria.........................................................................................29
3.4.
Treatment Discontinuations Criteria ......................................................................................................30
3.5.
Discontinuations.....................................................................................................................................30
3.6.
Pharmacogenomic Substudy ..................................................................................................................30
3.7.
Long-Term Follow-Up...........................................................................................................................30
3.8.
Breakthrough Futility Assessment .........................................................................................................31
4.
SUBJECT POPULATION..................................................................................................................................32
4.1.
Number of Subjects and Subject Selection ............................................................................................32
4.2.
Inclusion Criteria....................................................................................................................................32
4.3.
Exclusion Criteria...................................................................................................................................33
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................34
5.1.
Randomization and Blinding..................................................................................................................34
5.2.
Sofosbuvir ..............................................................................................................................................34
5.2.1.
Description and Handling.....................................................................................................34
5.2.2.
Storage and Handling...........................................................................................................35
5.2.3.
Dosage and Administration of SOF .....................................................................................36
5.3.
Ribavirin.................................................................................................................................................36
5.3.1.
Description and Handling of RBV .......................................................................................36
5.3.2.
Dosage and Administration of RBV.....................................................................................37
5.4.
Co-administration of SOF and RBV ......................................................................................................38
5.5.
Study Drug Compliance.........................................................................................................................38
5.6.
Prior and Concomitant Medications.......................................................................................................38
6.
STUDY PROCEDURES ....................................................................................................................................40


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6.1.
Subject Enrollment.................................................................................................................................40
6.2.
Screening Assessments ..........................................................................................................................40
6.2.1.
Screening Visit (Day –28 to Day 0) .....................................................................................40
6.3.
PK Lead-in: Treatment Assessments .....................................................................................................42
6.3.1.
Day 1 ....................................................................................................................................42
6.3.2.
Day 3 ....................................................................................................................................43
6.3.3.
Day 7 – Intensive PK ...........................................................................................................43
6.4.
Treatment Phase: Treatment Assessments .............................................................................................45
6.4.1.
Day 1 ....................................................................................................................................45
6.4.2.
Weeks 1 and 2 (3 days) .....................................................................................................47
6.4.3.
Weeks 4 and 8 (3 days) .....................................................................................................47
6.4.4.
Week 12 (3 days) ..............................................................................................................48
6.4.5.
Week 16 and 20 (3 days) – GT-3 Subjects only................................................................49
6.4.6.
Week 24 (3 days) – GT-3 Subjects only ...........................................................................49
6.4.7.
Unscheduled Visit/Early Termination Visit .........................................................................50
6.5.
Post-Treatment Assessments..................................................................................................................51
6.5.1.
4-Week Post-Treatment Visit (5 days)..............................................................................51
6.5.2.
12-Week Post-Treatment Visit (5 days)............................................................................52
6.5.3.
24-Week Post-Treatment Visit (5 days)............................................................................53
6.6.
Procedures and Specifications................................................................................................................53
6.6.1.
Clinical Laboratory Analytes ...............................................................................................53
6.6.2.
Medical History....................................................................................................................54
6.6.3.
Complete Physical Examination...........................................................................................54
6.6.4.
Tanner Pubertal Stage Assessment.......................................................................................54
6.6.5.
Height & Weight Measurement with Percentiles .................................................................54
6.6.6.
Bone Age Assessment..........................................................................................................55
6.6.7.
Swallowability Assessment..................................................................................................55
6.6.8.
Vital Signs............................................................................................................................55
6.6.9.
Body Mass Index (BMI).......................................................................................................55
6.6.10.
Estimated Glomerular Filtration Rate (GFR) .......................................................................55
6.6.11.
Viral Sequencing (Archive)..................................................................................................56
6.6.12.
Pregnancy Testing................................................................................................................56
6.6.13.
Quality of Life Survey (PedsQL™).......................................................................................56
6.6.14.
SOF Granule Palatability Assessment..................................................................................56
7.
TOXICITY MANAGEMENT............................................................................................................................57
7.1.
Modification of Dose/Schedule Due to Toxicity....................................................................................57
7.2.
Subject Stopping Rules for SOF ............................................................................................................57
8.
ADVERSE EVENTS MANAGEMENT ............................................................................................................58
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................58
8.1.1.
Adverse Events.....................................................................................................................58
8.1.2.
Serious Adverse Events........................................................................................................58
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................59
8.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................59
8.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................59
8.2.2.
Assessment of Severity ........................................................................................................60
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events.......................................................................................................................................60
8.4.
Gilead Reporting Requirements.............................................................................................................62
8.5.
Special Situations Reports......................................................................................................................62
8.5.1.
Definitions of Special Situations..........................................................................................62


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8.5.2.
Instructions for Reporting Special Situations.......................................................................63
9.
STATISTICAL CONSIDERATIONS................................................................................................................65
9.1.
Analysis Objectives and Endpoints........................................................................................................65
9.1.1.
Analysis Objectives..............................................................................................................65
9.1.2.
Primary Endpoints................................................................................................................66
9.1.3.
Secondary Endpoints............................................................................................................66
9.2.
Analysis Conventions.............................................................................................................................66
9.2.1.
Analysis Sets ........................................................................................................................66
9.2.2.
Data Handling Conventions .................................................................................................67
9.2.3.
Interim Analysis ...................................................................................................................68
9.3.
Demographic Data and Baseline Characteristics ...................................................................................68
9.4.
Pharmacokinetic Analysis......................................................................................................................68
9.5.
Safety Analysis.......................................................................................................................................69
9.5.1.
Extent of Exposure...............................................................................................................69
9.5.2.
Palatability of SOF oral granules will be summarized using descriptive 
statistics by appropriate age group, by genotype, by overall and by age 
group and genotype.Adverse Events....................................................................................69
9.5.3.
Laboratory Evaluations ........................................................................................................70
9.5.4.
Other Safety Evaluations......................................................................................................70
9.6.
Efficacy Analysis ...................................................................................................................................71
9.6.1.
Primary Efficacy Analysis....................................................................................................71
9.6.2.
Secondary Efficacy Analysis................................................................................................71
9.6.3.
Subgroup Analysis ...............................................................................................................71
9.7.
Quality of Life Analysis.........................................................................................................................72
9.8.
Data Monitoring Committee ..................................................................................................................72
9.9.
Sample Size............................................................................................................................................72
10.
RESPONSIBILITIES..........................................................................................................................................73
10.1.
Investigator Responsibilities ..................................................................................................................73
10.1.1.
Good Clinical Practice..........................................................................................................73
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval...............................................................................................................................73
10.1.3.
Informed Consent/Assent.....................................................................................................74
10.1.4.
Confidentiality......................................................................................................................74
10.1.5.
Study Files and Retention of Records ..................................................................................74
10.1.6.
Case Report Forms...............................................................................................................76
10.1.7.
Drug Accountability.............................................................................................................76
10.1.8.
Inspections............................................................................................................................76
10.1.9.
Protocol Compliance............................................................................................................76
10.2.
Sponsor Responsibilities ........................................................................................................................77
10.2.1.
Protocol Modifications.........................................................................................................77
10.2.2.
Study Report and Publications .............................................................................................77
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................77
10.3.1.
Access to Information for Monitoring..................................................................................77
10.3.2.
Access to Information for Auditing or Inspections ..............................................................78
10.3.3.
Study Discontinuation..........................................................................................................78
11.
REFERENCES ...................................................................................................................................................79
12.
APPENDICES ....................................................................................................................................................81
Appendix 1.
Investigator Signature Page....................................................................................................82
Appendix 2.
Study Procedures Table..........................................................................................................83


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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............90
Appendix 4.
Tanner Stages .......................................................................................................................113
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................114
LIST OF IN-TEXT TABLES
Table 1-1.
GS-US-334-1111: Statistical Comparison of SOF, GS-566500, and GS-331007 PK 
Parameters ..............................................................................................................................21
Table 7-1.
RBV Dose Reduction Guidelines...........................................................................................57
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................28


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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, Single-Arm Study 
to Investigate the Safety and Efficacy of Sofosbuvir + Ribavirin in 
Adolescents and Children with Genotype 2 or 3 Chronic HCV 
Infection
IND Number:
EudraCT Number:
106739
2014-002283-32
Study Centers:
Approximately 50 sites in the United States, Europe, Russia, 
Australia, New Zealand, and India
Number of Subjects:
Approximately 100 subjects
Target Population:
Adolescents and children (aged 3 to < 18) with chronic hepatitis C 
virus (HCV) infection
Treatment Duration:
PK Lead-in – 7 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 sofosbuvir (SOF) in HCV-infected pediatric subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety and tolerability of 7 days of dosing of SOF
+ ribavirin (RBV) in HCV-infected pediatric subjects
The primary objectives of the Treatment Phase of this study are:

To evaluate the safety and tolerability of SOF + RBV for 12 or 
24 weeks in HCV-infected pediatric subjects with genotype (GT)
GT-2 or GT-3, respectively


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The secondary objectives of the Treatment Phase of this study are:

To determine the antiviral efficacy of SOF + RBV treatment in 
GT-2 and GT-3 HCV-infected subjects separately, as assessed by 
the proportion of subjects with SVR 12 weeks after completion of 
treatment (SVR12)

To determine the antiviral efficacy of SOF + RBV treatment in 
GT-2 and GT-3 HCV-infected subjects separately, 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 SOF during 
treatment and after completion of treatment

To evaluate the palatability of SOF oral granules at Day 1, as 
applicable.
The exploratory objective of this study is:

 
 
Study Design:
Open-label, multi-cohort, two-part study evaluating the PK, safety, 
and antiviral activity of SOF in chronic HCV-infected pediatric 
subjects.
The study will be divided into 2 parts as follows:
PK Lead-in: Will evaluate and/or confirm age appropriate SOF
doses by analyzing PK, safety, and antiviral activity of SOF
administered in combination with RBV through 7 days of dosing for 
each of three cohorts. Children aged 3 < 6, children aged 6 to 
< 12 years and adolescents aged 12 to < 18 years with genotype GT-2 
or GT-3 HCV infection and evidence of HCV RNA ≥1000 IU/mL at 
study entry will be evaluated.  Subjects must be treatment naïve to 
participate in the PK Lead-in Phase.  
Three cohorts of up to 10 subjects each will be sequentially enrolled: 

Cohort 1: 12 to < 18 years old weighing ≥ 45kg

Cohort 2: 6 to < 12 years old 

Cohort 3: 3 to < 6 years old 
PPD


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The study will start with Cohort 1.  Subjects will receive SOF
(400 mg adult tablet or 4 x 100 mg tablets if determined necessary 
based on SOF swallowability assessment) + RBV for 7 days with 
intensive PK conducted on Day 7. 
PK Lead-in subjects in each cohort (Cohorts 1, 2 and 3) will 
immediately enroll in the Treatment Phase as they complete Day 7 of 
the PK Lead-in Phase.  They will continue dosing with SOF + RBV 
with no interruption of study drug administration.  Subjects rolling 
over from the PK Lead-in will not be required to perform 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 will be reviewed to confirm 
the appropriateness of the evaluated SOF 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: Will be initiated sequentially by cohort after 
confirmation of age-appropriate SOF dosage levels. Subjects who 
participated 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.  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.
Children aged 3 to < 12 years and adolescents aged 12 to < 18 years 
with GT-2 or GT-3 infection and evidence of HCV RNA ≥1000 
IU/mL at study entry (those who were dosed in the PK Lead-in Phase
will have met this criteria prior to enrollment) will be evaluated. 
Subjects enrolled in the study will receive the following regimen:

GT-2 subjects: SOF + RBV for 12 weeks

GT-3 subjects: SOF + RBV for 24 weeks
The study will enroll both treatment-naïve and treatment-experienced 
pediatric subjects, with up to 20 subjects allowed to be treatment 
experienced. Approximately 100 total subjects, including subjects 
that participate in the PK Lead-in Phase, will be enrolled in Treatment 
Phase as follows

Group 1: Approximately 50 adolescent subjects (12 to < 18 years 
of age)

Group 2: Approximately 50 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, 12 (and Weeks 16, 20, and 24 for GT-3) 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 experimental or approved anti-HCV therapy will be 
followed every 6 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 up to 20 subjects may 
be treatment experienced, male and female subjects aged 3 to < 18. 
Inclusion Criteria:

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

Infection with HCV GT-2 or GT-3 as determined at Screening
PPD


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
HCV RNA ≥1000 IU/mL at Screening 

For the PK Lead-in Phase: subjects in cohort 1 (age 12 to 
<18 years of age) must weigh ≥ 45kg

Agree to use 2 forms of highly effective contraception, as 
referenced in Appendix 5, for the duration of the study and for 
6 months (for female subjects) or 7 months (for male subjects)
after the last dose of study medication if age, cultural, and sexual 
activity status appropriate (e g: if sexually active; does not pertain 
to pre-pubertal subjects). Females of childbearing potential
(as defined in Appendix 5) must have a negative pregnancy test at 
Screening and Day 1.
Exclusion Criteria:

Hematologic or biochemical parameters at screening outside the
protocol-specified requirements

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)

Chronic use of systemic immunosuppressive agents or
immunomodulatory agents

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.

See Sections 4.2 and 4.3 of the protocol for full eligibility criteria.


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Study Procedures/
Frequency:
PK Lead-in Phase: 
Screening assessments will be completed within 28 days of the Day 1
visit. 
Screening assessments will include: physical examination, vital signs
(including height and weight), Tanner Pubertal Stage assessment, 
concomitant medications, safety laboratory tests, coagulation tests, 
HCV RNA, serology (HIV, HAV, HCV, HBV), alpha-1 anti-trypsin,
serum β-human chorionic gonadotropin hCG (females of childbearing 
potential only), thyroid stimulating hormone, HbA1c, IL28B 
genotyping, alpha fetoprotein, urinalysis, and urine drug screen.
Study Visits will occur at Screening, Day 1, Day 3, and Day 7.
On-Treatment assessments include adverse events (AEs), 
concomitant medications, physical examination, bone age assessment, 
vital signs, height, weight, safety laboratory tests, HCV RNA, viral 
sequencing sampling, urine pregnancy tests (females of child bearing 
potential only), and urinalysis. Coagulation will be performed at 
Day 1 and Day 7. SOF swallowability assessment with placebo will 
be performed at screening up to Day 1 to assess a subject’s ability to 
swallow the 400 mg or 100 mg SOF tablet (only subjects 
administered SOF in tablet form).
Subjects (up to 10 subjects) enrolled in the PK Lead-in Phase will 
participate in an intensive PK evaluation on Day 7. Following 
completion of the Day 7 intensive PK visit, subjects will then return 
for scheduled study visits outlined in the Treatment Phase and 
continue dosing with SOF + RBV with no interruption of study drug 
administration.  Subjects will be administered a dosing diary with 
instructions.
Treatment Phase: 
Screening assessments will be completed within 28 days of the Day 1 
visit. For subjects continuing from the PK Lead-in, screening for 
Treatment Phase will not be required.
Screening assessments will include physical examination, vital signs,
concomitant medications, safety laboratory tests, HCV RNA, 
serology (HIV, HAV, HCV, HBV), alpha-1 anti-trypsin serum 
β-human chorionic gonadotropin hCG (females of childbearing 
potential only), thyroid stimulating hormone, IL28B genotyping, 
urinalysis, and urine drug screen.

GT-2 Subjects: Study visits for GT-2 subjects will occur at 
screening, Day 1, and the end of Weeks 1, 2, 4, 8, and 12. 


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
GT-3 Subjects: Study visits for GT-3 subjects will occur at 
screening, Day 1, and the end of Weeks 1, 2, 4, 8, 12, 16, 20, 
and 24. 
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 adverse events, concomitant 
medications, physical examination, vital signs (including height and 
weight), safety laboratory tests, coagulation tests, HCV RNA, PK 
samples, and urine pregnancy tests (females of childbearing potential 
only). Height and weight measurements (with percentiles) and Tanner 
Pubertal Stage assessment will be performed at Day 1, end of 
treatment, post-treatment Week 12 and post-treatment 24-week; 
parental heights will be recorded at Day 1. The Bone Age Assessment 
will be performed at Day 1 and post-treatment Week 24 visit. If 
available, results from liver biopsies will be collected at screening.
SOF swallowability assessment with placebo will be performed at 
screening up to Day 1 to assess a subject’s ability to swallow a
400 mg or 100 mg SOF tablet For subjects continuing from the PK 
Lead-in, the screening, Day 1 and Week 1 visits of the Treatment 
Phase will not be required. Post-treatment assessments will include 
adverse events, concomitant medications, vital signs, safety 
laboratory tests, HCV RNA, and urine pregnancy tests (females of 
childbearing potential only). Samples for viral RNA 
sequencing/phenotyping will be collected at Day 1 and every visit 
thereafter.  
Palatability of SOF oral granules will be assessed at Day 1, as 
applicable.
 
 
Test Product, Dose, 
and Mode of 
Administration:
PK Lead-in: 
(Cohort 1) SOF 400 mg tablets will be administered once daily along 
with RBV weight-based dosing. Subjects determined unable to 
swallow the placebo for 400 mg SOF tablet (by SOF Placebo 
swallowability assessment at Screening or at any time during the 
study) will be re-assigned to 4 x 100 mg tablets daily.  
Intensive PK and safety results from the PK Lead-In of each Cohort 
will be reviewed to confirm the appropriateness of the evaluated SOF 
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.
PPD


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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.
RBV Weight-Based Dosing (All age groups):
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 (≥103)
15 
mg/kg/day
If the patient is unable to or unwilling to 
take the RBV Capsules, the Oral Solution 
can be used.  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.
65-80 (143 – 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.
The morning dose of RBV will be taken with food with an 
age-appropriate dose of SOF. The evening dose of RBV will be taken 
with food.
Reference Therapy:
None


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Evaluation Criteria:
Safety:
AEs, laboratory tests, and Tanner Pubertal Stage assessments will be 
collected throughout the study. 
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, steady-state PK of SOF and its major 
metabolites GS-566500 and GS-331007 will be assessed at Day 7.
For Cohorts 1 and 2, plasma samples will be collected for PK 
analyses following dosing of study drugs on Day 7 at the following 
time points: 0 (predose), 0.5, 1, 2, 3, 4, 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), 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 SOF, 
GS-566500 and GS-331007 and/or ribavirin will be assessed.
The effect of age and SOF dose on PK (SOF and GS-331007) will be 
explored. 
Statistical Methods:
For the PK Lead-in, plasma PK parameters Cmax, Tmax, Clast, Tlast, Ctau, 
AUCtau, and t1/2 will be estimated.  The PK parameters will be 
summarized by cohort. The effect of age and SOF dose on PK 
(SOF and GS-331007) 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 age group, by GT and by overall. Primary efficacy 
endpoint is SVR12 in all enrolled and treated subjects and will be 
summarized by age group, by genotype, by overall and by age group 
and GT.  Point estimate and its 95% confidence interval will be 
provided.  
In addition, SVR12 will be compared with historical SVR12 rate of 
80% from pegylated interferon + ribavirin for pediatric GT-2 and 
GT-3 subjects {20280}, using two-sided exact one-sample binomial 
test at the 0.05 significance level.  
Secondary efficacy endpoints are SVR4, SVR24, breakthrough and 
relapse.


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Palatability of SOF oral granules will be summarized using 
descriptive statistics by appropriate age group, by genotype, by 
overall and by age group and genotype.
Subgroup analysis on SVR12 will be performed by treatment 
experience (treatment-naive vs. experienced) and by treatment 
experience and 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). 
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.
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 age group, by GT, by 
overall and by age group and GT.
With approximately 50 subjects enrolled into each age group of 
Treatment Phase, a two-sided 95.0% confidence interval of the 
SVR12 rate will extend at most 11.1% in both directions from the 
observed SVR12 rate, assuming the expected SVR12 rate is 80%. In 
addition, a sample size of 100 subjects will provide over 80% power 
to detect an 11% improvement in SVR12 rate from 80% to 91% using 
two-sided one-sample binomial test at significance level of 0.05.
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
β-hCG
β-human chorionic gonadotropin
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)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BW
body weight
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)
CMH
Cochran-Mantel-Haenszel
COPD
Chronic obstructive pulmonary disease
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
Emax
maximal effect
EU
European Union
EVR
Early virologic response
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
GFR
glomerular filtration rate
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
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
IV
Intravenous
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDH
Lactase dehydrogenase
LLN
lower limit of the normal range
LLOD
Lower limit of detection
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


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
PI
Protease inhibitor
PK
Pharmacokinetic
RBC
Red blood cell count 
RBV
Ribavirin
RDRP
RNA-dependent RNA polymerase
RNA
ribonucleic acid
RVR
rapid virologic response 
SADR
Serious adverse drug reaction
SAE
serious adverse event
SD
Standard deviation
SOC
Standard of Care
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TND
Target not detected
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 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 standard of care 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.
Sofosbuvir
Sovaldi™(Sofosbuvir) is a potent nucleotide analogue that inhibits HCV RNA replication in 
vitro and has demonstrated high rates of sustained viral response (SVR) when given with RBV
+/- PEG to subjects with chronic GT- 1, 2, 3 or 4 HCV infection {27503}, {23275}, {24713}, 
{24715}.  Sovaldi™has been approved in the United States by the Food and Drug Administration 
(FDA) for the treatment of HCV infection GT- 1, 2, 3 and 4 including treatment naïve and 
experienced patients and HIV/HCV co-infected patients.  Sovaldi™is also approved in EU, 
Canada and Turkey.
For further information on the clinical pharmacology, virology, safety and efficacy of SOF, 
please refer to the current version of the Investigator’s Brochure and the local prescribing 
information.
1.2.1.
Summary of Additional Clinical Experience with Sofosbuvir
A phase 1 study (GS-US-334-1111) was conducted to evaluate the relative bioavailability of, and 
effect of food on Sofosbuvir oral granules in healthy adult subjects to support the use of this 
formulation in subjects unable to swallow the tablet formulations.  The preliminary results of this 
study are presented below.
1.2.1.1.
GS-US-334-1111 Study Design
Study GS-US-334-1111 is a single dose, randomized, 3-period crossover phase 1 study 
conducted in healthy adult subjects.  Subjects were administered 400 mg SOF in the following 
treatments in a randomized order: 1 x 400 mg SOF (adult formulation) in the fasted state, 
8 x 50 mg SOF granules in capsules in the fasted state, and 8 x 50 mg SOF granules in capsules 
after a standardized high-fat meal.  Prior to administration the SOF granules were removed from 
the capsules and administered orally with water.  18 healthy subjects were enrolled and 
completed all treatment periods of this study.


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1.2.1.2.
GS-US-334-1111 Preliminary Pharmacokinetic Results
Preliminary PK results are available for all 18 subjects.  Statistical comparisons of the primary 
PK parameters AUCinf, AUClast, and Cmax for SOF, its intermediate metabolite GS-566500, and 
the primary circulating metabolite GS-331007 which is considered the primary analyte of interest 
for PK studies are presented below.  Statistical comparisons include the %GMR and 90%CIs of 
exposures achieved after administration of 8 x 50 mg SOF granules in capsules fasted 
(Granules Fasted) relative to 1 x 400 mg SOF tablet fasted (Tablet Fasted), and 8 x 50 mg SOF 
granules in capsules fed (Granules Fed) relative to 8 x 50 mg SOF granules in capsules fasted 
(Granules Fasted) (Table 1-1).  Bioequivalence of the pediatric granule formulation and the adult 
tablet formulation was concluded as a result of the 90%CIs of the %GMRs for GS-331007 
AUClast, AUCinf, and Cmax (protocol specified primary endpoints) being contained within the 
predefined boundaries of 80-125%.  Additionally, administration of the pediatric granule 
formulation after a high-fat meal or fasted resulted in bioequivalent exposures of GS-331007 as 
the 90%CIs of the %GMRs for GS-331007 AUClast and AUCinf (protocol specified primary 
endpoints) were contained within the predefined boundaries of 80-125%. 
 
 
 
Table 1-1.
GS-US-334-1111: Statistical Comparison of SOF, GS-566500, and 
GS-331007 PK Parameters 
Parameter (N=18)
%GMR (90%CI)
Granules Fasted/Tablet Fasted
Granules Fed/Granules Fasted
SOF
AUCinf
100 (86.0, 117)
168 (144, 195)
AUClast
100 (85.8, 117)
167 (143, 195)
Cmax
83.6 (64.5, 108)
90.9 (70.2, 118)
GS-566500
AUCinf
96.2 (85.1, 109)
165 (144, 195)
AUClast
94.5 (82.3, 109)
166 (145, 191)
Cmax
91.8 (90.2, 105)
128 (112, 146)
GS-331007
AUCinf
104 (97.9, 111)
87.9 (82.5, 93.6)
AUClast
104 (97.6, 112)
86.3 (80.7, 92.7)
Cmax
106 (95.6, 117)
60.3 (54.5, 66.8)
Note: %GMR and 90%CIs are presented to 3 significant digits
PPD


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1.2.1.3.
GS-US-334-1111 Preliminary Conclusions
As assessed by GS-331007, the new sofosbuvir (8 x 50 mg) granule formulation was 
bioequivalent to the existing sofosbuvir 1 x 400 mg tablet formulation under fasted conditions.  
The sofosbuvir (8 x 50 mg) granule formulation is recommended to be administered without 
regard to food.
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.
1.4.
Rationale for the Current Study
This clinical study is designed to evaluate the efficacy and safety of treatment with SOF + RBV
for adolescents and children with GT-2 and GT-3 chronic HCV infection. 
Currently PEG and weight-based RBV are considered the standard of care for the treatment of 
HCV infection in children. However, this PEG and RBV regimen is long in duration, relatively 
toxic, and not well tolerated. Thus, there continues to be a need for new treatments for HCV that 
combine potent and sustained efficacy with improved tolerability and safety. Therapy that 
provides shorter duration and improved efficacy with an all-oral regimen would be a significant 
advancement over current options in pediatric patients.
The main aim for the treatment of pediatric patients with HCV is to eliminate the need to use 
PEG regimens. In this way, pediatric patients are able to avoid the necessity of weekly injections, 
which can be traumatic and burdensome, and also to significantly reduce the serious adverse 
events seen on administration of PEG regimens. 
Sovaldi (sofosbuvir 400 mg tablet) is approved in 35 countries worldwide in combination with 
other medicinal products, for the treatment of adults with chronic hepatitis C infection. SOF in
combination with RBV would provide an all-oral, IFN-free regimen with a shorter treatment 
duration (12 - 24 weeks of SOF treatment versus standard-of-care 24 to 48 weeks of treatment)
and would offer another important option in the treatment of HCV infection in the pediatric 
population.
Phase 3 data demonstrates that high SVR12 rates in subjects with GT-2 HCV infection can be 
achieved with 12 weeks treatment with SOF+RBV, however, these studies suggest that patients 


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with GT-3 infection may benefit from a longer treatment duration (i.e. 24 weeks) with 
SOF + RBV. Optimal duration of SOF + RBV, for GT-3 subjects, was established in FISSION 
and VALENCE.  Increasing treatment duration from 12 to 24 weeks increased SVR12 from 
61 to 93% in non-cirrhotics and from 34 to 92% in cirrhotics.
1.5.
Rationale for Dose Selection of SOF
SOF 400 mg, once daily, when dosed in combination with RBV with or without PEG has 
demonstrated broad genotypic efficacy and favorable safety profile in over 3300 HCV-infected 
adult subjects across multiple patient populations in Phase 2 and 3 trials. This dose is the 
marketed dose of SOF for the treatment of HCV-infection in adults.
Selection of doses of SOF for adolescents and younger age groups will target systemic exposures 
similar to those observed in adults at the marketed dose, taking into account body weight/body 
surface area, the potential ontogenic changes in hepatically expressed carboxylesterase 1 (CES1) 
and Cathepsin A (CatA) enzymes, and the results obtained in older age groups.  Available data 
suggest comparable hepatic expression of CES1 in adolescents and adults, with modestly 
decreased expression in children.  As such, the adult clinical dose, 400mg, will be evaluated in 
adolescents (12 to <18 years old) {20288}.  Safety and PK data in the adolescent group
(Cohort 1) in the PK Lead-in, will inform dose selection for the younger age groups in addition 
to body weight/body surface area. 
Age-appropriate formulations of SOF (a smaller, 100 mg strength tablet and a granule
formulation) that offer an important option in the treatment of HCV infection in the pediatric 
population will be evaluated in children below 12 years of age or children who are unable to 
swallow the adult solid-dose 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 standard of care 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. 
SOF has demonstrated efficient inhibition of viral replication in in vitro and in vivo studies. 
Available clinical data indicate SOF has a favorable safety profile and is well tolerated. SOF in 
combination with RBV is likely to provide significant therapeutic benefit in the treatment of 


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HCV infection in pediatric patients compared to currently available therapies in the following 
areas:

Expected improved efficacy in a pediatric population compared to the current standard of 
care

Expected improvement in safety and tolerability in relation to either adverse reactions or 
potential medication errors in the pediatric population compared to the current standard of 
care

Improved dosing scheme or method of administration (oral compared to subcutaneously 
administration and reduced treatment duration) leading to improved safety, efficacy,
tolerability, and compliance

Expected availability of a clinically relevant age-appropriate formulation

Different mechanism of action with potential advantage for the pediatric population in terms 
of improved efficacy and safety

Expected improvement in quality of life (e.g., minimized duration of therapy and avoidance 
of IFN-related adverse events that affect patient quality of life such as flulike syndrome and 
depression)
Additionally, the study sponsor will perform an ongoing review of safety data during the conduct 
of the study.


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2.
OBJECTIVES
The primary objective of the PK Lead-in of this study is:

To evaluate the steady state pharmacokinetics (PK) and confirm the dose of SOF in HCV-
infected pediatric subjects
The secondary objective of the PK Lead-in of this study is:

To evaluate the safety and tolerability of 7 days of dosing of SOF + RBV in HCV-infected
pediatric subjects
The primary objectives of the Treatment Phase of this study are:

To evaluate the safety and tolerability of SOF + RBV for 12 or 24 weeks in HCV infected 
pediatric subjects with GT-2 or GT-3, respectively
The secondary objectives of the Treatment Phase of this study are:

To determine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects separately, as assessed by the proportion of subjects with SVR 
12 weeks after completion of treatment (SVR12)

To determine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects separately, 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 SOF during treatment and after completion 
of treatment

To evaluate the palatability of SOF oral granules at Day 1, as applicable.
The exploratory objective of this study is:

 
 
PPD


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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 SOF + 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 SOF dose by analyzing 
PK, safety, and antiviral activity of SOF + RBV through 7 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 GT-2 or GT-3 HCV infection and evidence of HCV RNA ≥1000 IU/mL at study entry will 
be evaluated. Subjects must be treatment naïve to participate in the PK Lead-in Phase. 
Three cohorts of up to 10 subjects each will be sequentially enrolled: 

Cohort 1:  12 to < 18 years old weighing ≥45kg

Cohort 2:  6 to < 12 years old 

Cohort 3:  3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive SOF (400 mg adult tablet or 4 x 100 mg 
tablets if determined necessary based on SOF swallowability assessment) + RBV for 7 days with 
intensive PK conducted on Day 7. 
Following completion of study treatment in the PK Lead-in of Cohort 1 and pending PK and 
safety results, the PK Lead-in of Cohort 2 will initiate and receive study treatment 
(age appropriate dose and formulation). 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 7 of PK Lead-in.  They will continue dosing with 
SOF + RBV 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.
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 


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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 
GT-2 or GT-3 infection and evidence of 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:

GT-2 subjects: SOF + RBV for 12 weeks

GT-3 subjects: SOF + RBV for 24 weeks
The study will enroll both treatment-naïve and treatment–experienced pediatric subjects, with up 
to 20 subjects allowed to be treatment experienced. Approximately 100 total subjects, including 
subjects from the PK Lead-in Phase, will be enrolled in the Treatment Phase as follows:

Group 1: Approximately 50 adolescent subjects (12 to < 18 years of age)

Group 2: Approximately 50 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 standard-of-care (SOC) therapy with their healthcare provider.


Sofosbuvir 
Protocol GS-US-334-1112 
Gilead Sciences, Inc. 
Figure 3-1. 
Study Schema 
PK lead-in 
12 to< 18 years 
Baseline 
Day 7 
(Day 1) 
Intensive PK 
Scr~ning 
1 
I 
t-----j SOF + RBV 
, 
Treatment 
::; 28 day .,.;a to 
PI< and solely 
Phase• 
Baseline 
analysis 
• Subjects who participated in the 
PK Lead in will immediately roll 
into the treatment phase follmo.;ng 
the PK (Day 7) assessments 
Amendment 3 
-.-.-.-.-.-.-. -· -·-.-·-.-. -·-·-·-'-.-.-.-.-.-·-.-.-. -·-.-. -·-. -·-.-. -·-.-.-·-.-.-·-. -·-.-.-·-·-. -· -·-.-.-.-. -·-.-. -·-.-.-·-.-.-·-.-.-.-.-·-.-.-. -·-.-.-·-.-.-
Treatment Phase 
GT-2 Subjects: 
GT-3 Subjects: 
• Follmo.;ng completion of study treatment in the PK Lead-in, intensive PK and safety resu~s will be reviewed to confirm 
the appropriateness of the evaluated SOF dose for the Treatment Phase 
Baseline 
(Day 1) 
Week 12 
Post 
Treatment 
Week4 
Post 
Treatment 
Week 12 
Post 
Treatment 
Week24 
scre:ning 
1 
t-----jr. -S-
O-
F+-R-
BV---12-wks
--+1-----r----~r--------; 
::; 28 day priO< to L.......:..:..;_..:.=.;......;;::..=:.:.....a...----------------------' 
Baseli\e 
Baseline 
(Day 1) 
Week24 
Post 
Treatment 
Week4 
Post 
Treatment 
Week12 
Post 
Treatment 
Week24 
su~ning 1r---------------------+-----+------r-------_, 
t-------1 
SOF + RBV - 24 weeks 
3.2. 
3.2.1. 
:5 28 day prior to 
Baseline 
Visit Schedule 
PKLead-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 7. 
Subjects (up to 10 subjects per coh01i) enrolled in the PK Lead-in Phase will patiicipate in an 
intensive PK evaluation on Day 7. Subjects will be administered a dosing diaty with 
instmctions. 
Following completion of the Day 7 intensive PK visit, subjects will then retum for scheduled 
study visits outlined in the Treatment Phase and continue dosing with SOF + RBV with no 
intetmption of study dmg administration. Subjects rolling over from the PK Lead-in Phase will 
not be required to perf01m the screening, Day 1 or Week 1 visits of the Treatment Phase. 
CONFIDENTIAL 
Page28 
10 October 2014 


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3.2.2.
Treatment Phase
Screening assessments will be completed within 28 days of the Day 1 visit. For subjects 
continuing from the PK Lead-in Phase, screening, Day 1 and Week 1 of the Treatment Phase will 
not be required.

GT-2 Subjects: Study visits for GT-2 subjects will occur at screening, Day 1, and the end of
weeks 1, 2, 4, 8, and 12. 

GT-3 Subjects: Study visits for GT-3 subjects will occur at screening, Day 1, and the end of
weeks 1, 2, 4, 8, 12, 16, 20, and 24. 
All Treatment Phase 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).


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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 of the protocol, 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).
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 6.4.7.
Subjects who permanently discontinue all study drugs 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 
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.
PPD


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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.
Subjects with known or suspected study drug non-adherence will not be considered to meet the 
definition of virologic breakthrough, relapse or non-responder. 


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 100 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 (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: all subjects must be treatment naïve 
5. 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 Baseline/Day 1.
6. 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
7. Infection with HCV GT-2 or GT-3 as determined at Screening
8. HCV RNA ≥1000 IU/mL at Screening
9. Adequate hematologic function (absolute neutrophil count 1,500/mm3; hemoglobin 
12 g/dL for males and 11g/dL for females.)
10. Negative serum -HCG pregnancy test (for females of childbearing potential only, as defined 
in Appendix 5)
11. 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


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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. 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)
4. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)
5. -fetoprotein 50 ng/mL
6. Serum creatinine > 1.5 mg/dL
7. Estimated glomerular filtration rate 90 mL/min/1.73m2, as calculated by the Schwartz 
Formula
8. Evidence of hepatocellular carcinoma (HCC)
9. Co-infection with HIV, acute HAV, or HBV
10. Significant cardiovascular, pulmonary or neurological disease
11. Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of 
orally administered medications
12. History of solid organ or bone marrow transplantation
13. Chronic daily non-steroidal anti-inflammatory drug therapy
14. Systemic corticosteroid use for 5 days (pulmonary/nasal administration is permitted)
15. Investigational agents taken within the past 28 days (except with the expressed approval of 
the Sponsor)
16. Clinically-relevant alcohol or drug abuse within 12 months of screening.  A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator
17. Known hypersensitivity to the study drugs, the metabolites or formulation excipients
18. 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
19. Use of any prohibited concomitant medications as described in Section 5.6 within 28 days of 
the Day 1 visit


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
Not applicable.
5.2.
Sofosbuvir
5.2.1.
Description and Handling
5.2.1.1.
Formulations
SOF tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets debossed with “GSI” on 
one side and “7977” on the other side. In addition to the active ingredient, SOF tablets contain 
the following inactive ingredients: mannitol, microcrystalline cellulose, croscarmellose sodium, 
colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, 
talc, and yellow iron oxide.
Placebo tablets for Swallowability Assessment, 400 mg, are yellow, capsule-shaped, film-coated 
tablets debossed with “GSI” on one side and “7977” on the other side. The tablets contain 
mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, and yellow iron oxide.
SOF tablets, 100 mg, are yellow, round, film-coated, plain-faced tablets. In addition to the active 
ingredient, SOF tablets contain the following inactive ingredients: mannitol, microcrystalline 
cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl
alcohol, titanium dioxide, macrogol, talc, and yellow iron oxide.
Placebo tablets for Swallowability Assessment, 100 mg, are yellow, round, film-coated, 
plain-faced tablets. The tablets contain lactose monohydrate, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, 
and yellow iron oxide.
SOF oral granules, 50 mg, are encapsulated in a two-piece, clear, hard gelatin capsule. In 
addition to the active ingredient, SOF capsules contain the following inactive ingredients: 
gelatin, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl 
cellulose, sodium stearyl fumarate, colloidal silicon dioxide, hypromellose, macrogol, amino 
methacrylate copolymer, stearic acid, sodium lauryl sulfate, and talc.
5.2.1.2.
Packaging and Labeling
SOF 400 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains either 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.


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Placebo tablets for Swallowability Assessment, 400 mg, are packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 30 tablets and a silica gel desiccant canister or 
sachet and polyester packing material. Each bottle is enclosed with a white, continuous thread, 
child-resistant screw cap with an induction-sealed, aluminum-faced liner.
SOF 100 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 28 tablets and a 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 for Swallowability Assessment, 100 mg, are packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 28 tablets and polyester packing material. 
Each bottle is enclosed with a white, continuous thread, child-resistant screw cap with an 
induction-sealed, aluminum-faced liner.
SOF capsules, 50 mg, which contain SOF oral granules, are packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 28 capsules and is enclosed with a white, 
continuous thread, child-resistant polypropylene screw cap with an induction-sealed and 
aluminum faced liner.
SOF bottles to be distributed to centers in the US, EU and the rest of the countries will 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.
Placebo tablets for Swallowability Assessment, 100 mg and 400 mg, bottles 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.
5.2.2.
Storage and Handling
SOF tablet, 100 mg and 400 mg, and capsule (containing granules) bottles should be stored at 
controlled room temperature until required for administration. Controlled room temperature is 
defined as 25 C (77 F); excursions are permitted between 15 C and 30 C (59 F to 86 F).
Placebo tablets for Swallowability Assessment, 100 mg and 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).  
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling SOF.


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Sufficient quantities of SOF tablets, SOF capsules containing granules 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 SOF
PK Lead-in: (Cohort 1) SOF 400 mg tablets will be administered once daily along with RBV 
weight-based dosing. Subjects determined unable to swallow the placebo for the 400 mg SOF 
tablet (by SOF Placebo swallowability assessment at Screening up to Day 1) will be re-assigned 
to 4 x 100 mg tablets daily.  Subjects unable to swallow tablets will be re-assigned to 8 x 50 mg 
capsules containing granules.  Subjects who weigh < 45 kg will be excluded.  
Intensive PK and safety results from the PK Lead-In of each Cohort will be reviewed to confirm 
the appropriateness of the evaluated SOF 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.  
5.3.
Ribavirin 
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.


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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).
5.3.2.
Dosage and Administration of RBV
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 (≥103)
15 mg/kg/day
If the patient is unable to or unwilling to take the 
RBV Capsules, the Oral Solution can be used.  
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.
65-80 (143 – 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.
The morning dose of RBV will be taken with food and SOF. The evening dose of RBV will be 
taken with food.
RBV will be supplied by Gilead Sciences for all subjects.


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5.4.
Co-administration of SOF and RBV
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:

SOF

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 medication at the correct time, it may be taken later in the day; 
however, no more than 400 mg dose of SOF 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.  
5.5.
Study Drug Compliance
Subjects will be instructed to return any unused SOF and RBV in the original container on Day 7 
(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 of Screening, up to and including the date of the 
visit four weeks after discontinuation of study treatment, need to be recorded in the source 
documents and eCRFs. All concomitant medications should be recorded in the source 
documents.
The following medications are prohibited from 28 days prior to the Day 1 visit through the end 
of treatment:

Erythropoiesis-stimulating agents (ESAs); including but not limited to Procrit®, Aranesp®
and Epogen®

Granulocyte colony stimulating factor (GCSF)

Chronic systemic immunosuppressants including corticosteroids (prednisone equivalent of 
> 10 mg/day for > 2 weeks), azathioprine, or monoclonal antibodies (e.g., infliximab)

Investigational agents or devices for any indication


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
Drugs disallowed per prescribing information of REBETOL®

Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters i.e. P-gp) with study drug(s) may result in pharmacokinetic interactions resulting 
in decreases in exposure of study drug(s). Representative medications which are excluded 
from 21 days prior to Day 1 through the end of treatment are listed below:
Drug
Agents Disallowed
Concomitant use with study drug may 
potentially result in changes of study 
drug concentration as listed below
Anticonvulsants
Phenobarbital, Phenytoin, Carbamazepine, 
Oxcarbazepine
Decrease in concentration of study drug
Antimycobacterials
Rifampin, rifabutine, rifapentine
Decrease in concentration of study drug
Herbal/Natural 
Supplements
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
Decrease in concentration of study drug
Medications for disease conditions excluded from the protocol (e.g., HIV-1 infection, active 
cancer, transplantation) are not listed under this Concomitant Medication section and are 
disallowed in the study.


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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 (i.e., height and weight of parents, if known)
Liver biopsy results (if available)

Complete physical examination 

Vital signs (temperature, blood pressure, pulse, respiratory rate), body weight and height


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
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 SOF swallowability assessment (for subjects administered SOF in tablet form only)
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for the Day 1 visit assessments.


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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 (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)

 

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


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Amendment 3
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6.3.1.1.
Drug Administration

Dispense study drugs as directed by the IWRS

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 all study drugs

Perform SOF swallowability assessment (for subjects administered SOF in tablet form only if 
not previously completed at screening).  Observe the subject taking the first dose of study 
drugs (with 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 parent/guardian

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

Review subject dosing diary
6.3.3.
Day 7 – Intensive PK 
The Day 7 Intensive PK visit should occur on the protocol-specified visit date based on the 
Day 1 visit. For the purposes of scheduling, the Day 7 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).


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Amendment 3
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Subjects should come in a fasted state for the Day 7 Intensive PK visit (i.e., no food or drink 
except water at least 8 hours prior to the Day 7 Intensive PK visit). Subjects and/or 
parents/guardians should be instructed that the Day 7 dose of SOF+RBV must not be taken until 
the evaluations listed below are completed. 
If the subject has already dosed prior to the Day 7 clinic visit or is not in a fasted state, the Day 7
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 8, 9, or 10) 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 7 visit, the Day 7 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 7 intensive PK visit no sooner than 3 days following compliant dosing and no later than 
Day 11 (i.e., return on Day 10 or Day 11).  If dosing non-compliance is due to an AE, 
consultation with the Gilead Medical Monitor is required regarding the potential of rescheduling 
the Day 7 intensive PK visit.
In both scenarios described above, the subject and/or parents/guardians should be reminded not 
to take the SOF + RBV prior to arriving at the clinic on the day of the re-scheduled intensive PK 
visit. All Day 7 intensive PK assessments listed below should be completed when the subject 
returns.
The following evaluations are to be completed at the Day 7 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 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 
Coagulation tests


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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 
SOF + RBV per dosing requirements.
Post-dose blood samples will be collected as follows: 

For Cohorts 1 and 2:  0.5, 1, 2, 3, 4, 8, and 12 hours post-dose (with predose also 
serving as t= 24).

For Cohort 3 only: 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 7 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 with percentiles 

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Review of AEs and concomitant medications


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
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)

 

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 SOF swallowability assessment (for subjects administered SOF in tablet form only if 
not previously completed at screening). 

For subjects receiving SOF oral granules, following drug administration assess palatability
at Day 1, as applicable
6.4.1.1.
Drug Administration

Dispense study drugs as directed by the IWRS

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 all study drugs

Observe the subject taking the first dose of study drugs (with food) and record the time of 
first dose
PPD


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Amendment 3
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6.4.2.
Weeks 1 and 2 (3 days)
Subjects who participated in the PK Lead-in will start study visits in 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

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 


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Amendment 3
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
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 drugs at these visits)

Dispense study drugs as directed by the IWRS
6.4.4.
Week 12 (3 days)

Perform complete physical examination

Tanner Pubertal Staging Assessment

Vital signs, including body weight and height measurements with percentiles 

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. (GT-2 Subjects 
only)

Review medication compliance with subject and/or parent/guardian.


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
Dispense study drugs as directed by the IWRS (GT-3 Subjects Only)

GT-2 Subjects should return all bottles and kits at the Week 12 Visit
6.4.5.
Week 16 and 20 (3 days) – GT-3 Subjects 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 drugs at these visits)

Dispense study drugs as directed by the IWRS
6.4.6.
Week 24 (3 days) – GT-3 Subjects only

Perform complete physical examination

Tanner Staging Assessment

Vital signs, including body weight and height measurements with percentiles 

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)


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Amendment 3
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
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.

GT-3 Subjects should return all bottles and kits at the Week 24 Visit
6.4.7.
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.
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 with percentiles 

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)


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Protocol GS-US-334-1112
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Amendment 3
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
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 kits at the Early Termination Visit
All subjects should complete Post-Treatment assessments after early termination, as described in 
Section 6.5.
All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
experimental or approved anti-HCV therapy will be followed every 6 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.
6.5.
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: 


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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 (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) 
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 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 with percentiles 

Perform symptom-directed physical examination

Perform Tanner Pubertal Stage assessment

Obtain blood samples for 
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only


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Amendment 3
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
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)

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 with percentiles 

Perform symptom-directed physical examination

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)

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.
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 
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, 


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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 right 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: 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 Day 1.
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.  Perform Tanner Pubertal Stage assessment 
for subjects until Tanner Stage 5 has been reached. Date of first menses will be documented.  
6.6.5.
Height & Weight Measurement with Percentiles
Height and weight measurement will be collected at Day 1, End of Treatment, post-treatment 
Week 12 and post-treatment Week 24.  Percentiles will be calculated using the WHO reference 
charts and tables by age and gender for height and weight.  


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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 the bone age from x-ray.
6.6.7.
Swallowability Assessment
A SOF 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 for the 400 mg SOF 
tablet. This will confirm the swallowability of the 400 mg tablet size. If, a subject is unable to 
swallow the 400 mg tablet size he/she will repeat the assessment with a placebo for the 100 mg 
SOF tablet.    If unable to take the 100 mg SOF tablet, the subject will be dispensed the SOF oral 
granule formulation.
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.
6.6.9.
Body Mass Index (BMI)
BMI is calculated by the following equation.
BMI = weight (pounds) 703           or            weight in kilograms
   (height in inches)2                                (height in meters)2
6.6.10.
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)]


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6.6.11.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each visit for viral sequence analysis. Unused 
samples may be archived.
6.6.12.
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. If required by 
local regulations, additional pregnancy tests beyond 6 months may be added. In the event of a 
positive urine pregnancy result, subjects will be instructed to stop study drugs immediately and 
return to the clinic as soon as possible for a serum pregnancy test.
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.
6.6.13.
Quality of Life Survey (PedsQL™)
The PedsQL ™ Pediatric Quality of Life Inventory V4.0 Short Form (SF15) will be completed 
in Treatment Phase of the study at Day 1, End of Treatment (Week 12 for GT-2 subjects, 
Week 24 for GT-3 subjects, or at 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 will be administered to the subject for the current age group at the time 
of survey administration.  
6.6.14.
SOF Granule Palatability Assessment
A palatability assessment for the SOF granules will be performed in Treatment Phase of the 
study at Day 1 to subjects receiving the granules.


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Amendment 3
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7.
TOXICITY MANAGEMENT
7.1.
Modification of Dose/Schedule Due to Toxicity
Dose reduction of RBV 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/day 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
Dose reduction in pediatric patients 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 SOF
The Gilead Medical Monitor should be consulted prior to dose discontinuation of SOF unless the 
investigator believes that immediate action is warranted to ensure the continued safety of the 
subject.
Administration of SOF may be discontinued due to a clinical or laboratory event. There is no 
option for SOF dose reduction. If SOF is stopped for toxicity, it should not be restarted, RBV 
should be stopped and the subject should complete an Early Termination Visit.
Subjects who meet any of the following laboratory criteria must stop treatment with SOF and 
RBV:

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 

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event or lab abnormality assessed as related to treatment with SOF


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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)

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

Persistent or significant disability/incapacity


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
A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is 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 subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the 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.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting.


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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 
All SAEs, regardless of causal relationship, that occur 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 
from screening onwards.
All AEs, regardless of causal relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP 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 post-treatment follow up 
period.
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 this time and the event is 
deemed relevant to the use of IMP, he/she should promptly document and report the event 
directly to Gilead DSPH. Gilead DSPH contact information is as follows: Email: 
Safety_FC@gilead.com or Fax: +1 (650) 522-5477.  All AEs and SAEs will be recorded in the 
CRF/eCRF database within the timelines outlined in the CRF/eCRF completion guideline.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by 
emailing or faxing the report form within 24 hours of the investigator’s knowledge of the 
event to the attention of the designated CRO Pharmacovigilance Representative.


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Electronic Serious Adverse Event (eSAE) Reporting Process

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.

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 as described above.

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.
Contact information is as follows:
Gilead Sciences, Drug Safety and 
Public Health:
Fax:
+1 650 522-5477
E-mail:
Safety_FC@gilead.com
PRA International
Pharmacovigilance Representative:
Fax:
+1 888 772 6919 (North America);
+49 621 8782 181 (Rest of World)
E-mail:
CHOSafety@praintl.com
Gilead Sciences, Medical Monitor:
Name:
Bittoo Kanwar, MD
Telephone: 
Mobile:
Fax:
E-mail:

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.
PPD
PPD
PPD
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. 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, 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 the CRO Pharmacovigilance Representative using the 
pregnancy report form within 24 hours of becoming aware of the pregnancy.
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 8.1.1 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 CRO Pharmacovigilance Representative 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 drugs 
must also be reported and relevant information should be submitted to the CRO 
Pharmacovigilance Representative 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.


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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 the CRO Pharmacovigilance Representative within 24 hours of the investigator 
becoming aware of the situation. These reports must consist of situations that involve study IMP
and/or Gilead concomitant medications but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a non-
Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of contraindicated medications 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 SOF in 
HCV-infected pediatric subjects
The secondary objective of PK Lead-in of this study is:

To evaluate the safety and tolerability of 7 days of dosing of SOF + RBV in HCV-infected
pediatric subjects
The primary objectives of Treatment Phase of this study are:

To evaluate the safety and tolerability of SOF + RBV for 12 or 24 weeks in HCV-infected
pediatric subjects with GT-2 or GT-3, respectively
The secondary objectives of Treatment Phase of this study are:

To determine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects separately, as assessed by the proportion of subjects with SVR 
12 weeks after completion of treatment (SVR12)

To determine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects separately, 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 SOF during treatment and after completion 
of treatment
The exploratory objective of this study is:

 
 
PPD


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9.1.2.
Primary Endpoints
For the PK Lead-in Phase, AUCtau of GS-331007 is considered as the primary PK parameter for 
determining the appropriate SOF dose.
For Treatment Phase, the primary safety endpoint is any AE leading to permanent 
discontinuation of study drug (s). The primary efficacy endpoint is SVR12. 
9.1.3.
Secondary Endpoints
For the PK Lead-in Phase, the secondary PK endpoints include AUCtau, Cmax, AUClast, Tmax, Clast, 
Tlast, Ctau and t1/2for GS-331007 and SOF as appropriate. AEs leading to permanent 
discontinuation of study drug(s) will be evaluated as a secondary safety endpoint.
For Treatment Phase, 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.
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 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 SOF or GS-331007 are available. 
The PK analysis set will be used for analysis of general PK and single sample plasma
concentrations.


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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.


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
If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the pre-dose value and the change from pre-dose values.
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pre-treatment 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 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 SOF and metabolites (GS-566500 and GS-331007) 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 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).


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To evaluate the exposures of GS-331007 achieved in pediatric subjects of this study are similar 
to the exposures observed in adult subjects, GS-331007 exposure data from this study will be 
compared to the integrated adult data by carrying out an analysis of variance (ANOVA) for 
log-transformed AUCtau of GS-331007 as the primary endpoint while Cmax of GS-331007 as 
secondary endpoints. 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%. Individual 
patient management will be performed by maintaining exposures comparable to adults.  AUCtau
less than the 2.5th percentile of adult values may require dose adjustment as appropriate.
The effect of age and SOF dose on PK (SOF and GS-331007) will be assessed.
9.5.
Safety Analysis
Safety analysis will be performed for PK Lead-in and overall study Treatment Phaserespectively. 
Safety data will be summarized by age group, by GT, by overall and by age group and GT.
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.
Palatability of SOF oral granules will be summarized using descriptive 
statistics by appropriate age group, by genotype, by overall and by age group 
and genotype.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. 


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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,

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.


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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 age group, by GT, by overall, and by age group and GT
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.
9.6.1.
Primary Efficacy Analysis
The primary 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
The primary efficacy endpoint of SVR12 will be compared with historical SVR12 rate of 80% 
from pegylated interferon + ribavirin for pediatric GT2 and 3 subjects {20280}, using two-sided 
exact one-sample binomial test at the 0.05 significance level.  
The proportion of subjects with HCV RNA below LLOQ over time (including SVR endpoints 
SVR4 and SVR24) will be presented in Treatment Phase in tabular and graphical form. 
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 (treatment-naive vs. 
experienced), and by treatment experience and 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.
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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.
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 50 subjects enrolled into each age group of Treatment Phase, a two-sided 
95.0% confidence interval of the SVR12 rate will extend at most 11.1% in both directions from 
the observed SVR12 rate, assuming the expected SVR12 rate is 80%. In addition, a sample size 
of 100 subjects will provide over 80% power to detect a 11% improvement in SVR12 rate from 
80% to 91% using two-sided one-sample binomial test at significance level of 0.05.


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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 Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. 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 subinvestigators 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 
subinvestigator. The investigator and subinvestigator 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.


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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);

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.


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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 subinvestigator (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 prerandomization screening period if a CRF was initiated). If a subject 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.


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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 competent 
authority, IRB or IEC in accordance with local requirements. Approval must be obtained before 
changes can be implemented. 
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. 


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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.
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
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.
20280
Schwarz KB, Gonzalez-Peralta RP, Murray KF, Molleston JP, Haber BA, Jonas 
MM, et al. The combination of ribavirin and peginterferon is superior to 
peginterferon and placebo for children and adolescents with chronic hepatitis C. 
Gastroenterology 2011;140 (2):450-8 e1.
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.


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20285
Wirth S. Current treatment options and response rates in children with chronic 
hepatitis C. World J Gastroenterol 2012;18 (2):99-104.
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.
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.
23275
Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. 
Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J 
Med 2013;368 (1):34-44.
24713
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, 
Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients 
without treatment options. N Engl J Med 2013;368 (20):1867-77.
24715
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et 
al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J 
Med 2013;368 (20):1878-87.
27503
SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing Information. Gilead 
Sciences, Inc. Foster City, CA. December 2013.  


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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


PPD
Sofosbuvir 
Protocol GS-US-334-1112 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Amendment 3 
A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Arm Study to Investigate the 
Safety and Efficacy of Sofosbuvir + Ribavirin in Adolescents and Children with Genotype 2 
or 3 Chronic HCV Infection 
GS-US-334-1112, Protocol Amendment 3, 10 October 2014 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Bittoo Kanwar, MD (Printed) 
Medical Monitor 
\ 0 
OCTo\\ t. ~ 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
infonnation provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 82 
10 October 2014 


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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 7
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Complete Physical Examination
X
X
Symptom-directed Physical Examination
X
X
Tanner Pubertal Stage Assessment
X
Collect Height & Weight Measurement 
with Percentiles
X
Vital Signsa
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
Pregnancy Prevention Counselingf
X
SOF Swallowability Assessment
X
Xh
Quality of Life Survey
Xi
Review of Study 
Medication Compliance
X
X
Study Drug Dispensingb
X


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Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 7
(+ 3 days)
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X
X
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
Subject Dosing Diary
X
X
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
Palatability Assessment of Oral GranulesJ
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
PPD


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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 drugs on Day 7 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 8, 
and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 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 (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).
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
Palatability of SOF oral granules will be assessed at Day 1, applicable.
PPD


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Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningc
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12g
16g
20g
24g
Early 
Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Complete Physical Examination
X
X
X
X
X
Symptom-Directed Physical Examination
X
X
X
X
X
X
Tanner Pubertal Stage Assessment
X
X
X
X
Collect Height & Weight Measurement 
with Percentiles
X
X
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 Counselingh
X
X
X
X
SOF Swallowability Assessment
X
Xj
Quality of Life Surveye
X
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
X
X
X
Study Drug Dispensingb
X
X
X
Xi
X
X


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Amendment 3
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Screeningc
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12g
16g
20g
24g
Early 
Termination
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
Viral Sequencing d
X
X
X
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testing
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
X
X
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
Palatability Assessment of Oral Granulesk
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, 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 at Day 1, Week 12 (only GT-2 subjects), Week 24 (only GT-3 subjects) and Early Termination 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
GT-2 subjects will complete through the Week 12 visit; GT-3 subjects will complete through the Week 24 visit. 
PPD
PPD


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Protocol GS-US-334-1112
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Amendment 3
CONFIDENTIAL
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h
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).
i
Study Drug Dispensing at the Week 12 visit for GT-3 subjects only
j
Swallowability can occur at Day 1 if not completed during screening.
k
Palatability of SOF oral granules will be assessed at Day 1, applicable.


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Protocol GS-US-334-1112
Gilead Sciences, Inc
Amendment 3
CONFIDENTIAL
Page 89
10 October 2014
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
Xd
Xd
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment 
X
X
Collect Height & Weight Measurement with Percentiles
X
X
Bone Age Assessment
X
Pregnancy Prevention Counseling e
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Testc
X
X
X
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
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.
d
At Post Treatment Week 12 and 24, only SAEs will be captured
e
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).


Sofosbuvir
Protocol GS-US-334-1112
Gilead Sciences, Inc
Amendment 3
CONFIDENTIAL
Page 90
10 October 2014
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18June2012
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


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Protocol GS-US-334-1112
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Amendment 3
CONFIDENTIAL
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
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
Infant, 2 – 7 Days
1250 to 1500/mm3
1.25 to 1.50 GI/L
1000 to 1250/mm3
1.00 to < 1.25 GI/L
750 to 1000/mm3
0.75 to < 1.00 GI/L
750/mm3
< 0.75 GI/L
Infant, 1 Day
4000 to 5000/mm3
4.00 to 5.00 GI/L
3000 to 4000/mm3
3.00 to < 4.00 GI/L
1500 to 3000/mm3
1.50 to < 3.00 GI/L
1500/mm3
< 1.50 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


Sofosbuvir
Protocol GS-US-334-1112
Gilead Sciences, Inc
Amendment 3
CONFIDENTIAL
Page 92
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0% 


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Protocol GS-US-334-1112
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Amendment 3
CONFIDENTIAL
Page 93
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
146  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


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Protocol GS-US-334-1112
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Amendment 3
CONFIDENTIAL
Page 94
10 October 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4  mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


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Protocol GS-US-334-1112
Gilead Sciences, Inc
Amendment 3
CONFIDENTIAL
Page 95
10 October 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63  to LLN mmol/L
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.14 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 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol/L to LLN
57 to 87 μmol/L
27 to 57 μmol/L
27 μmol/L


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Protocol GS-US-334-1112
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Amendment 3
CONFIDENTIAL
Page 96
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Creatinine 
1.50 to 2.00 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol/L
177 to 265 μmol/L
265 to 530 μmol/L
530 μmol/L
Bicarbonate
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
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L
LDL
(Fasting)
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
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


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Protocol GS-US-334-1112
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Amendment 3
CONFIDENTIAL
Page 97
10 October 2014
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
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


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Protocol GS-US-334-1112
Gilead Sciences, Inc
Amendment 3
CONFIDENTIAL
Page 98
10 October 2014
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 
Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to Dipstick 
Hematuria.
With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for the 
AE.


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Protocol GS-US-334-1112
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Amendment 3
CONFIDENTIAL
Page 99
10 October 2014
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 
(e.g., 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 
(e.g., 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 
(e.g., tamponade) OR Urgent 
intervention indicated


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Amendment 3
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, e.g., 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, e.g., Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated 
(e.g., anticoagulation, lysis 
filter, invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (e.g., 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (e.g., 
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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Gilead Sciences, Inc
Amendment 3
CONFIDENTIAL
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RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70% to 80%
FEV1 or peak flow 50% to 69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak flow 
25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in affected 
eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in affected 
eye(s)


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


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Amendment 3
CONFIDENTIAL
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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 [e.g., tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (e.g., 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 
(e.g., sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(e.g., 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 
(e.g., 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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Protocol GS-US-334-1112
Gilead Sciences, Inc
Amendment 3
CONFIDENTIAL
Page 104
10 October 2014
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 (e.g., aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (e.g., 
IV fluids)
Life-threatening consequences 
(e.g., hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(e.g., sepsis, circulatory 
failure, hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(e.g., perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(e.g., hypotensive shock)


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


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


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Gilead Sciences, Inc
Amendment 3
CONFIDENTIAL
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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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Protocol GS-US-334-1112
Gilead Sciences, Inc
Amendment 3
CONFIDENTIAL
Page 109
10 October 2014
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 [e.g., 
tube feeding or total parenteral 
nutrition]


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Protocol GS-US-334-1112
Gilead Sciences, Inc
Amendment 3
CONFIDENTIAL
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10 October 2014
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 (e.g., upper 
arm/thigh)
Erythema OR Induration 
OR Edema involving 
50% surface area of the 
extremity segment (e.g., 
upper arm/thigh) OR 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR 
Drainage
Necrosis (involving dermis and 
deeper tissue)
Pruritis Associated with 
Injection 
See also Skin: Pruritis 
(itching—no skin lesions)
Itching localized to injection 
site AND Relieved 
spontaneously or with 
48 h treatment 
Itching beyond the injection 
site but not generalized OR 
Itching localized to injection 
site requiring 48 h treatment 
Generalized itching causing 
inability to perform usual 
social & functional activities
NA


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Protocol GS-US-334-1112
Gilead Sciences, Inc
Amendment 3
CONFIDENTIAL
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ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (e.g., 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 
(e.g., 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 
(e.g., 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 
(e.g., myxedema coma)
Lipoatrophy (e.g., 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


Sofosbuvir
Protocol GS-US-334-1112
Gilead Sciences, Inc
Amendment 3
CONFIDENTIAL
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10 October 2014
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 (e.g., stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing life-
threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic antiμbial 
treatment indicated AND 
Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening 
consequences (e.g., septic 
shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc


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Gilead Sciences, Inc
Amendment 3
CONFIDENTIAL
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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. 


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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 sofosbuvir demonstrated no adverse effect on fertility or embryo-
fetal development. However, there are no clinical studies of sofosbuvir 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 randomization. They must also agree to one of 
the following from 3 weeks prior to Day 1 until 6 months after last dose of RBV:

Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) is not permitted.
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 the last dose of RBV:
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent
tubal sterilization
vasectomy in male partner
implants of levonorgestrel


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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 Baseline 
until 7 months after the last dose of 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.
Male subjects must agree to refrain from sperm donation for at least 7 months after the last dose 
of 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. 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.

Prot_005.pdf: 
Study Title: 
Sponsor: 
IND No.: 
EudraCT Number: 
Indication: 
Protocol ID: 
Gilead Sciences Medical 
Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Aim 
Study to Investigate the Safety and Efficacy of 
Sofosbuvir + Ribavirin in Adolescents and Children with 
Genotype 2 or 3 Chronic HCV Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
106739 
2014-002283-32 
Hepatitis C Vims Infection 
GS-US-334-1112 
Name: 
Telephone: 
Mobile: 
Fax: 
E-mail: 
Original: 
Alnendment 1: 
Alnendment 2: 
Alnendment 3: 
Bittoo Kanwar, MD, 
~:~ 
PD 
t-'U 
20 December 2013 
10 Febrmuy 2014 
14 March 2014 
10 October 2014 
Alnendment 4: 
12 November 2014 
Alnendment 5: 
29 May20 15 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pmiicularly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Bom·d or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from Gilead 
Sciences, Inc., except to the extent necessmy to obtain infonned consent from those persons to 
whom the dmg may be administered. 


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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....................................................................16
1.
INTRODUCTION ..............................................................................................................................................19
1.1.
Background ............................................................................................................................................19
1.2.
Sofosbuvir ..............................................................................................................................................20
1.2.1.
Summary of Additional Clinical Experience with Sofosbuvir .............................................20
1.3.
Ribavirin (RBV).....................................................................................................................................22
1.4.
Rationale for the Current Study .............................................................................................................23
1.5.
Rationale for Dose Selection of SOF .....................................................................................................23
1.6.
Overall Risk/Benefit Assessment...........................................................................................................26
2.
OBJECTIVES.....................................................................................................................................................27
3.
STUDY DESIGN................................................................................................................................................28
3.1.
Treatment Plan and Regimen .................................................................................................................28
3.1.1.
PK Lead-in ...........................................................................................................................28
3.1.2.
Treatment Phase ...................................................................................................................29
3.2.
Visit Schedule ........................................................................................................................................30
3.2.1.
PK Lead-in ...........................................................................................................................30
3.2.2.
Treatment Phase ...................................................................................................................31
3.3.
Virologic Response-Based Stopping Criteria.........................................................................................31
3.4.
Treatment Discontinuations Criteria ......................................................................................................32
3.5.
Discontinuations.....................................................................................................................................32
3.6.
Pharmacogenomic Substudy ..................................................................................................................32
3.7.
Long-Term Follow-Up...........................................................................................................................32
3.8.
Breakthrough Futility Assessment .........................................................................................................33
3.9.
Reconsent...............................................................................................................................................33
4.
SUBJECT POPULATION..................................................................................................................................34
4.1.
Number of Subjects and Subject Selection ............................................................................................34
4.2.
Inclusion Criteria....................................................................................................................................34
4.3.
Exclusion Criteria...................................................................................................................................35
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................36
5.1.
Randomization and Blinding..................................................................................................................36
5.2.
Sofosbuvir ..............................................................................................................................................36
5.2.1.
Description and Handling.....................................................................................................36
5.2.2.
Storage and Handling...........................................................................................................37
5.2.3.
Dosage and Administration of SOF .....................................................................................38
5.3.
Ribavirin.................................................................................................................................................38
5.3.1.
Description and Handling of RBV .......................................................................................38
5.3.2.
Dosage and Administration of RBV.....................................................................................39
5.4.
Co-administration of SOF and RBV ......................................................................................................40
5.5.
Study Drug Compliance.........................................................................................................................40
5.6.
Prior and Concomitant Medications.......................................................................................................40


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6.
STUDY PROCEDURES ....................................................................................................................................42
6.1.
Subject Enrollment.................................................................................................................................42
6.2.
Screening Assessments ..........................................................................................................................42
6.2.1.
Screening Visit (Day –28 to Day 0) .....................................................................................42
6.3.
PK Lead-in: Treatment Assessments .....................................................................................................44
6.3.1.
Day 1 ....................................................................................................................................44
6.3.2.
Day 3 ....................................................................................................................................45
6.3.3.
Day 7 – Intensive PK ...........................................................................................................45
6.4.
Treatment Phase: Treatment Assessments .............................................................................................47
6.4.1.
Day 1 ....................................................................................................................................47
6.4.2.
Weeks 1 and 2 (3 days) .....................................................................................................49
6.4.3.
Weeks 4 and 8 (3 days) .....................................................................................................49
6.4.4.
Week 12 (3 days) ..............................................................................................................50
6.4.5.
Week 16 and 20 (3 days) – GT-3 Subjects only................................................................51
6.4.6.
Week 24 (3 days) – GT-3 Subjects only ...........................................................................51
6.4.7.
Unscheduled Visit/Early Termination Visit .........................................................................52
6.5.
Post-Treatment Assessments..................................................................................................................53
6.5.1.
4-Week Post-Treatment Visit (5 days)..............................................................................53
6.5.2.
12-Week Post-Treatment Visit (5 days)............................................................................54
6.5.3.
24-Week Post-Treatment Visit (5 days)............................................................................55
6.6.
Procedures and Specifications................................................................................................................55
6.6.1.
Clinical Laboratory Analytes ...............................................................................................55
6.6.2.
Medical History....................................................................................................................56
6.6.3.
Complete Physical Examination...........................................................................................56
6.6.4.
Tanner Pubertal Stage Assessment.......................................................................................56
6.6.5.
Height & Weight Measurement............................................................................................56
6.6.6.
Bone Age Assessment..........................................................................................................57
6.6.7.
Swallowability Assessment..................................................................................................57
6.6.8.
Vital Signs............................................................................................................................57
6.6.9.
Body Mass Index (BMI).......................................................................................................57
6.6.10.
Estimated Glomerular Filtration Rate (GFR) .......................................................................57
6.6.11.
Viral Sequencing (Archive)..................................................................................................58
6.6.12.
Pregnancy Testing................................................................................................................58
6.6.13.
Quality of Life Survey (PedsQL™).......................................................................................58
6.6.14.
SOF Granule Palatability Assessment..................................................................................58
7.
TOXICITY MANAGEMENT............................................................................................................................59
7.1.
Modification of Dose/Schedule Due to Toxicity....................................................................................59
7.2.
Subject Stopping Rules for SOF ............................................................................................................59
8.
ADVERSE EVENTS MANAGEMENT ............................................................................................................60
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................60
8.1.1.
Adverse Events.....................................................................................................................60
8.1.2.
Serious Adverse Events........................................................................................................60
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................61
8.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................61
8.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................61
8.2.2.
Assessment of Severity ........................................................................................................62
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events.......................................................................................................................................62
8.4.
Gilead Reporting Requirements.............................................................................................................64
8.5.
Special Situations Reports......................................................................................................................64


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8.5.1.
Definitions of Special Situations..........................................................................................64
8.5.2.
Instructions for Reporting Special Situations.......................................................................65
9.
STATISTICAL CONSIDERATIONS................................................................................................................67
9.1.
Analysis Objectives and Endpoints........................................................................................................67
9.1.1.
Analysis Objectives..............................................................................................................67
9.1.2.
Primary Endpoints................................................................................................................68
9.1.3.
Secondary Endpoints............................................................................................................68
9.2.
Analysis Conventions.............................................................................................................................68
9.2.1.
Analysis Sets ........................................................................................................................68
9.2.2.
Data Handling Conventions .................................................................................................69
9.2.3.
Interim Analysis ...................................................................................................................70
9.3.
Demographic Data and Baseline Characteristics ...................................................................................70
9.4.
Pharmacokinetic Analysis......................................................................................................................70
9.5.
Safety Analysis.......................................................................................................................................71
9.5.1.
Extent of Exposure...............................................................................................................71
9.5.2.
Palatability of SOF oral granules .........................................................................................71
9.5.3.
Adverse Events.....................................................................................................................72
9.5.4.
Laboratory Evaluations ........................................................................................................72
9.5.5.
Other Safety Evaluations......................................................................................................73
9.6.
Efficacy Analysis ...................................................................................................................................73
9.6.1.
Primary Efficacy Analysis....................................................................................................73
9.6.2.
Secondary Efficacy Analysis................................................................................................73
9.6.3.
Subgroup Analysis ...............................................................................................................74
9.7.
Quality of Life Analysis.........................................................................................................................74
9.8.
Data Monitoring Committee ..................................................................................................................74
9.9.
Sample Size............................................................................................................................................74
10.
RESPONSIBILITIES..........................................................................................................................................75
10.1.
Investigator Responsibilities ..................................................................................................................75
10.1.1.
Good Clinical Practice..........................................................................................................75
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval...............................................................................................................................75
10.1.3.
Informed Consent/Assent.....................................................................................................76
10.1.4.
Confidentiality......................................................................................................................76
10.1.5.
Study Files and Retention of Records ..................................................................................76
10.1.6.
Case Report Forms...............................................................................................................78
10.1.7.
Drug Accountability.............................................................................................................78
10.1.8.
Inspections............................................................................................................................78
10.1.9.
Protocol Compliance............................................................................................................78
10.2.
Sponsor Responsibilities ........................................................................................................................79
10.2.1.
Protocol Modifications.........................................................................................................79
10.2.2.
Study Report and Publications .............................................................................................79
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................79
10.3.1.
Access to Information for Monitoring..................................................................................79
10.3.2.
Access to Information for Auditing or Inspections ..............................................................80
10.3.3.
Study Discontinuation..........................................................................................................80
11.
REFERENCES ...................................................................................................................................................81
12.
APPENDICES ....................................................................................................................................................83
Appendix 1.
Investigator Signature Page....................................................................................................84
Appendix 2.
Study Procedures Table..........................................................................................................85


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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............91
Appendix 4.
Tanner Stages* .....................................................................................................................114
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................115
LIST OF IN-TEXT TABLES
Table 1-1.
GS-US-334-1111: Statistical Comparison of SOF, GS-566500, and GS-331007 PK 
Parameters ..............................................................................................................................21
Table 1-2.
Steady-state PK and Statistical Comparison of SOF and GS-331007 PK in 
Adolescent Subjects (PK Lead-in) and Adult Subjects (Phase 2/3 Population 
Analysis).................................................................................................................................22
Table 7-1.
RBV Dose Reduction Guidelines...........................................................................................59
LIST OF IN-TEXT FIGURES
Figure 1-1.
Predicted SOF and GS-331007 AUCtau following administration of SOF 200 mg to 
Children (6 to < 12 years of age)............................................................................................25
Figure 3-1.
Study Schema.........................................................................................................................30


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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, Single-Arm Study 
to Investigate the Safety and Efficacy of Sofosbuvir + Ribavirin in 
Adolescents and Children with Genotype 2 or 3 Chronic HCV 
Infection
IND Number:
EudraCT Number:
106739
2014-002283-32
Study Centers:
Approximately 50 sites in the United States, Europe, Russia, 
Australia, New Zealand, Belgium and India
Number of Subjects:
Approximately 100 subjects
Target Population:
Adolescents and children (aged 3 to < 18) with chronic hepatitis C 
virus (HCV) infection
Treatment Duration:
PK Lead-in – 7 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 sofosbuvir (SOF) in HCV-infected pediatric subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety and tolerability of 7 days of dosing of SOF
+ ribavirin (RBV) in HCV-infected pediatric subjects
The primary objective of the Treatment Phase of this study is:

To evaluate the safety and tolerability of SOF + RBV for 12 or 
24 weeks in HCV-infected pediatric subjects with genotype (GT)
GT-2 or GT-3, respectively


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Study Design: 
CONFIDENTIAL 
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The seconda!y objectives of the Treatment Phase of this study are: 
• 
To determine the antiviral efficacy of SOF + RBV u·eatment in 
GT-2 and GT-3 HCV-infected subjects separately, as assessed by 
the prop01iion of subjects with SVR 12 weeks after completion of 
u·eatment (SVR12) 
• 
To detennine the antiviral efficacy of SOF + RBV u·eatment in 
GT-2 and GT-3 HCV-infected subjects separately, as assessed by 
the prop01iion of subjects with SVR 4 and 24 weeks after 
completion ofu·eatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA dming u·eatment 
and after completion of u·eatment 
• 
To evaluate the emergence of viral resistance to SOF dming 
u·eatment and after completion of u·eatment 
• 
To evaluate the palatability of SOF oral granules at Day 1, as 
applicable. 
• 
To evaluate the effect of growth and development on pediau·ic 
subjects dming and after u·eatlnent 
The explorat01y objective of this study is: 
• 
PO 
Open-label, multi-coh01i, two-pati study evaluating the PK, safety, 
and antiviral activity of SOF in chronic HCV-infected pediau·ic 
subjects. 
The study will be divided into 2 parts as follows: 
PK Lead-in: Will evaluate and/or confitm age appropriate SOF doses 
by analyzing PK, safety, and antiviral activity of SOF administered in 
combination with RBV through 7 days of dosing for each of three 
coh01is. Children aged 3 < 6, children aged 6 to < 12 years and 
adolescents aged 12 to < 18 years with genotype GT-2 or GT-3 HCV 
infection and evidence of HCV RNA :=::: 1000 IU/mL at study entry 
will be evaluated. Subjects must be u·eatment naive to patiicipate in 
the PK Lead-in Phase. 
Three coh01is of up to 10 subjects each will be sequentially enrolled: 
• 
Cohort 1: 12 to < 18 yem·s old weighing :=::: 45kg 
• 
Cohort 2: 6 to < 12 yem·s old weighing :=::: 17kg and ::; 45kg 
• 
Coh01i 3: 3 to < 6 yem·s old 
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The study will start with Cohort 1.  Subjects will receive SOF (400 mg 
adult tablet or 4 x 100 mg tablets if determined necessary based on 
SOF swallowability assessment) + RBV for 7 days with intensive PK 
conducted on Day 7.   Cohort 2 subjects will receive 200 mg SOF 
(2 X 100 mg tablets or 4 x 50 mg capsules if determined necessary 
based on the SOF swallowability assessment) + RBV for 7 days with 
intensive PK conducted on Day 7.
PK Lead-in subjects in each cohort (Cohorts 1, 2 and 3) will 
immediately enroll in the Treatment Phase as they complete Day 7 of 
the PK Lead-in Phase.  They will continue dosing with SOF + RBV 
with no interruption of study drug administration.  Subjects rolling 
over from the PK Lead-in will not be required to perform 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 will be reviewed to confirm 
the appropriateness of the evaluated SOF 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: Will be initiated sequentially by cohort after 
confirmation of age-appropriate SOF dosage levels. Subjects who 
participated 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.  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.
Children aged 3 to < 12 years and adolescents aged 12 to < 18 years 
with GT-2 or GT-3 infection and evidence of HCV RNA 
≥1000 IU/mL at study entry (those who were dosed in the PK Lead-in 
Phase will have met this criteria prior to enrollment) will be evaluated. 
Subjects enrolled in the study will receive the following regimen:

GT-2 subjects: SOF + RBV for 12 weeks

GT-3 subjects: SOF + RBV for 24 weeks
The study will enroll both treatment-naïve and treatment-experienced 
pediatric subjects, with up to 20 subjects allowed to be treatment 
experienced. Approximately 100 total subjects, including subjects that 
participate in the PK Lead-in Phase, will be enrolled in Treatment 
Phase as follows

Group 1: Approximately 50 adolescent subjects (12 to < 18 years 
of age)


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Substudy and 
Long-Te1m 
Follow-Up Study: 
CONFIDENTIAL 
• 
Group 2: Approximately 50 pediau·ic subjects (3 to < 12 years of 
age) 
The following definitions will be used for u·eatment-experienced 
subjects: 
• 
Interferon intolerant: Subject who discontinued therapy 
(~ 12 weeks total) due to ~ 1 adverse event 
• 
Interferon non-responder: Subject who did not achieve 
lmdetectable HCV RNA levels while on u·eahnent 
• 
Relapse/breakthrough: Subject who achieved undetectable HCV 
RNA during u·eatment or within 4 weeks of the end of u·eahnent 
but did not achieve a sustained virologic response (SVR) 
The study schedule contains the following visits: Screening, Day 1, 
Weeks 1, 2, 4, 8, 12 (and Weeks 16, 20, and 24 for GT-3) during the 
u·eahnent phase followed by post-u·eatment 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 u·eahnent with standard-of-care (SOC) therapy 
with their healthcare provider. 
Pharmacogenomics (PG) Substudy 
PO 
Long-Term Follow-up 
Subjects who attain SVR24 or those who do not attain SVR24 and do 
not initiate experimental or approved anti-HCV therapy will be 
followed eve1y 6 months for the first two years followed by eve1y 
12 months for assessments of growth, quality of life, and long-te1m 
viral suppression (if applicable) in a separate protocol 
(GS-US-334-1113). This follow-up will continue for 5 years. 
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Diagnosis and Main 
Eligibility Criteria: 
Chronic HCV-infected, treatment-naïve and up to 20 subjects may 
be treatment experienced, male and female subjects aged 3 to < 18. 
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

a liver biopsy performed prior to the Day 1 visit with evidence of 
chronic HCV infection

Infection with HCV GT-2 or GT-3 as determined at Screening

HCV RNA ≥1000 IU/mL at Screening 

For the PK Lead-in Phase: subjects in cohort 1 (age 12 to 
<18 years of age) must weigh ≥ 45kg

For the PK Lead-in Phase:  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)

Chronic use of systemic immunosuppressive agents or
immunomodulatory agents

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.


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
Sexually active subjects who are not willing to use two 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 height and weight), concomitant medications, SOF 
swallowability assessment (may be performed at 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 7.
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 7. SOF swallowability 
assessment with placebo will be performed (if not performed at 
screening) on Day 1 to assess a subject’s ability to swallow the 
400 mg or 100 mg SOF tablet (only subjects administered SOF in 
tablet form).
Subjects (up to 10 subjects) enrolled in the PK Lead-in Phase will 
participate in an intensive PK evaluation on Day 7. Following 
completion of the Day 7 intensive PK visit, subjects will then return 
for scheduled study visits outlined in the Treatment Phase and 
continue dosing with SOF + RBV with no interruption of study drug 
administration.  Subjects will be administered a dosing diary with 
instructions.


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Treatment Phase: 
Final 
AmendmentS 
• 
GT-2 Subjects: Study visits for GT-2 subjects will occur at Day 1, 
and the end of Weeks 1, 2, 4, 8, and 12. 
• 
GT-3 Subjects: Study visits for GT-3 subjects will occur at Day 1, 
and the end of Weeks 1, 2, 4, 8, 12, 16, 20, and 24. 
All Treatment Phase subjects will then retu.m for follow-up visits at 4, 
12 and 24 weeks after discontinuation of therapy. 
On-u·eatment assessments will include physical examination, vital 
signs (including height and weight) adverse events, concomitant 
medications, pregnancy prevention cmmseling (all subjects:::: 12 years 
of age and subjects < 12 years of age at the discretion of the 
Investigator based on subject's pube1tal status), safety laborat01y tests, 
coagulation tests, HCV RNA, PK samples, a quality of life survey and 
urine pregnancy tests (females of childbearing potential only). Tanner 
Pubeiial Stage assessment will be perf01m ed at Day 1 and end of 
u·eatment visits; parental heights will be recorded at Day 1. , The 
Bone Age Assessment will be perf01m ed at Day 1 visit. If available, 
results from liver biopsies will be collected at screening. SOF 
swallowability assessment with placebo will be perf01m ed (if not 
perf01m ed at screening) on Day 1 to assess a subject's ability to 
swallow a 400 mg or 100 mg SOF tablet 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 eve1y visit 
thereafter. 
Post-u·eatment assessments will include adverse events, concomitant 
medications, vital signs (including body weight and height), symptom-
directed physical examination, safety laborat01y tests, HCV RNA, 
Tanner Pubertal Stage assessment (only post-u·eahnent Week 12 and 
post-u·eatment Week 24), Bone Age Assessment (only post-u·eatment 
Week 24) and urine pregnancy tests as defmed in Appendix 5. 
Palatability of SOF oral granules will be assessed at Day 1, as 
applicable. 
PO 
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Test Product, Dose, 
and Mode of 
Administration:
PK Lead-in: 
(Cohort 1) SOF 400 mg tablets will be administered once daily along 
with RBV weight-based dosing. Subjects determined unable to 
swallow the placebo for 400 mg SOF tablet (by SOF Placebo 
swallowability assessment at Screening or at any time during the 
study) will be re-assigned to 4 x 100 mg tablets daily.  
(Cohort 2) SOF 200 mg (2 X 100 mg tablets) will be administered 
once daily along with RBV weight-based dosing. Subjects determined 
unable to swallow the placebo for the 100 mg SOF tablet (by SOF 
Placebo swallowability assessment at Screening or at any time during 
the study) will be re-assigned to 4 X 50 mg capsules containing 
granules. Subjects who weigh outside of the ≥ 17kg and < 45 kg 
range will be excluded
Intensive PK and safety results from the PK Lead-In of each Cohort 
will be reviewed to confirm the appropriateness of the evaluated SOF 
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.
RBV Weight-Based Dosing (All age groups):
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.


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The morning dose of RBV will be taken with food with an 
age-appropriate dose of SOF. The evening dose of RBV will be taken 
with food.
Reference Therapy:
None
Evaluation Criteria:
Safety:
AEs, laboratory tests, physical examination, vital signs and Tanner 
Pubertal Stage assessments will be collected throughout the study. 
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, steady-state PK of SOF and its major 
metabolites GS-566500 and GS-331007 will be assessed at Day 7. For 
Cohorts 1 and 2, plasma samples will be collected for PK analyses
following dosing of study drugs on Day 7 at the following time points: 
0 (predose), 0.5, 1, 2, 3, 4, 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), 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 SOF, 
GS-566500 and GS-331007 and/or ribavirin will be assessed.
The effect of age and SOF dose on PK (SOF and GS-331007) will be 
explored. 
Statistical Methods:
For the PK Lead-in, plasma PK parameters Cmax, Tmax, Clast, Tlast, Ctau, 
AUCtau, and t1/2 will be estimated.  The PK parameters will be 
summarized by cohort. The effect of age and SOF dose on PK 
(SOF and GS-331007) 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 age group, by GT and overall. Primary efficacy 
endpoint is SVR12 in all enrolled and treated subjects and will be 
summarized by age group, by genotype, by overall and by age group 
and GT.  Point estimate and its 95% confidence interval will be 
provided.  
In addition, SVR12 will be compared with historical SVR12 rate of 
80% from pegylated interferon + ribavirin for pediatric GT-2 and 


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GT-3 subjects {20280}, using two-sided exact one-sample binomial 
test at the 0.05 significance level.  
Secondary efficacy endpoints are SVR4, SVR24, breakthrough and 
relapse.
Palatability of SOF oral granules will be summarized using 
descriptive statistics by appropriate age group, by genotype, by overall 
and by age group and genotype.
Subgroup analysis on SVR12 will be performed by treatment 
experience (treatment-naive vs. experienced) and 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). 
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.
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 age group, by GT, by 
overall and by age group and GT.
With approximately 50 subjects enrolled into each age group of 
Treatment Phase, a two-sided 95.0% confidence interval of the 
SVR12 rate will extend at most 11.1% in both directions from the 
observed SVR12 rate, assuming the expected SVR12 rate is 80%. In 
addition, a sample size of 100 subjects will provide over 80% power 
to detect an 11% improvement in SVR12 rate from 80% to 91% using 
two-sided one-sample binomial test at significance level of 0.05.
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
β-hCG
β-human chorionic gonadotropin
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)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BW
body weight
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)
CMH
Cochran-Mantel-Haenszel
COPD
Chronic obstructive pulmonary disease
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
Emax
maximal effect
EU
European Union
EVR
Early virologic response
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
GFR
glomerular filtration rate
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
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
IV
Intravenous
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDH
Lactase dehydrogenase
LLN
lower limit of the normal range
LLOD
Lower limit of detection
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


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
PI
Protease inhibitor
PK
Pharmacokinetic
RBC
Red blood cell count 
RBV
Ribavirin
RDRP
RNA-dependent RNA polymerase
RNA
ribonucleic acid
RVR
rapid virologic response 
SADR
Serious adverse drug reaction
SAE
serious adverse event
SD
Standard deviation
SOC
Standard of Care
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TND
Target not detected
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 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 standard of care 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.
Sofosbuvir
Sovaldi™(Sofosbuvir) is a potent nucleotide analogue that inhibits HCV RNA replication in 
vitro and has demonstrated high rates of sustained viral response (SVR) when given with RBV
+/- PEG to subjects with chronic GT- 1, 2, 3 or 4 HCV infection {27503}, {23275}, {24713}, 
{24715}.  Sovaldi™has been approved in the United States by the Food and Drug Administration 
(FDA) for the treatment of HCV infection GT- 1, 2, 3 and 4 including treatment naïve and 
experienced patients and HIV/HCV co-infected patients.  Sovaldi™is also approved in EU, 
Canada and Turkey.
For further information on the clinical pharmacology, virology, safety and efficacy of SOF, 
please refer to the current version of the Investigator’s Brochure and the local prescribing 
information.
1.2.1.
Summary of Additional Clinical Experience with Sofosbuvir
A phase 1 study (GS-US-334-1111) was conducted to evaluate the relative bioavailability of, and 
effect of food on Sofosbuvir oral granules in healthy adult subjects to support the use of this 
formulation in subjects unable to swallow the tablet formulations.  The preliminary results of this 
study are presented below.
1.2.1.1.
GS-US-334-1111 Study Design
Study GS-US-334-1111 is a single dose, randomized, 3-period crossover phase 1 study 
conducted in healthy adult subjects.  Subjects were administered 400 mg SOF in the following 
treatments in a randomized order: 1 x 400 mg SOF (adult formulation) in the fasted state, 
8 x 50 mg SOF granules in capsules in the fasted state, and 8 x 50 mg SOF granules in capsules 
after a standardized high-fat meal.  Prior to administration the SOF granules were removed from 
the capsules and administered orally with water.  18 healthy subjects were enrolled and 
completed all treatment periods of this study.


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1.2.1.2. 
GS-US-3 34-1111 Preliminruy Phan nacokinetic Results 
Preliminruy PK results ru·e available for all18 subjects. Statistical comparisons of the primaty 
PK parruneters AUCinr, AUC1ast, and Cmax for SOF, its intennediate metabolite GS-566500, and 
the primruy circulating metabolite GS-331007 which is considered the primruy analyte of interest 
for PK studies ru·e presented below. Statistical compru·isons include the %GMR and 90%Cis of 
exposures achieved after administration of 8 x 50 mg SOF granules in capsules fasted 
(Granules Fasted) relative to 1 x 400 mg SOF tablet fasted (Tablet Fasted), and 8 x 50 mg SOF 
granules in capsules fed (Granules Fed) relative to 8 x 50 mg SOF granules in capsules fasted 
(Granules Fasted) (Table 1-1). Bioequivalence of the pediatric granule f01mulation and the adult 
tablet fonnulation was concluded as a result of the 90%Cis of the %GMRs for GS-331 007 
AUC1ast, AUCinf, and Cmax (protocol specified primaty endpoints) being contained within the 
predefmed boundaries of 80-125%. Additionally, administration of the pediatric granule 
f01mulation after a high-fat meal or fasted resulted in bioequivalent exposures of GS-331007 as 
the 90%Cis of the %GMRs for GS-331 007 AUC1ast and AUCinf (protocol specified primat}' 
endj)oints were contained within the redefined bmmdat·ies of 80-125%. PPD 
Table 1-1. 
Parameter (N=18) 
SOF 
AUCinf 
AUCtast 
Cmax 
GS-566500 
AUCinf 
AUCtast 
cmax 
GS-331007 
AUCinf 
AUCtast 
cmax 
GS-US-334-1111: Statistical Comparison of SOF, GS-566500, and 
GS-331 007 PK Parameters 
o/oGMR (90%CI) 
Granules Fasted/Tablet Fasted 
Granules Fed/Granules Fasted 
100 (86.0, 117) 
168 (144, 195) 
100 (85.8, 117) 
167 (143, 195) 
83.6 (64.5, 108) 
90.9 (70.2, 118) 
96.2 (85.1, 109) 
165 (144, 195) 
94.5 (82.3, 109) 
166 (145, 191) 
91.8 (90.2, 105) 
128 (112, 146) 
104 (97.9, 111) 
87.9 (82.5, 93.6) 
104 (97.6, 112) 
86.3 (80.7, 92.7) 
106 (95.6, 117) 
60.3 (54.5, 66.8) 
Note: %GMR and 90%Cls are presented to 3 significant digits 
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1.2.1.3.
GS-US-334-1111 Preliminary Conclusions
As assessed by GS-331007, the new sofosbuvir (8 x 50 mg) granule formulation was 
bioequivalent to the existing sofosbuvir 1 x 400 mg tablet formulation under fasted conditions.  
The sofosbuvir (8 x 50 mg) granule formulation is recommended to be administered without 
regard to food.
1.2.1.4.
GS-US-334-1112 Preliminary Pharmacokinetic and Safety Results
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 SOF 400 mg. Mean exposures of SOF and GS-
331007 in these subjects were comparable to observed exposures in the adult subjects in the 
Phase 2/3 SOF clinical program; thereby confirming the appropriateness of adult dose in the 
adolescent population (12 to < 18 years of age) (Table 1-2).
Table 1-2.
Steady-state PK and Statistical Comparison of SOF and GS-331007 
PK in Adolescent Subjects (PK Lead-in) and Adult Subjects 
(Phase 2/3 Population Analysis)
Mean (%CV)
Adolescents (N=10)
Phase 2/3 (N=1695)
GMR% (90% CI)
SOF*
AUC
tau (ng*hr/ml)
1170 (67.6)
1030 (36.5)
101 (83.9, 121)
C
max (ng/ml)
592 (84.1)
511 (32.5)
97.4 (79.0, 120)
GS-331007
AUC
tau (ng*hr/ml)
9110 (28.6)
7120 (30.7)
129 (110, 152)
C
max (ng/ml)
981 (43.7)
582 (36.3)
168 (137, 206)
Data reported to 3 significant figures; *N=838
Safety data available for Cohort 1 adolescent subjects (N=10) who enrolled in the PK lead-in and 
received adult clinical dose of SOF 400mg resulted in no significant safety signals.
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 


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completion of treatment.  A comprehensive review of RBV is contained in the package 
insert/SmPC.
1.4.
Rationale for the Current Study
This clinical study is designed to evaluate the efficacy and safety of treatment with SOF + RBV
for adolescents and children with GT-2 and GT-3 chronic HCV infection. 
Currently PEG and weight-based RBV are considered the standard of care for the treatment of 
HCV infection in children. However, this PEG and RBV regimen is long in duration, relatively 
toxic, and not well tolerated. Thus, there continues to be a need for new treatments for HCV that 
combine potent and sustained efficacy with improved tolerability and safety. Therapy that 
provides shorter duration and improved efficacy with an all-oral regimen would be a significant 
advancement over current options in pediatric patients.
The main aim for the treatment of pediatric patients with HCV is to eliminate the need to use 
PEG regimens. In this way, pediatric patients are able to avoid the necessity of weekly injections, 
which can be traumatic and burdensome, and also to significantly reduce the serious adverse 
events seen on administration of PEG regimens. 
Sovaldi (sofosbuvir 400 mg tablet) is approved in 35 countries worldwide in combination with 
other medicinal products, for the treatment of adults with chronic hepatitis C infection. SOF in
combination with RBV would provide an all-oral, IFN-free regimen with a shorter treatment 
duration (12 - 24 weeks of SOF treatment versus standard-of-care 24 to 48 weeks of treatment)
and would offer another important option in the treatment of HCV infection in the pediatric 
population.
Phase 3 data demonstrates that high SVR12 rates in subjects with GT-2 HCV infection can be 
achieved with 12 weeks treatment with SOF+RBV, however, these studies suggest that patients 
with GT-3 infection may benefit from a longer treatment duration (i.e. 24 weeks) with 
SOF + RBV. Optimal duration of SOF + RBV, for GT-3 subjects, was established in FISSION 
and VALENCE.  Increasing treatment duration from 12 to 24 weeks increased SVR12 from 
61 to 93% in non-cirrhotics and from 34 to 92% in cirrhotics.
1.5.
Rationale for Dose Selection of SOF
SOF 400 mg, once daily, when dosed in combination with RBV with or without PEG has 
demonstrated broad genotypic efficacy and favorable safety profile in over 3300 HCV-infected 
adult subjects across multiple patient populations in Phase 2 and 3 trials. This dose is the 
marketed dose of SOF for the treatment of HCV-infection in adults.
Selection of doses of SOF for adolescents and younger age groups will target systemic exposures 
similar to those observed in adults at the marketed dose.  SOF is a substrate for efflux drug 
transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). 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 


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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 SOF 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 PK Lead-in which demonstrated comparable SOF and GS-331007 exposures in 
adolescent subjects and in adult subjects in Phase 2/3 population PK analyses.
SOF 200 mg dose is proposed for an evaluation in children (6 to < 12 years of age, weighing ≥ 
17 kg). This proposed dose was supported by scaling of adult exposures based on correlations 
between body weight and clearance capacity (liver volume/size for SOF, and renal capacity for 
GS-331007) {34882} for the expected body weight range in children (6 to < 12 years of age) 
(Figure 1-1).  Additionally, the dose of SOF 200 mg provides comparable dosing to the clinical 
adult dose on mg/kg basis (SOF range: 2.5 to 9.4 mg/kg) in Phase 2/3 program. Based on these 
scaling approaches, the dose SOF 200 mg is expected to achieve mean systemic exposures of 
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 
appropriateness of the dose for this age group and inform dose selection for children < 6 years 
old.


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Figure 1-1. 
Predicted SOF and GS-331007 AUCtau following administration of 
SOF 200 mg to Children (6 to < 12 years of age) 
SOF 200 mg 
5000 
··· ········· ·· ······••···· ················· ········ ······· ······· ·· ··········· ···· 
max 
95th percentile 
1000 
a~ 
Q1 
5th percentile 
.... .......... ... .......... ...... .... .. ... ............. ......... .......... ...... .. 
min 
100 +-~--,-~r--r--r--r--~-,--~~r--r--~~~ 
17 
19 
21 
23 
25 
27 
29 
31 
33 
35 
37 
39 
41 
43 
45 
weight (kg) 
o 5th percentile 
o 01 
6 
Q2 
V 03 
o 95th percentile 
SOF200mg 
~000 
.............. .. .......... ........................................................ 
max 
10000 
...... ....... ......................... ............................................ 
min 
17 
19 
21 
23 
25 
27 
29 
31 
33 
35 
37 
39 
41 
43 
45 
weight (kg) 
o 5th percentile 
o 
01 
ll. 02 
'V 03 
<> 
95th percentile 
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\) 
::r 
Sl) 
(/)Ill 
0~ 
.,.,"-' 
8~ 
co 
:3-g 
co-l\ 
0 :;, 
29 May 2015 


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Age-appropriate formulations of SOF (a smaller, 100 mg strength tablet and a granule
formulation) that offer an important option in the treatment of HCV infection in the pediatric 
population will be evaluated in children below 12 years of age or children who are unable to 
swallow the adult solid-dose 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 standard of care 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. 
SOF has demonstrated efficient inhibition of viral replication in in vitro and in vivo studies. 
Available clinical data indicate SOF has a favorable safety profile and is well tolerated. SOF in 
combination with RBV is likely to provide significant therapeutic benefit in the treatment of 
HCV infection in pediatric patients compared to currently available therapies in the following 
areas:

Expected improved efficacy in a pediatric population compared to the current standard of 
care

Expected improvement in safety and tolerability in relation to either adverse reactions or 
potential medication errors in the pediatric population compared to the current standard of 
care

Improved dosing scheme or method of administration (oral compared to subcutaneously 
administration and reduced treatment duration) leading to improved safety, efficacy,
tolerability, and compliance

Expected availability of a clinically relevant age-appropriate formulation

Different mechanism of action with potential advantage for the pediatric population in terms 
of improved efficacy and safety

Expected improvement in quality of life (e.g., minimized duration of therapy and avoidance 
of IFN-related adverse events that affect patient quality of life such as flulike syndrome and 
depression)
Additionally, the study sponsor will perform an ongoing review of safety data during the conduct 
of the study.


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2. 
OBJECTIVES 
The prima1y objective of the PK Lead-in of this study is: 
Final 
AmendmentS 
• 
To evaluate the steady state phrumacokinetics (PK) and confmn the dose of SOF in 
HCV -infected pediatric subjects 
The secondru·y objective of the PK Lead-in of this study is: 
• 
To evaluate the safety and tolerability of 7 days of dosing of SOF + RBV in HCV -infected 
pediatric subjects 
The primary objectives of the Treatment Phase of this study are: 
• 
To evaluate the safety and tolerability of SOF + RBV for 12 or 24 weeks in HCV infected 
pediatric subjects with GT-2 or GT-3, respectively 
The secondruy objective of the Treatment Phase of this study is: 
• 
To dete1mine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects sepru·ately, as assessed by the proportion of subjects with SVR 
12 weeks after completion of treatment (SVR12) 
• 
To dete1mine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects separately, as assessed by the prop01tion 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 SOF during treatment and after completion 
of treatment 
• 
To evaluate the palatability ofSOF oral granules at Day 1, as applicable. 
• 
To evaluate the effect of growth and development on pediatric subjects during and after 
treatment. 
The explorat01y objective ofthis study is: 
• 
PD 
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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 SOF + 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 SOF dose by analyzing 
PK, safety, and antiviral activity of SOF + RBV through 7 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 GT-2 or GT-3 HCV infection and evidence of HCV RNA ≥1000 IU/mL at study entry will 
be evaluated. Subjects must be treatment naïve to participate in the PK Lead-in Phase. 
Three cohorts of up to 10 subjects each will be sequentially enrolled: 

Cohort 1:  12 to < 18 years old weighing ≥45kg

Cohort 2:  6 to < 12 years old weighing ≥ 17kg and < 45 kg

Cohort 3:  3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive SOF (400 mg adult tablet or 4 x 100 mg 
tablets if determined necessary based on SOF swallowability assessment) + RBV for 7 days with 
intensive PK conducted on Day 7. 
Once Cohort 2 is opened, subjects will received SOF 200 mg (2 X 100 mg tablets or 4 x 50 mg 
tablets if determined necessary based on SOF swallowability assessment) + RBV for 7 days with 
intensive PK conducted on Day 7. Subjects who weigh outside of the ≥17kg and < 45 kg range 
will be excluded
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 7 of PK Lead-in.  They will continue dosing with 
SOF + RBV 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.


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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 
GT-2 or GT-3 infection and evidence of 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:

GT-2 subjects: SOF + RBV for 12 weeks

GT-3 subjects: SOF + RBV for 24 weeks
The study will enroll both treatment-naïve and treatment–experienced pediatric subjects, with up 
to 20 subjects allowed to be treatment experienced. Approximately 100 total subjects, including 
subjects from the PK Lead-in Phase, will be enrolled in the Treatment Phase as follows:

Group 1: Approximately 50 adolescent subjects (12 to < 18 years of age)

Group 2: Approximately 50 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 standard-of-care (SOC) therapy with their healthcare provider.


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Figure 3-1.
Study Schema
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 7.
Subjects (up to 10 subjects per cohort) enrolled in the PK Lead-in Phase will participate in an 
intensive PK evaluation on Day 7. Subjects will be administered a dosing diary with 
instructions.  
Following completion of the Day 7 intensive PK visit, subjects will then return for scheduled 
study visits outlined in the Treatment Phase and continue dosing with SOF + RBV 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.


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3.2.2.
Treatment Phase
Screening assessments will be completed within 28 days of the Day 1 visit. For subjects 
continuing from the PK Lead-in Phase, screening, Day 1 and Week 1 of the Treatment Phase will 
not be required.

GT-2 Subjects: Study visits for GT-2 subjects will occur at screening, Day 1, and the end of
weeks 1, 2, 4, 8, and 12. 

GT-3 Subjects: Study visits for GT-3 subjects will occur at screening, Day 1, and the end of
weeks 1, 2, 4, 8, 12, 16, 20, and 24. 
All Treatment Phase 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).


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3.4. 
Treatment Discontinuations Criteria 
Final 
Amendment S 
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 defmed in Section 7 of the protocol, 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 imp01tant to detennine 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, regulat01y agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC). 
3.5. 
Discontinuations 
Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an Early Tennination visit as described in the Section 6.4.7. 
Subjects who pennanently discontinue all study dtugs for any reason including safety and/or 
tolerability concems prior to completion of the assigned dosing period will be followed 
according to the post-u·eatment 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 evety 6 months for the 
first 2 years followed by evety 12 months for assessments of growth, quality of life, and 
long-tetm viral suppression (if applicable) in a separate protocol (GS-US-334-1113). This 
follow-up will continue for 5 years. 
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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.
Subjects with known or suspected study drug non-adherence will not be considered to meet the 
definition of virologic breakthrough, relapse or non-responder. 
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
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.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 100 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 (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 
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 Baseline/Day 1.
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
8. Infection with HCV GT-2 or GT-3 as determined at Screening
9. HCV RNA ≥1000 IU/mL at Screening
10. Adequate hematologic function (absolute neutrophil count 1,500/mm3; hemoglobin 
12 g/dL for males and 11g/dL for females.)
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


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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. 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)
4. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)
5. -fetoprotein 50 ng/mL
6. Serum creatinine > 1.5 mg/dL
7. Estimated glomerular filtration rate 90 mL/min/1.73m2, as calculated by the Schwartz 
Formula
8. Evidence of hepatocellular carcinoma (HCC) or other malignancy (with the exception of 
certain resolved skin cancers)
9. Co-infection with HIV, acute HAV, or HBV
10. Significant cardiovascular, pulmonary or neurological disease
11. Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of 
orally administered medications
12. History of solid organ or bone marrow transplantation
13. Chronic daily non-steroidal anti-inflammatory drug therapy
14. Systemic corticosteroid use for 5 days (pulmonary/nasal administration is permitted)
15. Investigational agents taken within the past 28 days (except with the expressed approval of 
the Sponsor)
16. Clinically-relevant alcohol or drug abuse within 12 months of screening.  A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator
17. Known hypersensitivity to the study drugs, the metabolites or formulation excipients
18. 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
19. Use of any prohibited concomitant medications as described in Section 5.6 within 28 days of 
the Day 1 visit
20. 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 enrolled or has not required medication in the last 12 months may be 
included.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
Not applicable.
5.2.
Sofosbuvir
5.2.1.
Description and Handling
5.2.1.1.
Formulations
SOF tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets debossed with “GSI” on 
one side and “7977” on the other side. In addition to the active ingredient, SOF tablets contain 
the following inactive ingredients: mannitol, microcrystalline cellulose, croscarmellose sodium, 
colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, 
talc, and yellow iron oxide.
Placebo tablets for Swallowability Assessment, 400 mg, are yellow, capsule-shaped, film-coated 
tablets debossed with “GSI” on one side and “7977” on the other side. The tablets contain 
mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, and yellow iron oxide.
SOF tablets, 100 mg, are yellow, round, film-coated, plain-faced tablets. In addition to the active 
ingredient, SOF tablets contain the following inactive ingredients: mannitol, microcrystalline 
cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl
alcohol, titanium dioxide, macrogol, talc, and yellow iron oxide.
Placebo tablets for Swallowability Assessment, 100 mg, are yellow, round, film-coated, 
plain-faced tablets. The tablets contain lactose monohydrate, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, 
and yellow iron oxide.
SOF oral granules, 50 mg, are encapsulated in a two-piece, clear, hard gelatin capsule. In 
addition to the active ingredient, SOF capsules contain the following inactive ingredients: 
gelatin, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl 
cellulose, sodium stearyl fumarate, colloidal silicon dioxide, hypromellose, macrogol, amino 
methacrylate copolymer, stearic acid, sodium lauryl sulfate, and talc.
5.2.1.2.
Packaging and Labeling
SOF 400 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains either 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.


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Placebo tablets for Swallowability Assessment, 400 mg, are packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 30 tablets and a silica gel desiccant canister or 
sachet and polyester packing material. Each bottle is enclosed with a white, continuous thread, 
child-resistant screw cap with an induction-sealed, aluminum-faced liner.
SOF 100 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 28 tablets and a 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 for Swallowability Assessment, 100 mg, are packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 28 tablets and polyester packing material. 
Each bottle is enclosed with a white, continuous thread, child-resistant screw cap with an 
induction-sealed, aluminum-faced liner.
SOF capsules, 50 mg, which contain SOF oral granules, are packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 28 capsules and is enclosed with a white, 
continuous thread, child-resistant polypropylene screw cap with an induction-sealed and 
aluminum faced liner.
SOF bottles to be distributed to centers in the US, EU and the rest of the countries will 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.
Placebo tablets for Swallowability Assessment, 100 mg and 400 mg, bottles 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.
5.2.2.
Storage and Handling
SOF tablet, 100 mg and 400 mg, and capsule (containing granules) bottles should be stored at 
controlled room temperature until required for administration. Controlled room temperature is 
defined as 25 C (77 F); excursions are permitted between 15 C and 30 C (59 F to 86 F).
Placebo tablets for Swallowability Assessment, 100 mg and 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).  
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling SOF.


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Sufficient quantities of SOF tablets, SOF capsules containing granules 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 SOF
PK Lead-in: (Cohort 1) SOF 400 mg tablets will be administered once daily along with RBV 
weight-based dosing. Subjects determined unable to swallow the placebo for the 400 mg SOF 
tablet (by SOF Placebo swallowability assessment at Screening up to Day 1) will be re-assigned 
to 4 x 100 mg tablets daily.  Subjects unable to swallow tablets will be re-assigned to 8 x 50 mg 
capsules containing granules.  Subjects who weigh < 45 kg will be excluded.  
PK Lead-in:  (Cohort 2) SOF 200mg (2 X 100 mg tablets) will be administered once daily along 
with RBV weight-based dosing.  Subjects determined unable to swallow the placebo for the 
100 mg SOF tablet (by SOF Placebo swallowability assessment at Screening up to Day 1) will be 
re-assigned to 4 X 50 mg capsules containing granules.  Subjects who weigh outside of the 
≥17kg and < 45 kg range will be excluded
Intensive PK and safety results from the PK Lead-In of each Cohort will be reviewed to confirm 
the appropriateness of the evaluated SOF 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.  
5.3.
Ribavirin 
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.


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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).
5.3.2.
Dosage and Administration of RBV
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 SOF. The evening dose of RBV will be 
taken with food.
RBV will be supplied by Gilead Sciences for all subjects.


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5.4.
Co-administration of SOF and RBV
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:

SOF

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 medication at the correct time, it may be taken later in the day; 
however, no more than 400 mg dose of SOF 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.  
5.5.
Study Drug Compliance
Subjects will be instructed to return any unused SOF and RBV in the original container on Day 7 
(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 of Screening, up to and including the date of the 
visit four weeks after discontinuation of study treatment, need to be recorded in the source 
documents and eCRFs. All concomitant medications should be recorded in the source 
documents.
The following medications are prohibited from 28 days prior to the Day 1 visit through the end 
of treatment:

Erythropoiesis-stimulating agents (ESAs); including but not limited to Procrit®, Aranesp®
and Epogen®

Granulocyte colony stimulating factor (GCSF)

Chronic systemic immunosuppressant’s including corticosteroids (prednisone equivalent of 
> 10 mg/day for > 2 weeks), azathioprine, or monoclonal antibodies (e.g., infliximab)

Investigational agents or devices for any indication


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
Drugs disallowed per prescribing information of REBETOL®

Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters i.e. P-gp) with study drug(s) may result in pharmacokinetic interactions resulting 
in decreases in exposure of study drug(s). Representative medications which are excluded 
from 21 days prior to Day 1 through the end of treatment are listed below:
Drug
Agents Disallowed
Concomitant use with study drug may 
potentially result in changes of study 
drug concentration as listed below
Anticonvulsants
Phenobarbital, Phenytoin, Carbamazepine, 
Oxcarbazepine
Decrease in concentration of study drug
Antimycobacterials
Rifampin, rifabutine, rifapentine
Decrease in concentration of study drug
Herbal/Natural 
Supplements
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
Decrease in concentration of study drug
Medications for disease conditions excluded from the protocol (e.g., HIV-1 infection, active 
cancer, transplantation) are not listed under this Concomitant Medication section and are 
disallowed in the study.


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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 (i.e., height of parents, if known)
Liver biopsy results (if available)

Complete physical examination 

Vital signs (temperature, blood pressure, pulse, respiratory rate), body weight and height


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
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 SOF swallowability assessment (for subjects administered SOF in tablet form only)
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for the Day 1 visit assessments.


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6.3. 
PK Lead-in: Treatment Assessments 
6.3.1. 
Day l 
Final 
Amendment S 
After confnmation of eligibility has been evaluated, the following tests and procedmes must be 
completed prior to emollment and dosing/dispensing on Day 1: 
• 
Perf01m complete physical examination 
• 
Tanner Pubertal Stage Assessment 
• 
Vital signs, including body weight and height measmements 
• 
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 
prui icipants (Subjects 12 to < 18 yeru·s of age and subjects < 12 years of age at the discretion 
of the Investigator based on subject's pube1i al status) 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (ru·chive) 
_ 
PD 
• 
Obtain mine samples for the following procedmes: 
-
Urinalysis 
-
~-hCG pregnancy test for females of childberu·ing potential only 
• 
Subject completes quality of life smvey: Subject is to review questionnaire with a 
parent/guardian and write/mru·k answers directly onto the questionnaire. 
CONFIDENTIAL 
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6.3.1.1.
Drug Administration

Dispense study drugs as directed by the IWRS

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 all study drugs

Perform SOF swallowability assessment (for subjects administered SOF in tablet form only if 
not previously completed at screening).  Observe the subject taking the first dose of study 
drugs (with 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 parent/guardian

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

Review subject dosing diary
6.3.3.
Day 7 – Intensive PK 
The Day 7 Intensive PK visit should occur on the protocol-specified visit date based on the 
Day 1 visit. For the purposes of scheduling, the Day 7 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).


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Subjects should come in a fasted state for the Day 7 Intensive PK visit (i.e., no food or drink 
except water at least 8 hours prior to the Day 7 Intensive PK visit). Subjects and/or 
parents/guardians should be instructed that the Day 7 dose of SOF+RBV must not be taken until 
the evaluations listed below are completed. 
If the subject has already dosed prior to the Day 7 clinic visit or is not in a fasted state, the Day 7
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 8, 9, or 10) 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 7 visit, the Day 7 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 7 intensive PK visit no sooner than 3 days following compliant dosing and no later than 
Day 11 (i.e., return on Day 10 or Day 11).  If dosing non-compliance is due to an AE, 
consultation with the Gilead Medical Monitor is required regarding the potential of rescheduling 
the Day 7 intensive PK visit.
In both scenarios described above, the subject and/or parents/guardians should be reminded not 
to take the SOF + RBV prior to arriving at the clinic on the day of the re-scheduled intensive PK 
visit. All Day 7 intensive PK assessments listed below should be completed when the subject 
returns.
The following evaluations are to be completed at the Day 7 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 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 
Coagulation tests


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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 
SOF + RBV per dosing requirements.
Post-dose blood samples will be collected as follows: 

For Cohorts 1 and 2:  0.5, 1, 2, 3, 4, 8, and 12 hours post-dose (with predose also 
serving as t= 24).

For Cohort 3 only: 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 7 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


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AmendmentS 
• 
Pregnancy prevention cmmseling including partner pregnancy prevention for male 
pmi icipants (Subjects 12 to < 18 years of age and subjects <12 years of age at the discretion 
of the Investigator based on subject's pube1ial status). 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (m·chive) 
_ 
PD 
• 
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 
pm·ent/gum·dian and write/mm·k answers directly onto the questionnaire. 
• 
Perf01m SOF swallowability assessment (for subjects administered SOF in tablet f01m only if 
not previously completed at screening). 
• 
For subjects receiving SOF oral granules, following dmg adminisu·ation assess palatability 
at Day 1, as applicable 
6.4.1.1. 
Dmg Adminisu·ation 
• 
Dispense study mugs as directed by the IWRS 
• 
Instiuct the subject on the appropriate RBV dose after weight-based dosage is calculated 
using Day 1 weight 
• 
Instiuct the subject on the packaging, storage and adminisu·ation of all study mugs 
• 
Observe the subject taking the first dose of study dmgs (with food) and record the time of 
first dose 
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6.4.2.
Weeks 1 and 2 (3 days)
Subjects who participated in the PK Lead-in will start study visits in 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

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 


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
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 drugs at these visits)

Dispense study drugs as directed by the IWRS
6.4.4.
Week 12 (3 days)

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 (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. (GT-2 Subjects 
only)

Review medication compliance with subject and/or parent/guardian.


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
Dispense study drugs as directed by the IWRS (GT-3 Subjects Only)

GT-2 Subjects should return all bottles and kits at the Week 12 Visit
6.4.5.
Week 16 and 20 (3 days) – GT-3 Subjects 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 drugs at these visits)

Dispense study drugs as directed by the IWRS
6.4.6.
Week 24 (3 days) – GT-3 Subjects 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)


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
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.

GT-3 Subjects should return all bottles and kits at the Week 24 Visit
6.4.7.
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.
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 (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)


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
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 kits at the Early Termination Visit
All subjects should complete Post-Treatment assessments after early termination, as described in 
Section 6.5.
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


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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 (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) 
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 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

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 (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)


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
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)

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.
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 
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.


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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 right 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: Hemoglobin A1c (HbA1c), TSH (reflex Free T4), Alfa fetoprotein (AFP), 
Alpha-1 anti-trypsin (AAT), Urine drug screen (for amphetamines, cocaine, methadone, opiates).
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.
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.  Perform Tanner Pubertal Stage assessment 
for subjects until Tanner Stage 5 has been reached. Date of first menses will be documented.  
6.6.5.
Height & Weight Measurement 
Height and weight measurement will be collected at all study visits.  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.


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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 the bone age from x-ray.
6.6.7.
Swallowability Assessment
A SOF 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 for the 400 mg SOF 
tablet. This will confirm the swallowability of the 400 mg tablet size. If, a subject is unable to 
swallow the 400 mg tablet size he/she will repeat the assessment with a placebo for the 100 mg 
SOF tablet.    If unable to take the 100 mg SOF tablet, the subject will be dispensed the SOF oral 
granule formulation.
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.
6.6.9.
Body Mass Index (BMI)
BMI is calculated by the following equation.
BMI = weight (pounds) 703           or            weight in kilograms
   (height in inches)2                                (height in meters)2
6.6.10.
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)]


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6.6.11.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each visit for viral sequence analysis. Unused 
samples may be archived.
6.6.12.
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. If required by 
local regulations, additional pregnancy tests beyond 6 months may be added. In the event of a 
positive urine pregnancy result, subjects will be instructed to stop study drugs immediately and 
return to the clinic as soon as possible for a serum pregnancy test.
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.
6.6.13.
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 (Week 12 for GT-2 subjects, Week 24 for GT-3 subjects, or at 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/guardian) for the current age group at the time of survey 
administration.  
6.6.14.
SOF Granule Palatability Assessment
A palatability assessment for the SOF granules will be performed in Treatment Phase of the 
study at Day 1 to subjects receiving the granules.


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7.
TOXICITY MANAGEMENT
7.1.
Modification of Dose/Schedule Due to Toxicity
Dose reduction of RBV 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/day 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
Dose reduction in pediatric patients 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 SOF
The Gilead Medical Monitor should be consulted prior to dose discontinuation of SOF unless the 
investigator believes that immediate action is warranted to ensure the continued safety of the 
subject.
Administration of SOF may be discontinued due to a clinical or laboratory event. There is no 
option for SOF dose reduction. If SOF is stopped for toxicity, it should not be restarted, RBV 
should be stopped and the subject should complete an Early Termination Visit.
Subjects who meet any of the following laboratory criteria must stop treatment with SOF and 
RBV:

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 

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event or lab abnormality assessed as related to treatment with SOF


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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)

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

Persistent or significant disability/incapacity


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
A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is 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 subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the 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.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting.


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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 
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.
All SAEs, regardless of causal relationship, that occur 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 
from screening onwards.
All AEs, regardless of causal relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP 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 post-treatment follow up 
period.
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 this time and the event is 
deemed relevant to the use of IMP, he/she should promptly document and report the event 
directly to Gilead DSPH. Gilead DSPH contact information is as follows: Email: 
Safety_FC@gilead.com or Fax: +1 (650) 522-5477.  All AEs and SAEs will be recorded in the 
CRF/eCRF database within the timelines outlined in the CRF/eCRF completion guideline.


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Serious Adverse Event Paper Repmiing Process 
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All SAEs will be recorded on the serious adverse event repmi fmm and submitted by 
emailing or faxing the repmi fmm within 24 hours of the investigator's knowledge of the 
event to the attention of Gilead DSPH or to the designated CRO Phannacovigilance 
Representative. 
Electronic Serious Adverse Event (eSAE) Repmiing Process 
• 
All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit the SAE 
infmm ation 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 infmm ation electr·onically, i.e., the 
eCRF database is not fimctioning, record the SAE on the paper serious adverse event 
repmiing fmm and submit within 24 hours as described above. 
• 
As soon as it is possible to do so, any SAE repmi ed via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repmied via a paper fonn because the eCRF database has been locked, no 
fmiher action is necessaty. 
Conta.ct infonnation is as follows: 
Gilead Sciences, Dmg Safety and 
Public Health: 
PRA Intemational 
Phrum acovigilance Representative: 
Klinera Phrum acovigilance 
Representative (India only): 
Gilead Sciences, Medical Monitor: 
CONFIDENTIAL 
Fax: 
E-mail: 
Fax: 
E-mail: 
Name: 
Phone: 
Fax: 
E-mail: 
Name: 
Telephone: 
Mobile: 
Fax: 
E-mail: 
Page 63 
+ 1 650 522-5477 
Safety_ FC@gilead.com 
+1 888 772 6919 (Nmih America); 
+49 621 8782 181 (Rest of World 
CHOSafety@praintl.com 
Dr. Vikrrun Vora 
+91 22 25004573 (India) 
+91 22 25004588 
safetyrepmiing@klinera.com 
Bittoo Kanwru·, MD 
FPD 
l PD 
PD 
t-'U 
29 May 2015 


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
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.
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. 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 associate 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.


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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.  
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 the designated CRO Pharmacovigilance Representative using 
the pregnancy report form within 24 hours of becoming aware of the pregnancy.
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 8.1.1 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 CRO Pharmacovigilance Representative 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 drugs 
must also be reported and relevant information should be submitted to the CRO 
Pharmacovigilance Representative 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. 


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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 the designated CRO Pharmacovigilance Representative within 24 hours of the 
investigator becoming aware of the situation. These reports must consist of situations that 
involve study IMP and/or Gilead concomitant medications but do not apply to non-Gilead 
concomitant medications. 
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of contraindicated medications 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 SOF in 
HCV-infected pediatric subjects
The secondary objective of PK Lead-in of this study is:

To evaluate the safety and tolerability of 7 days of dosing of SOF + RBV in HCV-infected
pediatric subjects
The primary objective of Treatment Phase of this study is:

To evaluate the safety and tolerability of SOF + RBV for 12 or 24 weeks in HCV-infected
pediatric subjects with GT-2 or GT-3, respectively
The secondary objectives of Treatment Phase of this study are:

To determine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects separately, as assessed by the proportion of subjects with SVR 
12 weeks after completion of treatment (SVR12)

To determine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects separately, 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 SOF during treatment and after completion 
of treatment

To evaluate the palatability of SOF oral granules at Day 1, as applicable.

To evaluate the effect of growth and development of pediatric subjects during and after 
treatment.
The exploratory objective of this study is:


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9.1.2. 
Primary Endpoints 
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AmendmentS 
For the PK Lead-in Phase, the appropriateness of the SOF dose will be assessed by evaluating 
the steady-state PK of the SOF and its metabolite GS-331007. The primaty endpoint is AUCtau 
of GS-331 007. Additional steady-state PK parameters of SOF and GS-331 007 (e.g., AUC1ast' 
Cmax, Tmax, Clast, T1ast, Ctau, 'Az, CLIF, VzJF and tv, and AUCtau of SOF) will be estimated and 
summarized as described in Section 9.4. 
For Treatment Phase, the primary safety endpoint is any AE leading to petmanent 
discontinuation of study dmg (s). The primruy efficacy endpoint is SVR12. 
9.1.3. 
Secondary Endpoints 
For the PK Lead-in Phase, the secondaty endpoints include antiviral activity measmements, 
including assessment of HCV RNA. AEs leading to petmanent discontinuation of study dmg(s) 
will be evaluated as a secondaty safety endpoint. 
For Treatment Phase, secondaty efficacy endpoints include SVR4, SVR24, breakthrough and 
relapse. Additional efficacy evaluations may include HCV RNA change from Day 1; AL T 
n01malization; viral kinetic pm·ameters, and palatability of SOF oral granules. Secondaty safety 
endpoints of growth and development measmements will be assessed (e.g. height, weight, and 
Tanner Stage Assessment). 
9.2. 
Analysis Conventions 
All individual subject data will be listed as measmed. All statistical summat1es and analyses will 
be perfonned using SAS® softwm·e (SAS Institute, Caty, North Cm·olina, USA). 
9.2.1. 
Analysis Sets 
9.2.1.1. 
Phatmacokinetics (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 dmg and for whom at least one non-missing PK concentration data, dming the intensive 
satnpling period, reported by PK lab. The PK analysis set will be used for detailed 
phatmacokinetic analysis of SOF, and metabolites. 
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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 SOF or GS-331007 are available. 
The PK analysis set will be used for analysis of general PK and single sample plasma
concentrations.
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. 


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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.
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 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 SOF and metabolites (GS-566500 and GS-331007) 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 


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summarized for 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 the exposures of GS-331007 achieved in pediatric subjects of this study are similar 
to the exposures observed in adult subjects, GS-331007 exposure data from this study will be 
compared to the integrated adult data by carrying out an analysis of variance (ANOVA) for 
log-transformed AUCtau of GS-331007 as the primary endpoint while Cmax of GS-331007 as 
secondary endpoints. 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%. Individual 
patient management will be performed by maintaining exposures comparable to adults.  AUCtau
less than the 2.5th percentile of adult values may require dose adjustment as appropriate.
The effect of age and SOF dose on PK (SOF and GS-331007) will be assessed.
9.5.
Safety Analysis
Safety analysis will be performed for PK Lead-in and overall study Treatment Phaserespectively. 
Safety data will be summarized by age group, by GT, by overall and by age group and GT.
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.
Palatability of SOF oral granules
Palatability of SOF oral granules will be summarized using descriptive statistics by appropriate 
age group, by genotype, by overall and by age group and genotype.


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9.5.3.
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,

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.
9.5.4.
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 


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data are missing, then any graded abn01mality (i.e., at least a Grade 1) will be considered 
treatment emergent. 
Alllaborat01y abn01malities will be included in the listings of laboratory data. 
9.5.5. 
Other Safety Evaluations 
9.5.5.1. 
Tanner Pube1ial 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. 
9.6. 
Efficacy Analysis 
Efficacy will be evaluated using scheduled assessments of HCV RNA perf01med using CO BAS® 
TaqMan® HCV Test, v2.0 for use with the High Pure System. 
Efficacy analysis will be perf01med by age group, by GT, by overall, and by age group and GT 
for Treatment Phase. 
All continuous endpoints will be summarized using an 8-number summruy (n, mean, standru·d 
deviation, median, Q1, Q3, minimum, maximum). All categorical endpoints will be summru·ized 
by number and percentage of subjects who meet the endpoint defmition. 
9.6.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
treatment) in the F AS population. Point estimate and its 95% confidence interval will be 
provided. 
9.6.2. 
Secondary Efficacy Analysis 
The prima1y efficacy endpoint of SVR12 will be compru·ed with historical SVR12 rate of 80% 
from pegylated interferon + ribavirin for pediatric GT2 and 3 subjects {20280}, using two-sided 
exact one-sample binomial test at the 0.05 significance level. 
The proportion of subjects with HCV RNA below LLOQ over time (including SVR endpoints 
SVR4 and SVR24) will be presented in Treatment Phase in tabular and graphical fonn. 
Descriptive summru·ies and listings will be provided for additional efficacy evaluations including 
sennn HCV RNA actual values and change from baseline, prop01iion of subjects with virologic 
failmes, and other endpoints of interest including AL T n01malization. 
PD 
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Subgroup Analysis 
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Subgroup analysis on SVR12 will be perf01m ed by treatment experience (treatment-naive vs. 
experienced), and by treatment experience and 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 extemal multidisciplinruy data monitoring committee (DMC) will review the progress of the 
study and perf01m interim reviews of safety and provide recommendation to Gilead about 
whether the nature, frequency, and severity of adverse effects associated with study u·eatment 
wruTant the eru·ly te1mination of the study in the best interests of the pruiicipants, whether the 
study should continue as planned, or the study should continue with modifications. 
The DMC's specific activities will be defmed by a mutually agreed chruier, which will define the 
DMC's membership, conduct and meeting schedule. 
While the DMC will be asked to advise Gilead regru·ding future conduct of the study, including 
possible eru·ly study tennination, Gilead retains fmal decision-making authority on all aspects of 
the study. 
9.9. 
Sample Size 
With approximately 50 subjects enrolled into each age group of Treatment Phase, a two-sided 
95.0% confidence interval of the SVR12 rate will extend at most 11.1% in both directions from 
the observed SVR12 rate, assuming the expected SVR12 rate is 80%. In addition, a saiUple size 
of 100 subjects will provide over 80% power to detect a 11% improvement in SVR12 rate from 
80% to 91% using two-sided one-sample binomial test at significance level of 0.05. 
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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.


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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);

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.


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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 
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.


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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 competent 
authority, IRB or IEC in accordance with local requirements. Approval must be obtained before 
changes can be implemented.
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.


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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.
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
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Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. 
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McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et 
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COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
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Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
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Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus 
infection in Europe. J Hepatol 2008;48 (1):148-62.
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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.
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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 
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Bortolotti F, Verucchi G, Camma C, Cabibbo G, Zancan L, Indolfi G, et al. Long-
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20280
Schwarz KB, Gonzalez-Peralta RP, Murray KF, Molleston JP, Haber BA, Jonas 
MM, et al. The combination of ribavirin and peginterferon is superior to 
peginterferon and placebo for children and adolescents with chronic hepatitis C.
Gastroenterology 2011;140 (2):450-8 e1.


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Gilead Sciences, Inc
Amendment 5
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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.
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.
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Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. 
Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J 
Med 2013;368 (1):34-44.
24713
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, 
Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients 
without treatment options. N Engl J Med 2013;368 (20):1867-77.
24715
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et 
al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J 
Med 2013;368 (20):1878-87.
27503
Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US 
Prescribing Information.  Foster City, CA. December 2013.  2013:
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.
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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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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 5
CONFIDENTIAL
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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


Sofosbuvir 
Protocol GS-US-334-1112 
Final 
Gilead Sciences, Inc 
Amendment 5 
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, Single-Arm Study to Investigate the 
Safety and Efficacy of Sofosbuvir + Ribavirin in Adolescents and Children with Genotype 2 
or 3 Chronic HCV Infection 
GS-US-334-1112, Protocol Amendment 5, 29 May 2015 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PPD 
Bittoo Kanwar, MD (Printed) 
Medical Monitor 
zq 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
-
CONFIDENTIAL 
Page 84 
29 May 2015 


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Final
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Amendment 5
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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 7
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
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
SOF Swallowability Assessment
X
Xh
Quality of Life Survey
Xi
Review of Study 
Medication Compliance
X
X
Study Drug Dispensingb
X


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Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 7
(+ 3 days)
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X
X
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
Subject Dosing Diary
X
X
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
Palatability Assessment of Oral GranulesJ
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, body weight, and height
PPD


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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 drugs on Day 7 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 8, 
and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 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 (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).
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
Palatability of SOF oral granules will be assessed at Day 1, applicable.
PPD


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 5
CONFIDENTIAL
Page 88
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Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningc
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12g
16g
20g
24g
Early 
Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Complete Physical Examination
X
X
X
X
X
Symptom-Directed Physical Examination
X
X
X
X
X
X
Tanner Pubertal Stage Assessment
X
X
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 Counselingh
X
X
X
X
SOF Swallowability Assessment
X
Xj
Quality of Life Surveye
X
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
X
X
X
Study Drug Dispensingb
X
X
X
Xi
Xi
Xi
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
Viral Sequencing d
X
X
X
X
X
X
X
X
X
X


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Final
Gilead Sciences, Inc
Amendment 5
CONFIDENTIAL
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Screeningc
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12g
16g
20g
24g
Early 
Termination
Serum or Urine Pregnancy Testing
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
X
X
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
Palatability Assessment of Oral Granulesk
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, 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 at Day 1, Week 12 (only GT-2 subjects), Week 24 (only GT-3 subjects) and Early Termination 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
GT-2 subjects will complete through the Week 12 visit; GT-3 subjects will complete through the Week 24 visit. 
h
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).
i
Study Drug Dispensing at the Week 12, Week 16, and Week 20 visit for GT-3 subjects only
j
Swallowability can occur at Day 1 if not completed during screening.
k
Palatability of SOF oral granules will be assessed at Day 1, applicable.
PPD
PPD


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Protocol GS-US-334-1112
Final
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Amendment 5
CONFIDENTIAL
Page 90
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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
Xd
Xd
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment 
X
X
Bone Age Assessment
X
Pregnancy Prevention Counseling e
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Testc
X
X
X
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
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.
d
At Post Treatment Week 12 and 24, only SAEs will be captured
e
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).


Sofosbuvir
Protocol GS-US-334-1112
Final
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Amendment 5
CONFIDENTIAL
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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


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Protocol GS-US-334-1112
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Amendment 5
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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
—
—


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Protocol GS-US-334-1112
Final
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Amendment 5
CONFIDENTIAL
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29 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.  


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


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Protocol GS-US-334-1112
Final
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Amendment 5
CONFIDENTIAL
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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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 5
CONFIDENTIAL
Page 96
29 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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 5
CONFIDENTIAL
Page 97
29 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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 5
CONFIDENTIAL
Page 98
29 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.  


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 5
CONFIDENTIAL
Page 99
29 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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 5
CONFIDENTIAL
Page 100
29 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 
(e.g., 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 
(e.g., 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 
(e.g., tamponade) OR Urgent 
intervention indicated


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 5
CONFIDENTIAL
Page 101
29 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, e.g., 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, e.g., Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated 
(e.g., anticoagulation, lysis 
filter, invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (e.g., 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (e.g., 
pulmonary embolism, life-
threatening thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure,
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 5
CONFIDENTIAL
Page 102
29 May 2015
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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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 5
CONFIDENTIAL
Page 103
29 May 2015
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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 5
CONFIDENTIAL
Page 104
29 May 2015
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening consequences 
OR Aggressive intervention 
indicated [e.g., tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (e.g., 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 
(e.g., sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(e.g., 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 
(e.g., 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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 5
CONFIDENTIAL
Page 105
29 May 2015
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 (e.g., aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (e.g., 
IV fluids)
Life-threatening consequences 
(e.g., hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(e.g., sepsis, circulatory 
failure, hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(e.g., perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(e.g., hypotensive shock)


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 5
CONFIDENTIAL
Page 106
29 May 2015
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood (e.g., 
agitation, anxiety, 
depression, mania, 
psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities 
Alteration causing greater than 
minimal interference with 
usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional activities 
Behavior potentially harmful 
to self or others (e.g., 
suicidal/homicidal ideation or 
attempt, acute psychosis) OR 
Causing inability to perform 
basic self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no 
or minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities 
Disabling ataxia causing 
inability to perform basic self-
care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater than 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 5
CONFIDENTIAL
Page 107
29 May 2015
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate 
for the setting 
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting 
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or
other neurologic function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic self-
care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual 
social & functional activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social &
functional activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 5
CONFIDENTIAL
Page 108
29 May 2015
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (e.g., 
status epilepticus), or difficult 
to control (e.g., refractory 
epilepsy)
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase 
from Previous Level of 
Control to Any of These 
Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (e.g., 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (e.g., 
status epilepticus), or difficult 
to control (e.g., refractory 
epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 5–20 
minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated 
with a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic self-
care functions


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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 [e.g., 
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 (e.g., upper 
arm/thigh)
Erythema OR Induration 
OR Edema involving 
50% surface area of the 
extremity segment (e.g., 
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 (e.g., 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 
(e.g., 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 
(e.g., 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 
(e.g., myxedema coma)
Lipoatrophy (e.g., 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 (e.g., stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing life-
threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic antiμbial 
treatment indicated AND 
Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening 
consequences (e.g., septic 
shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc


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Appendix 4.
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}


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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 sofosbuvir demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of sofosbuvir 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:

Complete abstinence from intercourse. Abstinence is an acceptable method of contraception 
only when it is in line with 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 the last dose of RBV:
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent
tubal sterilization
vasectomy in male partner


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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 Baseline 
until 7 months after the last dose of 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.
Male subjects must agree to refrain from sperm donation for at least 7 months after the last dose 
of 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. 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.

Prot_002.pdf: 
Study Title: 
Sponsor: 
IND No.: 
EudraCT Number: 
Indication: 
Protocol ID: 
Gilead Sciences Medical 
Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Aim 
Study to Investigate the Safety and Efficacy of 
Sofosbuvir + Ribavirin in Adolescents and Children with 
Genotype 2 or 3 Chronic HCV Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
106739 
TBD 
Hepatitis C Vims Infection 
GS-US-334-1112 
Name: 
Telephone: 
Mobile: 
Fax: 
E-mail: 
Original: 
Alnendment 1: 
Alnendment 2: 
Luisa Stamm, MD, PhD 
~:~ 
PD 
t-'U 
20 December 2013 
10 Febmmy 2014 
14 Mm·ch 2014 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pmi iculm·ly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Institutional Review Board or Independent Ethics Committee. The inf01mation is 
only to be used by you in connection with authorized clinical studies of the investigational 
dmg described in the protocol. You will not disclose any of the infonnation to others without 
written authorization from Gilead Sciences, Inc., except to the extent necessmy to obtain 
inf01med consent from those persons to whom the dmg may be administered. 


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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 ............................................................16
1.
INTRODUCTION .......................................................................................................................................19
1.1.
Background.....................................................................................................................................19
1.2.
Sofosbuvir.......................................................................................................................................20
1.3.
Ribavirin (RBV)..............................................................................................................................20
1.4.
Rationale for the Current Study ......................................................................................................21
1.5.
Rationale for Dose Selection of SOF ..............................................................................................21
1.6.
Overall Risk/Benefit Assessment....................................................................................................22
2.
OBJECTIVES..............................................................................................................................................23
3.
STUDY DESIGN ........................................................................................................................................24
3.1.
Treatment Plan and Regimen..........................................................................................................24
3.1.1.
PK Lead-in ....................................................................................................................24
3.1.2.
Treatment Phase............................................................................................................24
3.2.
Visit Schedule .................................................................................................................................26
3.2.1.
PK Lead-in ....................................................................................................................26
3.2.2.
Treatment Phase............................................................................................................27
3.3.
Virologic Response-Based Stopping Criteria..................................................................................27
3.4.
Treatment Discontinuations Criteria...............................................................................................28
3.5.
Discontinuations .............................................................................................................................28
3.6.
Pharmacogenomic Substudy...........................................................................................................28
3.7.
Long-Term Follow-Up....................................................................................................................28
3.8.
Breakthrough Futility Assessment ..................................................................................................29
4.
SUBJECT POPULATION...........................................................................................................................30
4.1.
Number of Subjects and Subject Selection .....................................................................................30
4.2.
Inclusion Criteria ............................................................................................................................30
4.3.
Exclusion Criteria ...........................................................................................................................31
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ....................................................................................33
5.1.
Randomization and Blinding...........................................................................................................33
5.2.
Sofosbuvir.......................................................................................................................................33
5.2.1.
Description and Handling..............................................................................................33
5.2.2.
Storage and Handling....................................................................................................34
5.2.3.
Dosage and Administration of SOF ..............................................................................35
5.3.
Ribavirin .........................................................................................................................................35
5.3.1.
Description and Handling of RBV................................................................................35
5.3.2.
Dosage and Administration of RBV .............................................................................36
5.4.
Co-administration of SOF and RBV...............................................................................................37
5.5.
Study Drug Compliance..................................................................................................................37
5.6.
Prior and Concomitant Medications................................................................................................37
6.
STUDY PROCEDURES .............................................................................................................................39
6.1.
Subject Enrollment..........................................................................................................................39


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6.2.
Screening Assessments ...................................................................................................................39
6.2.1.
Screening Visit (Day –28 to Day 0)..............................................................................39
6.3.
PK Lead-in: Treatment Assessments ..............................................................................................41
6.3.1.
Day 1 Visit ....................................................................................................................41
6.3.2.
Day 3.............................................................................................................................42
6.3.3.
Day 7 – Intensive PK ....................................................................................................42
6.4.
Treatment Phase: Treatment Assessments ......................................................................................44
6.4.1.
Day 1 Visit ....................................................................................................................44
6.4.2.
Weeks 1 and 2 (3 days)..............................................................................................46
6.4.3.
Weeks 4 and 8 (3 days)..............................................................................................46
6.4.4.
Week 12 (3 days) .......................................................................................................47
6.4.5.
Week 16 and 20 (3 days) – GT-3 Subjects only.........................................................48
6.4.6.
Week 24 (3 days) – GT-3 Subjects only ....................................................................48
6.4.7.
Unscheduled Visit/Early Termination Visit ..................................................................49
6.5.
Post-Treatment Assessments...........................................................................................................50
6.5.1.
4-Week Post-Treatment Visit (5 days).......................................................................50
6.5.2.
12-Week Post-Treatment Visit (5 days).....................................................................51
6.5.3.
24-Week Post-Treatment Visit (5 days).....................................................................52
6.6.
Procedures and Specifications.........................................................................................................52
6.6.1.
Clinical Laboratory Analytes ........................................................................................52
6.6.2.
Medical History.............................................................................................................53
6.6.3.
Complete Physical Examination ...................................................................................53
6.6.4.
Tanner Pubertal Stage Assessment................................................................................53
6.6.5.
Height & Weight Measurement with Percentiles..........................................................53
6.6.6.
Bone Age Assessment...................................................................................................53
6.6.7.
Swallowability Assessment...........................................................................................54
6.6.8.
Vital Signs.....................................................................................................................54
6.6.9.
Body Mass Index (BMI) ...............................................................................................54
6.6.10.
Estimated Glomerular Filtration Rate (GFR)................................................................54
6.6.11.
Viral Sequencing (Archive) ..........................................................................................54
6.6.12.
Pregnancy Testing.........................................................................................................54
6.6.13.
Quality of Life Survey (PedsQL™)................................................................................55
7.
TOXICITY MANAGEMENT.....................................................................................................................56
7.1.
Modification of Dose/Schedule Due to Toxicity ............................................................................56
7.2.
Subject Stopping Rules for SOF .....................................................................................................56
8.
ADVERSE EVENTS MANAGEMENT.....................................................................................................57
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events..........................57
8.1.1.
Adverse Events..............................................................................................................57
8.1.2.
Serious Adverse Events.................................................................................................57
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events..............................................................58
8.2.
Assessment of Adverse Events and Serious Adverse Events..........................................................58
8.2.1.
Assessment of Causality for Study Drugs and Procedures............................................58
8.2.2.
Assessment of Severity .................................................................................................59
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events ...............................................................................................................................59
8.4.
Gilead Reporting Requirements......................................................................................................61
8.5.
Special Situations Reports ..............................................................................................................61
8.5.1.
Definitions of Special Situations...................................................................................61
8.5.2.
Instructions for Reporting Special Situations................................................................62


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9.
STATISTICAL CONSIDERATIONS.........................................................................................................64
9.1.
Analysis Objectives and Endpoints.................................................................................................64
9.1.1.
Analysis Objectives.......................................................................................................64
9.1.2.
Primary Endpoints.........................................................................................................65
9.1.3.
Secondary Endpoints.....................................................................................................65
9.2.
Analysis Conventions .....................................................................................................................65
9.2.1.
Analysis Sets.................................................................................................................65
9.2.2.
Data Handling Conventions ..........................................................................................66
9.2.3.
Interim Analysis............................................................................................................67
9.3.
Demographic Data and Baseline Characteristics ............................................................................67
9.4.
Pharmacokinetic Analysis...............................................................................................................68
9.5.
Safety Analysis ...............................................................................................................................68
9.5.1.
Extent of Exposure........................................................................................................68
9.5.2.
Adverse Events..............................................................................................................69
9.5.3.
Laboratory Evaluations .................................................................................................69
9.5.4.
Other Safety Evaluations...............................................................................................70
9.6.
Efficacy Analysis............................................................................................................................70
9.6.1.
Primary Efficacy Analysis ............................................................................................70
9.6.2.
Secondary Efficacy Analysis ........................................................................................70
9.6.3.
Subgroup Analysis ........................................................................................................71
9.7.
Quality of Life Analysis..................................................................................................................71
9.8.
Data Monitoring Committee ...........................................................................................................71
9.9.
Sample Size.....................................................................................................................................71
10.
RESPONSIBILITIES ..................................................................................................................................72
10.1.
Investigator Responsibilities ...........................................................................................................72
10.1.1.
Good Clinical Practice ..................................................................................................72
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) Approval..............................................................................................................72
10.1.3.
Informed Consent/Assent..............................................................................................73
10.1.4.
Confidentiality ..............................................................................................................73
10.1.5.
Study Files and Retention of Records...........................................................................73
10.1.6.
Case Report Forms........................................................................................................75
10.1.7.
Drug Accountability......................................................................................................75
10.1.8.
Inspections ....................................................................................................................75
10.1.9.
Protocol Compliance.....................................................................................................75
10.2.
Sponsor Responsibilities.................................................................................................................76
10.2.1.
Protocol Modifications..................................................................................................76
10.2.2.
Study Report and Publications ......................................................................................76
10.3.
Joint Investigator/Sponsor Responsibilities ....................................................................................76
10.3.1.
Access to Information for Monitoring...........................................................................76
10.3.2.
Access to Information for Auditing or Inspections .......................................................77
10.3.3.
Study Discontinuation...................................................................................................77
11.
REFERENCES ............................................................................................................................................78
12.
APPENDICES .............................................................................................................................................80
Appendix 1.
Investigator Signature Page...........................................................................................81
Appendix 2.
Study Procedures Table.................................................................................................82
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities .............................................................................................89
Appendix 4.
Tanner Stages..............................................................................................................112


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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements ................................................................113
LIST OF IN-TEXT TABLES
Table 7-1.
RBV Dose Reduction Guidelines..................................................................................56
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema................................................................................................................26


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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, Single-Arm 
Study to Investigate the Safety and Efficacy of 
Sofosbuvir + Ribavirin in Adolescents and Children with 
Genotype 2 or 3 Chronic HCV Infection
IND Number:
EudraCT Number:
106739
TBD
Study Centers:
Approximately 50 sites in the United States, Europe, Russia, 
Australia, and New Zealand
Number of Subjects:
Approximately 100 subjects
Target Population:
Adolescents and children (aged 3 to < 18) with chronic hepatitis C 
virus (HCV) infection
Treatment Duration:
PK Lead-in – 7 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 sofosbuvir (SOF) in HCV-infected 
pediatric subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety and tolerability of 7 days of dosing of 
SOF + ribavirin (RBV) in HCV-infected pediatric subjects
The primary objectives of the Treatment Phase of this study are:

To evaluate the safety and tolerability of SOF + RBV for 12 or 
24 weeks in HCV-infected pediatric subjects with genotype
(GT) GT-2 or GT-3, respectively


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Study Design: 
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The seconda!y objectives of the Treatment Phase of this study are: 
• 
To detennine the antiviral efficacy of SOF + RBV u·eatment in 
GT-2 and GT-3 HCV-infected subjects separately, as assessed 
by the proportion of subjects with SVR 12 weeks after 
completion ofu·eatment (SVR12) 
• 
To detennine the antiviral efficacy of SOF + RBV u·eatment in 
GT-2 and GT-3 HCV-infected subjects separately, as assessed 
by the proportion of subjects with SVR 4 and 24 weeks after 
completion ofu·eatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA dming 
u·eatment and after completion of u·eatment 
• 
To evaluate the emergence of viral resistance to SOF dming 
u·eatment and after completion of u·eatment 
The explorat01y objective of this study is: 
• 
PO 
Open-label, multi-cohort, two-part study evaluating the PK, safety, 
and antiviral activity ofSOF in chronic HCV-infected pediau·ic 
subjects. 
The study will be divided into 2 parts as follows: 
PK Lead-in: Will evaluate and/or confi1m age appropriate SOF 
doses by analyzing PK, safety, and antiviral activity of SOF 
administered in combination with RBV through 7 days of dosing 
for each of three coh01is. Children aged 3 < 6, children aged 6 to 
< 12 years and adolescents aged 12 to < 18 years with genotype 
GT-2 or GT-3 HCV infection and evidence of HCV RNA 
~ 1000 ID/mL at study enu·y will be evaluated. Subjects must be 
u·eatment naive to pruiicipate in the PK Lead-in Phase. 
Three coh01is of up to 10 subjects each will be sequentially 
emolled: 
• 
Cohort 1: 12 to < 18 yeru·s old weighing ~ 45kg 
• 
Coh01i 2: 6 to < 12 yeru·s old 
• 
Cohort 3: 3 to < 6 yeru·s old 
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The study will start with Cohort 1.  Subjects will receive SOF
(400 mg adult tablet or 4 x 100 mg tablets if determined necessary 
based on SOF swallowability assessment) + RBV for 7 days with 
intensive PK conducted on Day 7. 
PK Lead-in subjects in each cohort (Cohorts 1, 2 and 3) will 
immediately enroll in the Treatment Phase as they complete Day 7 
of the PK Lead-in Phase.  They will continue dosing with SOF +
RBV 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 will be reviewed to confirm 
the appropriateness of the evaluated SOF 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: Will be initiated sequentially by cohort after 
confirmation of age-appropriate SOF dosage levels. Subjects who 
participated 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.  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.
Children aged 3 to < 12 years and adolescents aged 12 to 
< 18 years with GT-2 or GT-3 infection and evidence of HCV 
RNA ≥1000 IU/mL at study entry (those who were dosed in the 
PK Lead-in Phase will have met this criteria prior to enrollment) 
will be evaluated. 
Subjects enrolled in the study will receive the following regimen:

GT-2 subjects: SOF + RBV for 12 weeks

GT-3 subjects: SOF + RBV for 24 weeks
The study will enroll both treatment-naïve and 
treatment-experienced pediatric subjects, with up to 20 subjects 
allowed to be treatment experienced. Approximately 100 total 
subjects, including subjects that participate in the PK Lead-in
Phase, will be enrolled in Treatment Phase as follows

Group 1: Approximately 50 adolescent subjects (12 to 
< 18 years of age)


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Substudy and 
Long-Te1m 
Follow-Up Study: 
• 
Group 2: Approximately 50 pediau·ic subjects (3 to < 12 years 
of age) 
The following definitions will be used for u·eatment-experienced 
subjects: 
• 
Interferon intolerant: Subject who discontinued therapy 
(~ 12 weeks total) due to ~ 1 adverse event 
• 
Interferon non-responder: Subject who did not achieve 
lmdetectable HCV RNA levels while on u·eahnent 
• 
Relapse/breakthrough: Subject who achieved undetectable 
HCV RNA dming u·eahnent or within 4 weeks of the end of 
u·eahnent but did not achieve a sustained virologic response 
(SVR) 
The study schedule contains the following visits: Screening, Day 1, 
Weeks 1, 2, 4, 8, 12 (and Weeks 16, 20, and 24 for GT-3) dming 
the u·eatment phase followed by post-u·eahnent visits 4, 12 and 
24 weeks after discontinuation of therapy. 
All subjects who do not attain SVR or have viral relapse will be 
encomaged to discuss u·eatment with standard-of-care (SOC) 
therapy with their healthcare provider. 
Pharmacogenomics (PG) Substudy 
PO 
Long-Term Follow-up 
Subjects who attain SVR24 or those who do not attain SVR24 and 
do not initiate experimental or approved anti-HCV therapy will be 
followed eve1y 6 months for assessments of growth, quality of life, 
and long-te1m viral suppression (if applicable) in a separate 
protocol (GS-US-334-1113). This follow-up will continue for 
5 years. 
Diagnosis and Main Chronic HCV-infected, u·eahnent-na'ive and up to 20 subjects may 
Eligibility Criteria: 
be u·eahnent experienced, male and female subjects aged 3 to < 18. 
CONFIDENTIAL 
Inclusion Criteria: 
• 
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 
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b) a liver biopsy performed prior to the Day 1 visit with 
evidence of chronic HCV infection

Infection with HCV GT-2 or GT-3 as determined at Screening

HCV RNA ≥1000 IU/mL at Screening 

For the PK Lead-in Phase: subjects in cohort 1 (age 12 to 
<18 years of age) must weigh ≥ 45kg

Agree to use 2 forms of highly effective contraception, as 
referenced in Appendix 5, for the duration of the study and for 
6 months (for female subjects) or 7 months (for male subjects)
after the last dose of study medication if age, cultural, and 
sexual activity status appropriate (eg: if sexually active; does 
not pertain to pre-pubertal subjects). Females of childbearing 
potential (as defined in Appendix 5) must have a negative
pregnancy test at Screening and Day 1.
Exclusion Criteria:

Hematologic or biochemical parameters at screening outside 
the protocol-specified requirements

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 
(eg, hemochromatosis, Wilson’s disease, alpha-1 antitrypsin 
deficiency)

Chronic use of systemic immunosuppressive agents or
immunomodulatory agents

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.

See Sections 4.2 and 4.3 of the protocol for full eligibility 
criteria.


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Study Procedures/
Frequency:
PK Lead-in Phase: 
Screening assessments will be completed within 28 days of the 
Day 1 visit. 
Screening assessments will include: physical examination, vital 
signs (including height and weight), Tanner Pubertal Stage 
assessment, concomitant medications, safety laboratory tests, 
coagulation tests, HCV RNA, serology (HIV, HAV, HCV, HBV), 
alpha-1 anti-trypsin, serum β-human chorionic gonadotropin hCG 
(females of childbearing potential only), thyroid stimulating 
hormone, HbA1c, IL28B genotyping, alpha fetoprotein, urinalysis, 
and urine drug screen.
Study Visits will occur at Screening, Day 1, Day 3, and Day 7.
On-Treatment assessments include adverse events (AEs), 
concomitant medications, physical examination, bone age 
assessment, vital signs, height, weight, safety laboratory tests, 
HCV RNA, viral sequencing sampling, urine pregnancy tests 
(females of child bearing potential only), and urinalysis. 
Coagulation will be performed at Day 1 and Day 7. SOF
swallowability assessment with placebo will be performed at 
screening up to Day 1 to assess a subject’s ability to swallow the 
400 mg or 100 mg SOF tablet (only subjects administered SOF in 
tablet form).
Subjects (up to 10 subjects) enrolled in the PK Lead-in Phase will 
participate in an intensive PK evaluation on Day 7. Following 
completion of the Day 7 intensive PK visit, subjects will then 
return for scheduled study visits outlined in the Treatment Phase
and continue dosing with SOF + RBV with no interruption of 
study drug administration.  Subjects will be administered a dosing 
diary with instructions.
Treatment Phase: 
Screening assessments will be completed within 28 days of the 
Day 1 visit. For subjects continuing from the PK Lead-in, 
screening for Treatment Phase will not be required.
Screening assessments will include physical examination, vital 
signs, concomitant medications, safety laboratory tests, HCV 
RNA, serology (HIV, HAV, HCV, HBV), alpha-1 anti-trypsin 
serum β-human chorionic gonadotropin hCG (females of 
childbearing potential only), thyroid stimulating hormone, IL28B 
genotyping, urinalysis, and urine drug screen.


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Test Product, Dose, 
and Mode of 
Administration: 
CONFIDENTIAL 
• 
GT-2 Subjects: Study visits for GT-2 subjects will occur at 
screening, Day 1, and the end of Weeks 1, 2, 4, 8, and 12. 
• 
GT-3 Subjects: Study visits for GT-3 subjects will occur at 
screening, Day 1, and the end of Weeks 1, 2, 4, 8, 12, 16, 20, 
and 24. 
All Treatment Phase subjects will then retum for follow-up visits 
at 4, 12 and 24 weeks after discontinuation of therapy. 
On-u·eatment assessments will include adverse events, concomitant 
medications, physical examination, vital signs (including height 
and weight), safety laborat01y tests, coagulation tests, HCV RNA, 
PK samples, and urine pregnancy tests (females of childbearing 
potential only). Height and weight measurements (with percentiles) 
and Tanner Pubertal Stage assessment will be perfonned at Day 1, 
end ofu·eahnent, post-u·eatment Week 12 and post-u·eahnent 
24-week; parental heights will be recorded at Day 1. The Bone 
Age Assessment will be perfonned at Day 1 and post-u·eatment 
Week 24 visit. If available, results from liver biopsies will be 
collected at screening. SOF swallowability assessment with 
placebo will be perf01med at screening up to Day 1 to assess a 
subject's ability to swallow a 400 mg or 100 mg SOF tablet (all 
subjects administered SOF in tablet f01m). For subjects continuing 
from the PK Lead-in, the screening, Day 1 and Week 1 visits of the 
Treatment Phase will not be required. Post-u·eatment assessments 
will include adverse events, concomitant medications, vital signs, 
safety laborat01y tests, HCV RNA, and urine pregnancy tests 
(females of childbearing potential only). Samples for viral RNA 
sequencing/phenotyping will be collected at Day 1 and eve1y visit 
thereafter. 
PO 
PKLead-in: 
(Coh01t 1) SOF 400 mg tablets will be administered once daily 
along with RBV weight-based dosing. Subjects dete1mined unable 
to swallow the placebo for 400 mg SOF tablet (by SOF Placebo 
swallowability assessment at Screening or at any time during the 
study) will be re-assigned to 4 x 100 mg tablets daily. 
Intensive PK and safety results from the PK Lead-In of each 
Cohort will be reviewed to confnm the appropriateness of the 
evaluated SOF dose for the Treatment Phase of that Coh01t as well 
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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.
RBV Weight-Based Dosing (All age groups):
The RBV dose is:
Body Weight kg
(lbs)
RBV Daily Dose
RBV Number of Capsules
<47 (<103)
15 mg/kg/day
Use Oral Solution
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.
65-80 (143 – 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.
The morning dose of RBV will be taken with food with an age-
appropriate dose of SOF. The evening dose of RBV will be taken 
with food.
Reference Therapy:
None
Evaluation Criteria:
Safety:
AEs, laboratory tests, and Tanner Pubertal Stage assessments will 
be collected throughout the study. 
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV 
RNA performed using COBAS® AmpliPrep/COBAS® TaqMan®
HCV Test.


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PK:
For subjects in the PK Lead-in, steady-state PK of SOF and its 
major metabolites GS-566500 and GS-331007 will be assessed at
Day 7. For Cohorts 1 and 2, plasma samples will be collected for 
PK analyses following dosing of study drugs on Day 7 at the 
following time points: 0 (predose), 0.5, 1, 2, 3, 4, 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), 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 SOF, 
GS-566500 and GS-331007 and/or ribavirin will be assessed.
The effect of age and SOF dose on PK (SOF and GS-331007) will
be explored. 
Statistical Methods:
For the PK Lead-in, plasma PK parameters Cmax, Tmax, Clast, Tlast, 
Ctau, AUCtau, and t1/2 will be estimated.  The PK parameters will be 
summarized by cohort. The effect of age and SOF dose on PK 
(SOF and GS-331007) 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 age group, by GT and by overall. Primary efficacy 
endpoint is SVR12 in all enrolled and treated subjects and will be 
summarized by age group, by genotype, by overall and by age 
group and GT.  Point estimate and its 95% confidence interval will 
be provided.  
In addition, SVR12 will be compared with historical SVR12 rate of 
80% from pegylated interferon + ribavirin for pediatric GT-2 and 
GT-3 subjects {20280}, using two-sided exact one-sample binomial 
test at the 0.05 significance level.  
Secondary efficacy endpoints are SVR4, SVR24, breakthrough and 
relapse.
Subgroup analysis on SVR12 will be performed by treatment 
experience (treatment-naive vs. experienced) and by treatment 
experience and 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). 
All continuous endpoints will be summarized using an 8-number 


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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.
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 age group, by GT, by 
overall and by age group and GT.
With approximately 50 subjects enrolled into each age group of 
Treatment Phase, a two-sided 95.0% confidence interval of the 
SVR12 rate will extend at most 11.1% in both directions from the 
observed SVR12 rate, assuming the expected SVR12 rate is 80%. 
In addition, a sample size of 100 subjects will provide over 80% 
power to detect a 11% improvement in SVR12 rate from 80% to 
91% using two-sided one-sample binomial test at significance level 
of 0.05.
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
β-hCG
β-human chorionic gonadotropin
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)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BW
body weight
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)
CMH
Cochran-Mantel-Haenszel
COPD
Chronic obstructive pulmonary disease
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
Emax
maximal effect
EU
European Union
EVR
Early virologic response
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor
GFR
glomerular filtration rate


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
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
IV
Intravenous
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDH
Lactase dehydrogenase
LLN
lower limit of the normal range
LLOD
Lower limit of detection
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


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
QD
once daily (use only in tables)
QTcF
QT interval corrected using Fridericia’ formula
RBC
Red blood cell count 
RBV
Ribavirin
RDRP
RNA-dependent RNA polymerase
RNA
ribonucleic acid
RVR
rapid virologic response 
SADR
Serious adverse drug reaction
SAE
serious adverse event
SD
Standard deviation
SOC
Standard of Care
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TND
Target not detected
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 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 standard of care 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.
Sofosbuvir
Sovaldi™(Sofosbuvir) is a potent nucleotide analogue that inhibits HCV RNA replication in 
vitro and has demonstrated high rates of sustained viral response (SVR) when given with 
RBV +/- PEG to subjects with chronic GT- 1, 2, 3 or 4 HCV infection {27503}, {23275}, 
{24713}, {24715}.  Sovaldi™has been approved in the United States by the Food and Drug 
Administration (FDA) for the treatment of HCV infection GT- 1, 2, 3 and 4 including 
treatment naïve and experienced patients and HIV/HCV co-infected patients.  Sovaldi™is
also approved in EU, Canada and Turkey.
For further information on the clinical pharmacology, virology, safety and efficacy of SOF, 
please refer to the current version of the Investigator’s Brochure and the local prescribing 
information.  
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 SOF +
RBV for adolescents and children with GT-2 and GT-3 chronic HCV infection. 
Currently PEG and weight-based RBV are considered the standard of care for the treatment 
of HCV infection in children. However, this PEG and RBV regimen is long in duration, 
relatively toxic, and not well tolerated. Thus, there continues to be a need for new treatments 
for HCV that combine potent and sustained efficacy with improved tolerability and safety. 
Therapy that provides shorter duration and improved efficacy with an all-oral regimen would 
be a significant advancement over current options in pediatric patients.
The main aim for the treatment of pediatric patients with HCV is to eliminate the need to use 
PEG regimens. In this way, pediatric patients are able to avoid the necessity of weekly 
injections, which can be traumatic and burdensome, and also to significantly reduce the 
serious adverse events seen on administration of PEG regimens. 
SOF is a promising candidate to combine with RBV based on its acceptable safety profile 
and its antiviral activity.  Clinical trials from adult studies have demonstrated the antiviral 
efficacy, potency, and safety of SOF in subjects with HCV infection. SOF in combination 
with RBV would provide an all-oral, IFN-free regimen with a shorter treatment duration 
(12 - 24 weeks of SOF treatment versus standard-of-care 24 to 48 weeks of treatment) and 
would offer another important option in the treatment of HCV infection in the pediatric 
population.
While emerging Phase 3 data demonstrate high SVR12 rates in subjects with GT-2 HCV 
infection, these studies suggest that patients with GT-3 infection may benefit from a longer 
treatment duration with SOF + RBV. Optimal duration of SOF + RBV, for GT-3 subjects,
was established in FISSION and VALENCE.  Increasing treatment duration from 12 to 
24 weeks increased SVR12 from 61 to 93% in non-cirrhotics and from 34 to 92% in 
cirrhotics.
1.5.
Rationale for Dose Selection of SOF
SOF 400 mg, once daily, when dosed in combination with RBV with or without PEG has 
demonstrated broad genotypic efficacy and favorable safety profile in over 
3300 HCV-infected adult subjects across multiple patient populations in Phase 2 and 3 trials. 
This dose is the marketed dose of SOF for the treatment of HCV-infection in adults.
Selection of doses of SOF for adolescents and younger age groups will target systemic 
exposures similar to those observed in adults at the marketed dose, taking into account body 
weight/body surface area, the potential ontogenic changes in hepatically expressed 
carboxylesterase 1 (CES1) and Cathepsin A (CatA) enzymes, and the results obtained in 
older age groups.  Available data suggest comparable hepatic expression of CES1 in 
adolescents and adults, with modestly decreased expression in children.  As such, the adult 
clinical dose, 400mg, will be evaluated in adolescents (12 to <18 years old) {20288}.  Safety 
and PK data in the adolescent group (Cohort 1) in the PK Lead-in, will inform dose selection 
for the younger age groups in addition to body weight/body surface area. 


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Age-appropriate formulations of SOF (a smaller, 100 mg strength tablet and a non-tablet 
formulation currently in 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 solid-dose 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 standard of care 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. 
SOF has demonstrated efficient inhibition of viral replication in in vitro and in vivo studies. 
Available clinical data indicate SOF has a favorable safety profile and is well tolerated. SOF 
in combination with RBV is likely to provide significant therapeutic benefit in the treatment 
of HCV infection in pediatric patients compared to currently available therapies in the 
following areas:

Expected improved efficacy in a pediatric population compared to the current standard of 
care

Expected improvement in safety and tolerability in relation to either adverse reactions or 
potential medication errors in the pediatric population compared to the current standard 
of care

Improved dosing scheme or method of administration (oral compared to subcutaneously 
administration and reduced treatment duration) leading to improved safety, efficacy,
tolerability, and compliance

Expected availability of a clinically relevant age-appropriate formulation

Different mechanism of action with potential advantage for the pediatric population in 
terms of improved efficacy and safety

Expected improvement in quality of life (eg, minimized duration of therapy and
avoidance of IFN-related adverse events that affect patient quality of life such as flulike
syndrome and depression)
Additionally, the study sponsor will perform an ongoing review of safety data during the 
conduct of the study.


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2. 
OBJECTIVES 
The prima1y objective of the PK Lead-in of this study is: 
Final 
Amendment2 
• 
To evaluate the steady state phrumacokinetics (PK) and confmn the dose of SOF in 
HCV -infected pediatric subjects 
The secondruy objective of the PK Lead-in of this study is: 
• 
To evaluate the safety and tolerability of 7 days of dosing of SOF + RBV in 
HCV -infected pediatric subjects 
The primary objectives of the Treatment Phase of this study are: 
• 
To evaluate the safety and tolerability of SOF + RBV for 12 or 24 weeks in HCV 
infected pediatric subjects with GT-2 or GT-3, respectively 
The secondruy objectives of the Treatment Phase of this study ru·e: 
• 
To dete1mine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects sepru·ately, as assessed by the proportion of subjects with SVR 
12 weeks after completion of treatment (SVR12) 
• 
To dete1mine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects separately, as assessed by the prop01tion 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 SOF during treatment and after 
completion of treatment 
The explorat01y objective ofthis study is: 
• 
PD 
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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 SOF + 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 SOF dose by 
analyzing PK, safety, and antiviral activity of SOF + RBV through 7 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 GT-2 or GT-3 HCV infection and evidence of HCV RNA ≥1000 IU/mL at 
study entry will be evaluated. Subjects must be treatment naïve to participate in the PK 
Lead-in Phase. Three cohorts of up to 10 subjects each will be sequentially enrolled: 

Cohort 1:  12 to < 18 years old weighing ≥45kg

Cohort 2:  6 to < 12 years old 

Cohort 3:  3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive SOF (400 mg adult tablet or 
4 x 100 mg tablets if determined necessary based on SOF swallowability assessment) + RBV 
for 7 days with intensive PK conducted on Day 7. 
Following completion of study treatment in the PK Lead-in of Cohort 1 and pending PK and 
safety results, the PK Lead-in of Cohort 2 will initiate and receive study treatment (age 
appropriate dose and formulation). 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 7 of PK Lead-in.  They will continue 
dosing with SOF + RBV 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.
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 


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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 GT-2 or GT-3 infection and evidence of 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:

GT-2 subjects: SOF + RBV for 12 weeks

GT-3 subjects: SOF + RBV for 24 weeks
The study will enroll both treatment-naïve and treatment–experienced pediatric subjects, with 
up to 20 subjects allowed to be treatment experienced. Approximately 100 total subjects, 
including subjects from the PK Lead-in Phase, will be enrolled in the Treatment Phase as 
follows:

Group 1: Approximately 50 adolescent subjects (12 to < 18 years of age)

Group 2: Approximately 50 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 standard-of-care (SOC) therapy with their healthcare provider.


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Figure 3-1.
Study Schema
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 7.
Subjects (up to 10 subjects) enrolled in the PK Lead-in Phase will participate in an intensive 
PK evaluation on Day 7. Subjects will be administered a dosing diary with instructions.  
Following completion of the Day 7 intensive PK visit, subjects will then return for scheduled 
study visits outlined in the Treatment Phase and continue dosing with SOF + RBV with no 
interruption of study drug administration.  Subjects rolling over from the PK Lead-in Phase
will not be required to perform the Treatment Phase screening, Day 1 or Week 1 visits of 
Treatment Phase.


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3.2.2.
Treatment Phase
Screening assessments will be completed within 28 days of the Day 1 visit. For subjects 
continuing from the PK Lead-in Phase, screening, Day 1 and Week 1 of the Treatment Phase
will not be required.

GT-2 Subjects: Study visits for GT-2 subjects will occur at screening, Day 1, and the 
end of weeks 1, 2, 4, 8, and 12. 

GT-3 Subjects: Study visits for GT-3 subjects will occur at screening, Day 1, and the 
end of weeks 1, 2, 4, 8, 12, 16, 20, and 24. 
All Treatment Phase 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).


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Treatment Discontinuations Criteria 
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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 defmed in Section 7 of the protocol, 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 imp01tant to detennine 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, regulat01y agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC). 
3.5. 
Discontinuations 
Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an Early Tennination visit as described in the Section 6.4.7. 
Subjects who pennanently discontinue all study dmgs for any reason including safety and/or 
tolerability concems prior to completion of the assigned dosing period will be followed 
according to the post-u·eatment study assessments described in Section 6.5. 
3.6. 
Pharmacogenomic Substudy 
PD 
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 eve1y 6 months for 
assessments of growth, quality of life, and long-te1m viral suppression (if applicable) in a 
separate protocol (GS-US-334-1113). This follow-up will continue for 5 years. 
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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 5 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.
Subjects with known or suspected study drug non-adherence will not be considered to meet 
the definition of virologic breakthrough, relapse or non-responder. 


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 100 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 (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: all subjects must be treatment naïve 
5. 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 Baseline/Day 1.
6. Chronic HCV infection documented by either:
c) 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
d) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV 
infection
7. Infection with HCV GT-2 or GT-3 as determined at Screening
8. HCV RNA ≥1000 IU/mL at Screening
9. Adequate hematologic function (absolute neutrophil count 1,500/mm3; hemoglobin 
12 g/dL for males and 11g/dL for females.)


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10. Negative serum -HCG pregnancy test (for females of childbearing potential only, as 
defined in Appendix 5)
11. 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. 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)
4. Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)
5. -fetoprotein 50 ng/mL
6. Serum creatinine > 1.5 mg/dL
7. Estimated glomerular filtration rate 90 mL/min/1.73m2, as calculated by the Schwartz 
Formula
8. Evidence of hepatocellular carcinoma (HCC)
9. Co-infection with HIV, acute HAV, or HBV
10. Significant cardiovascular, pulmonary or neurological disease
11. Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption 
of orally administered medications
12. History of solid organ or bone marrow transplantation
13. Chronic daily non-steroidal anti-inflammatory drug therapy
14. Systemic corticosteroid use for 5 days (pulmonary/nasal administration is permitted)
15. Investigational agents taken within the past 30 days (except with the expressed approval 
of the Sponsor)


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16. Clinically-relevant alcohol or drug abuse within 12 months of screening.  A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator
17. Known hypersensitivity to the study drugs, the metabolites or formulation excipients
18. 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
19. Use of any prohibited concomitant medications as described in Section 5.6 within 
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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
Not applicable.
5.2.
Sofosbuvir
5.2.1.
Description and Handling
5.2.1.1.
Formulation:
SOF tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets debossed with “GSI” on 
one side and “7977” on the other side. In addition to the active ingredient, SOF tablets 
contain the following inactive ingredients: mannitol, microcrystalline cellulose, 
croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, 
titanium dioxide, macrogol, talc, and yellow iron oxide.
Placebo tablets for Swallowability Assessment, 400 mg, are yellow, capsule-shaped, film-
coated tablets debossed with “GSI” on one side and “7977” on the other side. The tablets 
contain mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon 
dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, and yellow 
iron oxide.
SOF tablets, 100 mg, are yellow, round, film-coated, plain-faced tablets. In addition to the 
active ingredient, SOF tablets contain the following inactive ingredients: mannitol, 
microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium 
stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, and yellow iron oxide.
Placebo tablets for Swallowability Assessment, 100 mg, are yellow, round, film-coated, 
plain-faced tablets. The tablets contain lactose, monohydrate, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, 
talc, and yellow iron oxide.
The formulation of SOF Oral Granules will be based on the PK results obtained from cohorts 
1 and/or 2 of this study. The formulation strength and composition 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.
5.2.1.2.
Packaging and Labeling
SOF 400 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 30 tablets and a silica gel desiccant canister or sachet and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant screw cap 
with an induction-sealed, aluminum-faced liner.


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Placebo tablets for Swallowability Assessment, 400 mg, are packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 30 tablets and a silica gel desiccant 
canister or sachet and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child-resistant screw cap with an induction-sealed, aluminum-faced liner.
SOF 100 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 28 tablets and a 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 for Swallowability Assessment, 100 mg, are packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 10 tablets and polyester packing material. 
Each bottle is enclosed with a white, continuous thread, child-resistant screw cap with an 
induction-sealed, aluminum-faced liner.
The packaging and labeling of SOF Oral Granules 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.
SOF bottles to be distributed to centers in the US, EU and the rest of the countries will 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.
Placebo tablets for Swallowability Assessment, 100 mg and 400 mg, bottles 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.
5.2.2.
Storage and Handling
SOF tablets, 100 mg and 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 tablets for Swallowability Assessment, 100 mg and 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).  
The storage and handling of the SOF Oral Granules 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 study drug and to ensure proper product 


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identification, the drug product should not be stored in a container other than the container in 
which they are supplied. Consideration should be given to handling, preparation, and 
disposal through measures that minimize drug contact with the body. Appropriate 
precautions should be followed to avoid direct eye contact or exposure through inhalation 
when handling SOF.
Sufficient quantities of SOF tablets, SOF Oral Granules and placebo tablets will be shipped 
to the investigator or qualified designee from Gilead Sciences Materials & Logistics (or its 
designee).
5.2.3.
Dosage and Administration of SOF
PK Lead-in: (Cohort 1) SOF 400 mg tablets will be administered once daily along with RBV 
weight-based dosing. Subjects determined unable to swallow the placebo for the 400 mg SOF 
tablet (by SOF Placebo swallowability assessment at Screening up to Day 1) will be 
re-assigned to 4 x 100 mg tablets daily.  Subjects who weigh < 45 kg will be excluded.  
Intensive PK and safety results from the PK Lead-In of each Cohort will be reviewed to 
confirm the appropriateness of the evaluated SOF 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.  
An additional age-appropriate formulation for SOF 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.
5.3.
Ribavirin 
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.


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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).
5.3.2.
Dosage and Administration of RBV
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
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.
65-80 (143 – 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.


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The morning dose of RBV will be taken with food and SOF. 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 SOF and RBV
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:

SOF

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 medication at the correct time, it may be taken later in the day; 
however, no more than 400 mg dose of SOF 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.  
5.5.
Study Drug Compliance
Subjects will be instructed to return any unused SOF and RBV in the original container on 
Day 7 (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 of Screening, up to and including the date of 
the visit four weeks after discontinuation of study treatment, need to be recorded in the 
source documents and eCRFs. All concomitant medications should be recorded in the source 
documents.
The following medications are prohibited from 28 days prior to the Day 1 visit through the 
end of treatment:

Erythropoiesis-stimulating agents (ESAs); including but not limited to Procrit®, Aranesp®
and Epogen®

Granulocyte colony stimulating factor (GCSF)


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
Chronic systemic immunosuppressants including 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®

Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters i.e. P-gp) with study drug(s) may result in pharmacokinetic interactions 
resulting in decreases in exposure of study drug(s). Representative medications which are 
excluded from 21 days prior to Day 1 through the end of treatment are listed below:
Drug
Agents Disallowed
Concomitant use with study drug may 
potentially result in changes of study 
drug concentration as listed below
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Decrease in concentration of study drug
Antimycobacterials
Rifampin, rifabutine, rifapentine
Decrease in concentration of study drug
Herbal/Natural 
Supplements
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-
to (or Xiao-Shai-Hu-Tang)
Decrease in concentration of study drug
Medications for disease conditions excluded from the protocol (e.g., HIV-1 infection, active 
cancer, transplantation) are not listed under this Concomitant Medication section and are 
disallowed in the study.


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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 (i.e., height and weight of parents, if known)
— Liver biopsy results (if available)

Complete physical examination 

Vital signs (temperature, blood pressure, pulse, respiratory rate), body weight and height


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
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 SOF swallowability assessment (for subjects administered SOF in tablet form 
only)
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to 
the clinic for the Day 1 visit assessments.


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6.3. 
PK Lead-in: Treatment Assessments 
6.3.1. 
Day 1 Visit 
Final 
Amendment2 
After confnmation of eligibility has been evaluated, the following tests and procedmes must 
be completed prior to enrollment and dosing/dispensing on Day 1: 
• 
Perf01m complete physical examination 
• 
Tanner Pubertal Stage Assessment 
• 
Vital signs, including body weight and height measmements 
• 
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 
pruiicipants (Subjects 12 to < 18 yeru·s of age only) 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (ru·chive) 
PD 
• 
Obtain mine samples for the following procedmes: 
-
Urinalysis 
-
~ -hCG pregnancy test for females of childberu·ing potential only 
• 
Subject completes quality of life smvey: Subject is to review questionnaire with a 
parent/guardian and write/mru·k answers directly onto the questionnaire. 
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6.3.1.1.
Drug Administration

Dispense study drugs as directed by the IWRS

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 all study drugs

Perform SOF swallowability assessment (for subjects administered SOF in tablet form 
only if not previously completed at screening).  Observe the subject taking the first dose 
of study drugs (with 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 parent/guardian

Obtain blood samples for:
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing (archive)

Review subject dosing diary
6.3.3.
Day 7 – Intensive PK 
The Day 7 Intensive PK visit should occur on the protocol-specified visit date based on the 
Day 1 visit. For the purposes of scheduling, the Day 7 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).


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Subjects should come in a fasted state for the Day 7 Intensive PK visit (i.e., no food or drink 
except water at least 8 hours prior to the Day 7 Intensive PK visit). Subjects and/or 
parents/guardians should be instructed that the Day 7 dose of SOF+RBV must not be taken 
until the evaluations listed below are completed. 
If the subject has already dosed prior to the Day 7 clinic visit or is not in a fasted state, the 
Day 7 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 8, 9, or 10) 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 7 visit, the Day 7 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 7 intensive PK visit no sooner than 3 days following compliant dosing and 
no later than Day 11 (i.e., return on Day 10 or Day 11).  If dosing non-compliance is due to 
an AE, consultation with the Gilead Medical Monitor is required regarding the potential of
rescheduling the Day 7 intensive PK visit.
In both scenarios described above, the subject and/or parents/guardians should be reminded 
not to take the SOF + RBV prior to arriving at the clinic on the day of the re-scheduled 
intensive PK visit. All Day 7 intensive PK assessments listed below should be completed 
when the subject returns.
The following evaluations are to be completed at the Day 7 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 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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— 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 
SOF + RBV per dosing requirements.
— Post-dose blood samples will be collected as follows: 

For Cohorts 1 and 2:  0.5, 1, 2, 3, 4, 8, and 12 hours post-dose (with predose also 
serving as t= 24).

For Cohort 3 only: 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 7 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 Visit
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 with percentiles 

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Review of AEs and concomitant medications


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• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
pmi icipants (Subjects 12 to < 18 years of age only). 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemis1:Iy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (m·chive) 
PD 
• 
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 
pm·ent/gum·dian and write/mark answers directly onto the questionnaire. 
• 
Perf01m SOF swallowability assessment (for subjects administered SOF in tablet f01m 
only if not previously completed at screening). 
6.4.1.1. 
Dmg Adminisu·ation 
• 
Dispense study <hugs as directed by the IWRS 
• 
lns1:Iuct the subject on the appropriate RBV dose after weight-based dosage is calculated 
using Day 1 weight 
• 
lns1:Iuct the subject on the packaging, storage and adminisu·ation of all study <hugs 
• 
Observe the subject taking the first dose of study dm gs (with food) and record the time of 
first dose 
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6.4.2.
Weeks 1 and 2 (3 days)
Subjects who participated in the PK Lead-in will start study visits in 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

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 


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
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 drugs at these visits)

Dispense study drugs as directed by the IWRS
6.4.4.
Week 12 (3 days)

Perform complete physical examination

Tanner Pubertal Staging Assessment

Vital signs, including body weight and height measurements with percentiles 

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)

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. (GT-2 Subjects 
only)

Review medication compliance with subject and/or parent/guardian.


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
Dispense study drugs as directed by the IWRS (GT-3 Subjects Only)

GT-2 Subjects should return all bottles and kits at the Week 12 Visit
6.4.5.
Week 16 and 20 (3 days) – GT-3 Subjects 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 drugs at these visits)

Dispense study drugs as directed by the IWRS
6.4.6.
Week 24 (3 days) – GT-3 Subjects only

Perform complete physical examination

Tanner Staging Assessment

Vital signs, including body weight and height measurements with percentiles 

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)


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
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.

GT-3 Subjects should return all bottles and kits at the Week 24 Visit
6.4.7.
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.
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 with percentiles 

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)


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
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 kits at the Early Termination Visit
All subjects should complete Post-Treatment assessments after early termination, as 
described in Section 6.5.
Subjects who do not attain SVR24 and do not initiate experimental or approved anti-HCV 
therapy will be followed every 6 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.
6.5.
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


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— 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 (Subjects 12 to < 18 years of age 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 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 with percentiles 

Perform symptom-directed physical examination

Perform Tanner Pubertal Stage assessment

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 (Subjects 12 to < 18 years of age only)

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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6.5.3.
24-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements with percentiles 

Perform symptom-directed physical examination

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)

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.

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)
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 
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.


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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 right 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: 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.
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.  Perform Tanner Pubertal Stage 
assessment for subjects until Tanner Stage 5 has been reached. Date of first menses will be 
documented.  
6.6.5.
Height & Weight Measurement with Percentiles
Height and weight measurement will be collected at Day 1, End of Treatment, post-treatment 
Week 12 and post-treatment Week 24.  Percentiles will be calculated using the WHO 
reference charts and tables by age and gender for height and weight.  
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 to determine bone age from x-ray.


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6.6.7.
Swallowability Assessment
A SOF 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 for the 400 mg SOF 
tablet. This will confirm the swallowability of the 400 mg tablet size. If, a subject is unable to 
swallow the 400 mg tablet size he/she will repeat the assessment with a placebo for the
100 mg SOF tablet.    If unable to take the 100 mg SOF 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.
6.6.9.
Body Mass Index (BMI)
BMI is calculated by the following equation.
BMI = weight (pounds) 703           or            weight in kilograms
   (height in inches)2                                (height in meters)2
6.6.10.
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)]
6.6.11.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each visit for viral sequence analysis. Unused 
samples may be archived.
6.6.12.
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. If required 


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by local regulations, additional pregnancy tests beyond 6 months may be added. In the event 
of a positive urine pregnancy result, subjects will be instructed to stop study drugs 
immediately and return to the clinic as soon as possible for a serum pregnancy test.
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.
6.6.13.
Quality of Life Survey (PedsQL™)
The PedsQL ™  Pediatric Quality of Life Inventory V4.0 Short Form (SF15) will be 
completed in Treatment Phase of the study at Day 1, End of Treatment (Week 12 for GT-2 
subjects, Week 24 for GT-3 subjects, or at 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 will be administered to the subject 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 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/day 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
Dose reduction in pediatric patients 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 SOF
The Gilead Medical Monitor should be consulted prior to dose discontinuation of SOF unless 
the investigator believes that immediate action is warranted to ensure the continued safety of 
the subject.
Administration of SOF may be discontinued due to a clinical or laboratory event. There is no 
option for SOF dose reduction. If SOF is stopped for toxicity, it should not be restarted, RBV 
should be stopped and the subject should complete an Early Termination Visit.
Subjects who meet any of the following laboratory criteria should stop treatment with SOF
and RBV:

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 

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event or lab abnormality assessed as related to treatment with SOF


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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)

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.)


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
In-patient hospitalization or prolongation of existing hospitalization

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 (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 8.1.1 and 8.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
8.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event
information and assessments.
8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to 
IMP therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the 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 (eg., 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 
All SAEs, regardless of causal relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required 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 from screening onwards.
All AEs, regardless of causal relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP 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 post-treatment follow 
up period.
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 this time 
and the event is deemed relevant to the use of IMP, he/she should promptly document and 
report the event directly to Gilead DSPH. Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com or Fax: +1 (650) 522-5477.  All AEs and SAEs will be
recorded in the CRF/eCRF database within the timelines outlined in the CRF/eCRF 
completion guideline.


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Serious Adverse Event Paper Repmiing Process 
Final 
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• 
All SAEs will be recorded on the serious adverse event repmi fmm and submitted by 
emailing or faxing the repmi fmm within 24 hours of the investigator's knowledge of the 
event to the attention of the designated CRO Phrumacovigilance Representative. 
Electronic Serious Adverse Event (eSAE) Repmiing Process 
• 
All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines 
outlined in the CRF/eCRF completion guideline. 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit the SAE 
infmmation 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 infmmation electr·onically, ie, the 
eCRF database is not ftmctioning, record the SAE on the paper serious adverse event 
repmiing fmm and submit within 24 hours as described above. 
• 
As soon as it is possible to do so, any SAE repmied via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repmied via a paper fonn because the eCRF database has been 
locked, no fmiher action is necessruy. 
Conta.ct infonnation is as follows: 
Gilead Sciences, 
Dmg Safety and 
Public Health: 
PRA Intemational 
Phrumacovigilance 
Representative: 
Gilead Sciences, 
Medical Monitor: 
CONFIDENTIAL 
Fax: 
E-mail: 
Fax: 
E-mail: 
Nrune: 
Phone: 
Mobile: 
Fax: 
E-mail: 
+ 1 650 522-5477 
Safety _FC@gilead.com 
+1 888 772 6919 (NmihAmerica); 
+49 621 8782 181 (Rest of World) 
CHOSafety@praintl.com 
Luisa Stamm, MD, PhD 
PPD 
PPD 
PPD 
t-'t-'U 
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
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.
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. 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, and 
pregnancy reports regardless of an associated AE.  Also includes reports of adverse reactions 
in infants following exposure from breastfeeding, and reports of adverse reactions associated 
with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following maternal or paternal exposure 
to the medicinal product. 
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.


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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.  
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 (ie, signs the informed consent) and throughout the 
study, including the post-treatment follow-up period, to the CRO Pharmacovigilance 
Representative using the pregnancy report form within 24 hours of becoming aware of the 
pregnancy.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate 
a pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as 
an SAE. The underlying medical reason for this procedure should be recorded as the AE
term.
A spontaneous abortion is always considered to be an SAE and will be reported as described 
in Sections 8.1.1 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 CRO Pharmacovigilance Representative 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 drugs 
must also be reported and relevant information should be submitted to the CRO 
Pharmacovigilance Representative 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 


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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 the CRO Pharmacovigilance Representative within 24 hours of the investigator 
becoming aware of the situation. These reports must consist of situations that involve study 
IMP, but do not apply to concomitant medications. Except for situations that result in AEs, 
special situations involving concomitant medications will not be reported. Any inappropriate 
use of contraindicated medications 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 prima1y objective ofPK Lead-in Phase of this study is: 
Final 
Amendment2 
• 
To evaluate the steady state phrumacokinetics (PK) and confnm the dose of SOF in 
HCV -infected pediatric subjects 
The secondruy objective ofPK Lead-in of this study is: 
• 
To evaluate the safety and tolerability of 7 days of dosing of SOF + RBV in 
HCV -infected pediatric subjects 
The primru·y objectives of Treatment Phase of this study are: 
• 
To evaluate the safety and tolerability of SOF + RBV for 12 or 24 weeks in 
HCV-infected pediatric subjects with GT-2 or GT-3, respectively 
The secondruy objectives of Treatment Phase of this study are: 
• 
To dete1mine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects sepru·ately, as assessed by the proportion of subjects with SVR 
12 weeks after completion oftreatment (SVR12) 
• 
To dete1mine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects sepru·ately, 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 SOF during treatment and after 
completion of treatment 
The explorat01y objective of this study is: 
• 
PD 
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9.1.2.
Primary Endpoints
For the PK Lead-in Phase, AUCtau of GS-331007 is considered as the primary PK parameter 
for determining the appropriate SOF dose.
For Treatment Phase, the primary safety endpoint is any AE leading to permanent 
discontinuation of study drug (s). The primary efficacy endpoint is SVR12. 
9.1.3.
Secondary Endpoints
For the PK Lead-in Phase, the secondary PK endpoints include AUCtau, Cmax, AUClast, Tmax, 
Clast, Tlast, Ctau and t1/2for GS-331007 and SOF as appropriate. AEs leading to permanent 
discontinuation of study drug(s) will be evaluated as a secondary safety endpoint.
For Treatment Phase, 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.
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 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 SOF or GS-331007 are 
available. The PK analysis set will be used for analysis of general PK and single sample 
plasma concentrations.


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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. 


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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.
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 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.


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9.4.
Pharmacokinetic Analysis
PK analysis will be performed for PK Lead-in using the intensive PK analysis set. The 
concentration data of SOF and metabolites (GS-566500 and GS-331007) 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 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 the exposures of GS-331007 achieved in pediatric subjects of this study are 
similar to the exposures observed in adult subjects, GS-331007 exposure data from this study 
will be compared to the integrated adult data by carrying out an analysis of variance 
(ANOVA) for log-transformed AUCtau of GS-331007 as the primary endpoint while Cmax of 
GS-331007 as secondary endpoints. 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%. Individual patient management will be performed by maintaining exposures 
comparable to adults.  AUCtau less than the 2.5th percentile of adult values may require dose 
adjustment as appropriate.
The effect of age and SOF dose on PK (SOF and GS-331007) will be assessed.
9.5.
Safety Analysis
Safety analysis will be performed for PK Lead-in and overall study Treatment 
Phaserespectively. Safety data will be summarized by age group, by GT, by overall and by 
age group and GT.
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.


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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,

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 


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baseline data are missing, then any graded abn01mality (i.e., at least a Grade 1) will be 
considered treatment emergent. 
Alllaborat01y abn01malities will be included in the listings of laborat01y data. 
9.5.4. 
Other Safety Evaluations 
9.5.4.1. 
Tanner Pube1ial 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. 
9.6. 
Efficacy Analysis 
Efficacy will be evaluated using scheduled assessments of HCV RNA perf01med using 
COBAS® TaqMan® HCV Test, v2.0 for use with the High Pure System. 
Efficacy analysis will be perf01med by age group, by GT, by overall, and by age group and 
GT for Treatment Phase. 
All continuous endpoints will be summarized using an 8-number summruy (n, mean, 
standru·d deviation, median, Q1, Q3, minimum, maximum). All categorical endpoints will be 
smnmru·ized by number and percentage of subjects who meet the endpoint definition. 
9.6.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
treatment) in the F AS population. Point estimate and its 95% confidence interval will be 
provided. 
9.6.2. 
Secondary Efficacy Analysis 
The prima1y efficacy endpoint of SVR12 will be compru·ed with historical SVR12 rate of 
80% from pegylated interferon + ribavirin for pediatric GT2 and 3 subjects {20280}, using 
two-sided exact one-sample binomial test at the 0.05 significance level. 
The proportion of subjects with HCV RNA below LLOQ over time (including SVR 
endpoints SVR4 and SVR24) will be presented in Treatment Phase in tabulru· and graphical 
f01m. 
Descriptive summru·ies and listings will be provided for additional efficacy evaluations 
including senun HCV RNA actual values and change from baseline, prop01iion of subjects 
with virologic failures, and other endpoints of interest including ALT n01malization. 
PD 
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Subgroup Analysis 
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Subgroup analysis on SVR12 will be perf01m ed by treatment experience (treatment-naive vs. 
experienced), and by treatment experience and 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 TM Pediau·ic Quality of Life survey will be summarized by visit and 
age group and overall. 
9.8. 
Data Monitoring Committee 
An extemal multidisciplinruy data monitoring committee (DMC) will review the progress of 
the study and perf01m interim reviews of safety and PK data and provide recommendation to 
Gilead about whether the nature, frequency, and severity of adverse effects associated with 
study u·eahnent wan ant the early te1mination of the study in the best interests of the 
pruiicipants, whether the study should continue as planned, or the study should continue with 
modifications. 
The DMC's specific activities will be defmed by a mutually agreed chruier, which will defme 
the DMC's membership, conduct and meeting schedule. 
While the DMC will be asked to advise Gilead regru·ding future conduct of the study, 
including possible early study tennination, Gilead retains fmal decision-making authority on 
all aspects of the study. 
9.9. 
Sample Size 
With approximately 50 subjects enrolled into each age group of Treahnent Phase, a two-
sided 95.0% confidence inte1val of the SVR12 rate will extend at most 11.1% in both 
directions from the obse1ved SVR12 rate, assuming the expected SVR12 rate is 80%. In 
addition, a sample size of 100 subjects will provide over 80% power to detect a 11% 
improvement in SVR12 rate from 80% to 91% using two-sided one-sample binomial test at 
significance level of 0.05. 
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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 Harmonisation (ICH) guidelines, or with the laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the study subject. 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 subinvestigators 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 subinvestigator. The investigator and subinvestigator 
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.


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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);


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
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);

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 10 years for purposes of this study.


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10.1.6.
Case Report Forms
For each subject enrolled, a CRF (or eCRF) must be completed and signed by the principal 
investigator or subinvestigator (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 prerandomization screening period if a CRF was initiated). If a subject 
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.


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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 or IEC in accordance with local requirements. Approval must be obtained before 
changes can be implemented.
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.


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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.
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
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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 
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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 
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COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
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Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
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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 
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20280
Schwarz KB, Gonzalez-Peralta RP, Murray KF, Molleston JP, Haber BA, Jonas 
MM, et al. The combination of ribavirin and peginterferon is superior to 
peginterferon and placebo for children and adolescents with chronic hepatitis C. 
Gastroenterology 2011;140 (2):450-8 e1.
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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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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.
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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.
23275
Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. 
Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J 
Med 2013;368 (1):34-44.
24713
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, 
Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without 
treatment options. N Engl J Med 2013;368 (20):1867-77.
24715
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et 
al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 
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Sciences, Inc. Foster City, CA. December 2013.  


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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


Sofosbuvir 
Protocol GS-US-334-1112 
Final 
Gilead Sciences, Inc. 
Amendment 2 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Arm Study to Investigate the 
Safety and Efficacy of Sofosbuvir + Ribavirin in Adolescents and Children with 
Genotype 2 or 3 Chronic HCV Infection 
GS-US-334-1112, Protocol Amendment 2, 14 March 2014 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PD 
tiTTVO 
Bittoo Kanwar, MD (Printed) 
Medical Monitor 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to 
all information provided by Gilead Sciences, Inc. I will discuss this material with them to 
ensure that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 81 
14 March 2014 


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Final
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Amendment 2
CONFIDENTIAL
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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 7
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Complete Physical Examination
X
X
Symptom-directed Physical Examination
X
X
Tanner Pubertal Stage Assessment
X
Collect Height & Weight Measurement 
with Percentiles
X
Vital Signsa
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
Pregnancy Prevention Counselingf
X
SOF Swallowability Assessment
X
Xh
Quality of Life Survey
Xi
Review of Study 
Medication Compliance
X
X
Study Drug Dispensingb
X


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Protocol GS-US-334-1112
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Amendment 2
CONFIDENTIAL
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14 March 2014
Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 7
(+ 3 days)
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X
X
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
Subject Dosing Diary
X
X
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
PPD


Sofosbuvir
Protocol GS-US-334-1112
Final
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Amendment 2
CONFIDENTIAL
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14 March 2014
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 drugs on Day 7 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 8, 
and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 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 (subjects 12 to < 18 years of age only).
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.
PPD


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 2
CONFIDENTIAL
Page 85
14 March 2014
Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningc
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12g
16g
20g
24g
Early 
Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Complete Physical Examination
X
X
X
X
X
Symptom-Directed Physical Examination
X
X
X
X
X
X
Tanner Pubertal Stage Assessment
X
X
X
X
Collect Height & Weight Measurement 
with Percentiles
X
X
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 Counselingh
X
X
X
X
SOF Swallowability Assessment
X
Xj
Quality of Life Surveye
X
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
X
X
X
Study Drug Dispensingb
X
X
X
Xi
X
X


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Protocol GS-US-334-1112
Final
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Amendment 2
CONFIDENTIAL
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Screeningc
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12g
16g
20g
24g
Early 
Termination
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
Viral Sequencing d
X
X
X
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testing
X
X
X
X
X
X
X
X
X
Single PK
X
X
X
X
X
X
X
X
X
Urinalysis, Urine Drug Test
X
HCV Genotyping, IL28B
X
HCV antibody, HIV 1/2 antibody, HBs 
antigen, HAV antibody
X
HbA1c
X
TSH
X
X
X
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, 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 at Day 1, Week 12 (only GT-2 subjects), Week 24 (only GT-3 subjects) and Early Termination 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
GT-2 subjects will complete through the Week 12 visit; GT-3 subjects will complete through the Week 24 visit. 
h
Including partner pregnancy prevention for male participants (subjects 12 to < 18 years of age only).
i
Study Drug Dispensing at the Week 12 visit for GT-3 subjects only
j
Swallowability can occur at Day 1 if not completed during screening.
PPD
PPD


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Protocol GS-US-334-1112
Final
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Amendment 2
CONFIDENTIAL
Page 87
14 March 2014
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
Xd
Xd
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment 
X
X
Collect Height & Weight Measurement with Percentiles
X
X
Bone Age Assessment
X
Pregnancy Prevention Counseling e
X
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Testc
X
X
X
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
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.


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 2
CONFIDENTIAL
Page 88
14 March 2014
d
At Post Treatment Week 12 and 24, only SAEs will be captured
e
Including partner pregnancy prevention for male participants (subjects 12 to < 18 years of age only).


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 2
CONFIDENTIAL
Page 89
14 March 2014
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18June2012
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


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 2
CONFIDENTIAL
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
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
Infant, 2 – 7 Days
1250 to 1500/mm3
1.25 to 1.50 GI/L
1000 to 1250/mm3
1.00 to < 1.25 GI/L
750 to 1000/mm3
0.75 to < 1.00 GI/L
750/mm3
< 0.75 GI/L
Infant, 1 Day
4000 to 5000/mm3
4.00 to 5.00 GI/L
3000 to 4000/mm3
3.00 to < 4.00 GI/L
1500 to 3000/mm3
1.50 to < 3.00 GI/L
1500/mm3
< 1.50 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


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 2
CONFIDENTIAL
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0% 


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Protocol GS-US-334-1112
Final
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Amendment 2
CONFIDENTIAL
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
146  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 2
CONFIDENTIAL
Page 93
14 March 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4  mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


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Protocol GS-US-334-1112
Final
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Amendment 2
CONFIDENTIAL
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14 March 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63  to LLN mmol/L
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.14 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 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L


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Protocol GS-US-334-1112
Final
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Amendment 2
CONFIDENTIAL
Page 95
14 March 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol/L to LLN
57 to 87 μmol/L
27 to 57 μmol/L
27 μmol/L
Creatinine 
1.50 to 2.00 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol/L
177 to 265 μmol/L
265 to 530 μmol/L
530 μmol/L
Bicarbonate
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
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L
LDL
(Fasting)
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
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


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Amendment 2
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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


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


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


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


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


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


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Amendment 2
CONFIDENTIAL
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening consequences 
OR Aggressive intervention 
indicated [eg, tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (eg, diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening consequences 
(eg, sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock


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Amendment 2
CONFIDENTIAL
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14 March 2014
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids)
Life-threatening consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(eg, hypotensive shock)


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Amendment 2
CONFIDENTIAL
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14 March 2014
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood (eg, 
agitation, anxiety, 
depression, mania, 
psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities 
Alteration causing greater than 
minimal interference with 
usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional activities 
Behavior potentially harmful 
to self or others (eg, 
suicidal/homicidal ideation or 
attempt, acute psychosis) OR 
Causing inability to perform 
basic self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no 
or minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities 
Disabling ataxia causing 
inability to perform basic self-
care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater than 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 


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


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Amendment 2
CONFIDENTIAL
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14 March 2014
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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Amendment 2
CONFIDENTIAL
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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


Sofosbuvir
Protocol GS-US-334-1112
Final
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Amendment 2
CONFIDENTIAL
Page 108
14 March 2014
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. 


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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1. Background
RBV 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 sofosbuvir demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of sofosbuvir 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 randomization. They must also agree 
to one of the following from 3 weeks prior to Day 1 until 6 months after last dose of RBV:

Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) is not permitted.
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 the last dose of RBV:
— intrauterine device (IUD) with a failure rate of < 1% per year
— female barrier method: cervical cap or diaphragm with spermicidal agent
— tubal sterilization
— vasectomy in male partner


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— 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 
Baseline until 7 months after the last dose of 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.
Male subjects must agree to refrain from sperm donation for at least 7 months after the last 
dose of 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. 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.

Prot_004.pdf: 
Study Title: 
Sponsor: 
IND No.: 
EudraCT Number: 
Indication: 
Protocol ID: 
Gilead Sciences Medical 
Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Aim 
Study to Investigate the Safety and Efficacy of 
Sofosbuvir + Ribavirin in Adolescents and Children with 
Genotype 2 or 3 Chronic HCV Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
106739 
2014-002283-32 
Hepatitis C Vims Infection 
GS-US-334-1112 
Name: 
Telephone: 
Mobile: 
Fax: 
E-mail: 
Original: 
Alnendment 1: 
Alnendment 2: 
Bittoo Kanwar, MD, 
rpo 
PD 
PD 
I"'U 
20 December 2013 
10 Febrmuy 2014 
14 March 2014 
Alnendment 3: 
10 October 2014 
Alnendment 4: 
12 November 2014 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, particularly lmpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, yom staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from Gilead 
Sciences, Inc., except to the extent necessruy to obtain infonned consent from those persons to 
whom the dmg may be administered. 


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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....................................................................16
1.
INTRODUCTION ..............................................................................................................................................19
1.1.
Background ............................................................................................................................................19
1.2.
Sofosbuvir ..............................................................................................................................................20
1.2.1.
Summary of Additional Clinical Experience with Sofosbuvir .............................................20
1.3.
Ribavirin (RBV).....................................................................................................................................22
1.4.
Rationale for the Current Study .............................................................................................................22
1.5.
Rationale for Dose Selection of SOF .....................................................................................................23
1.6.
Overall Risk/Benefit Assessment...........................................................................................................23
2.
OBJECTIVES.....................................................................................................................................................25
3.
STUDY DESIGN................................................................................................................................................26
3.1.
Treatment Plan and Regimen .................................................................................................................26
3.1.1.
PK Lead-in ...........................................................................................................................26
3.1.2.
Treatment Phase ...................................................................................................................26
3.2.
Visit Schedule ........................................................................................................................................28
3.2.1.
PK Lead-in ...........................................................................................................................28
3.2.2.
Treatment Phase ...................................................................................................................29
3.3.
Virologic Response-Based Stopping Criteria.........................................................................................29
3.4.
Treatment Discontinuations Criteria ......................................................................................................30
3.5.
Discontinuations.....................................................................................................................................30
3.6.
Pharmacogenomic Substudy ..................................................................................................................30
3.7.
Long-Term Follow-Up...........................................................................................................................30
3.8.
Breakthrough Futility Assessment .........................................................................................................31
3.9.
Reconsent...............................................................................................................................................31
4.
SUBJECT POPULATION..................................................................................................................................32
4.1.
Number of Subjects and Subject Selection ............................................................................................32
4.2.
Inclusion Criteria....................................................................................................................................32
4.3.
Exclusion Criteria...................................................................................................................................33
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................34
5.1.
Randomization and Blinding..................................................................................................................34
5.2.
Sofosbuvir ..............................................................................................................................................34
5.2.1.
Description and Handling.....................................................................................................34
5.2.2.
Storage and Handling...........................................................................................................35
5.2.3.
Dosage and Administration of SOF .....................................................................................36
5.3.
Ribavirin.................................................................................................................................................36
5.3.1.
Description and Handling of RBV .......................................................................................36
5.3.2.
Dosage and Administration of RBV.....................................................................................37
5.4.
Co-administration of SOF and RBV ......................................................................................................38
5.5.
Study Drug Compliance.........................................................................................................................38
5.6.
Prior and Concomitant Medications.......................................................................................................38


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6.
STUDY PROCEDURES ....................................................................................................................................40
6.1.
Subject Enrollment.................................................................................................................................40
6.2.
Screening Assessments ..........................................................................................................................40
6.2.1.
Screening Visit (Day –28 to Day 0) .....................................................................................40
6.3.
PK Lead-in: Treatment Assessments .....................................................................................................42
6.3.1.
Day 1 ....................................................................................................................................42
6.3.2.
Day 3 ....................................................................................................................................43
6.3.3.
Day 7 – Intensive PK ...........................................................................................................43
6.4.
Treatment Phase: Treatment Assessments .............................................................................................45
6.4.1.
Day 1 ....................................................................................................................................45
6.4.2.
Weeks 1 and 2 (3 days) .....................................................................................................47
6.4.3.
Weeks 4 and 8 (3 days) .....................................................................................................47
6.4.4.
Week 12 (3 days) ..............................................................................................................48
6.4.5.
Week 16 and 20 (3 days) – GT-3 Subjects only................................................................49
6.4.6.
Week 24 (3 days) – GT-3 Subjects only ...........................................................................49
6.4.7.
Unscheduled Visit/Early Termination Visit .........................................................................50
6.5.
Post-Treatment Assessments..................................................................................................................51
6.5.1.
4-Week Post-Treatment Visit (5 days)..............................................................................51
6.5.2.
12-Week Post-Treatment Visit (5 days)............................................................................52
6.5.3.
24-Week Post-Treatment Visit (5 days)............................................................................53
6.6.
Procedures and Specifications................................................................................................................53
6.6.1.
Clinical Laboratory Analytes ...............................................................................................53
6.6.2.
Medical History....................................................................................................................54
6.6.3.
Complete Physical Examination...........................................................................................54
6.6.4.
Tanner Pubertal Stage Assessment.......................................................................................54
6.6.5.
Height & Weight Measurement with Percentiles .................................................................54
6.6.6.
Bone Age Assessment..........................................................................................................55
6.6.7.
Swallowability Assessment..................................................................................................55
6.6.8.
Vital Signs............................................................................................................................55
6.6.9.
Body Mass Index (BMI).......................................................................................................55
6.6.10.
Estimated Glomerular Filtration Rate (GFR) .......................................................................55
6.6.11.
Viral Sequencing (Archive)..................................................................................................56
6.6.12.
Pregnancy Testing................................................................................................................56
6.6.13.
Quality of Life Survey (PedsQL™).......................................................................................56
6.6.14.
SOF Granule Palatability Assessment..................................................................................56
7.
TOXICITY MANAGEMENT............................................................................................................................57
7.1.
Modification of Dose/Schedule Due to Toxicity....................................................................................57
7.2.
Subject Stopping Rules for SOF ............................................................................................................57
8.
ADVERSE EVENTS MANAGEMENT ............................................................................................................58
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................58
8.1.1.
Adverse Events.....................................................................................................................58
8.1.2.
Serious Adverse Events........................................................................................................58
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................59
8.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................59
8.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................59
8.2.2.
Assessment of Severity ........................................................................................................60
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events.......................................................................................................................................60
8.4.
Gilead Reporting Requirements.............................................................................................................62
8.5.
Special Situations Reports......................................................................................................................62


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8.5.1.
Definitions of Special Situations..........................................................................................62
8.5.2.
Instructions for Reporting Special Situations.......................................................................63
9.
STATISTICAL CONSIDERATIONS................................................................................................................65
9.1.
Analysis Objectives and Endpoints........................................................................................................65
9.1.1.
Analysis Objectives..............................................................................................................65
9.1.2.
Primary Endpoints................................................................................................................66
9.1.3.
Secondary Endpoints............................................................................................................66
9.2.
Analysis Conventions.............................................................................................................................66
9.2.1.
Analysis Sets ........................................................................................................................66
9.2.2.
Data Handling Conventions .................................................................................................67
9.2.3.
Interim Analysis ...................................................................................................................68
9.3.
Demographic Data and Baseline Characteristics ...................................................................................68
9.4.
Pharmacokinetic Analysis......................................................................................................................68
9.5.
Safety Analysis.......................................................................................................................................69
9.5.1.
Extent of Exposure...............................................................................................................69
9.5.2.
Palatability of SOF oral granules .........................................................................................69
9.5.3.
Adverse Events.....................................................................................................................69
9.5.4.
Laboratory Evaluations ........................................................................................................70
9.5.5.
Other Safety Evaluations......................................................................................................70
9.6.
Efficacy Analysis ...................................................................................................................................71
9.6.1.
Primary Efficacy Analysis....................................................................................................71
9.6.2.
Secondary Efficacy Analysis................................................................................................71
9.6.3.
Subgroup Analysis ...............................................................................................................71
9.7.
Quality of Life Analysis.........................................................................................................................72
9.8.
Data Monitoring Committee ..................................................................................................................72
9.9.
Sample Size............................................................................................................................................72
10.
RESPONSIBILITIES..........................................................................................................................................73
10.1.
Investigator Responsibilities ..................................................................................................................73
10.1.1.
Good Clinical Practice..........................................................................................................73
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval...............................................................................................................................73
10.1.3.
Informed Consent/Assent.....................................................................................................74
10.1.4.
Confidentiality......................................................................................................................74
10.1.5.
Study Files and Retention of Records ..................................................................................74
10.1.6.
Case Report Forms...............................................................................................................76
10.1.7.
Drug Accountability.............................................................................................................76
10.1.8.
Inspections............................................................................................................................76
10.1.9.
Protocol Compliance............................................................................................................76
10.2.
Sponsor Responsibilities ........................................................................................................................77
10.2.1.
Protocol Modifications.........................................................................................................77
10.2.2.
Study Report and Publications .............................................................................................77
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................77
10.3.1.
Access to Information for Monitoring..................................................................................77
10.3.2.
Access to Information for Auditing or Inspections ..............................................................78
10.3.3.
Study Discontinuation..........................................................................................................78
11.
REFERENCES ...................................................................................................................................................79
12.
APPENDICES ....................................................................................................................................................81
Appendix 1.
Investigator Signature Page....................................................................................................82
Appendix 2.
Study Procedures Table..........................................................................................................83


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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............89
Appendix 4.
Tanner Stages .......................................................................................................................112
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................113
LIST OF IN-TEXT TABLES
Table 1-1.
GS-US-334-1111: Statistical Comparison of SOF, GS-566500, and GS-331007 PK 
Parameters ..............................................................................................................................21
Table 7-1.
RBV Dose Reduction Guidelines...........................................................................................57
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................28


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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, Single-Arm Study 
to Investigate the Safety and Efficacy of Sofosbuvir + Ribavirin in 
Adolescents and Children with Genotype 2 or 3 Chronic HCV 
Infection
IND Number:
EudraCT Number:
106739
2014-002283-32
Study Centers:
Approximately 50 sites in the United States, Europe, Russia, 
Australia, New Zealand, and India
Number of Subjects:
Approximately 100 subjects
Target Population:
Adolescents and children (aged 3 to < 18) with chronic hepatitis C 
virus (HCV) infection
Treatment Duration:
PK Lead-in – 7 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 sofosbuvir (SOF) in HCV-infected pediatric subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety and tolerability of 7 days of dosing of SOF
+ ribavirin (RBV) in HCV-infected pediatric subjects
The primary objectives of the Treatment Phase of this study are:

To evaluate the safety and tolerability of SOF + RBV for 12 or 
24 weeks in HCV-infected pediatric subjects with genotype (GT)
GT-2 or GT-3, respectively


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Study Design: 
CONFIDENTIAL 
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Amendment4 
The seconda!y objectives of the Treatment Phase ofthis study are: 
• 
To detennine the antiviral efficacy of SOF + RBV treatment in 
GT-2 and GT-3 HCV-infected subjects separately, as assessed by 
the proportion of subjects with SVR 12 weeks after completion of 
treatment (SVR12) 
• 
To detennine the antiviral efficacy of SOF + RBV treatment in 
GT-2 and GT-3 HCV-infected subjects separately, 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 u·eatment 
• 
To evaluate the emergence of viral resistance to SOF during 
u·eatment and after completion of u·eatment 
• 
To evaluate the palatability of SOF oral granules at Day 1, as 
applicable. 
The explorat01y objective of this study is: 
• 
PD 
Open-label, multi-cohort, two-part study evaluating the PK, safety, 
and antiviral activity of SOF in chronic HCV -infected pediau·ic 
subjects. 
The study will be divided into 2 patts as follows: 
PK Lead-in: Will evaluate and/or confitm age appropriate SOF 
doses by analyzing PK, safety, and antiviral activity of SOF 
administered in combination with RBV through 7 days of dosing for 
each of three cohorts. Children aged 3 < 6, children aged 6 to 
< 12 years and adolescents aged 12 to < 18 years with genotype GT-2 
or GT-3 HCV infection and evidence ofHCV RNA~ 1000 ID/mL at 
study ently will be evaluated. Subjects must be u·eatment naive to 
pruticipate in the PK Lead-in Phase. 
Three coh01ts of up to 10 subjects each will be sequentially enrolled: 
• 
Coh01t 1: 12 to < 18 yeru·s old weighing~ 45kg 
• 
Coh01t 2: 6 to < 12 yeru·s old 
• 
Coh01t 3: 3 to < 6 yeru·s old 
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The study will start with Cohort 1.  Subjects will receive SOF
(400 mg adult tablet or 4 x 100 mg tablets if determined necessary 
based on SOF swallowability assessment) + RBV for 7 days with 
intensive PK conducted on Day 7. 
PK Lead-in subjects in each cohort (Cohorts 1, 2 and 3) will 
immediately enroll in the Treatment Phase as they complete Day 7 of 
the PK Lead-in Phase.  They will continue dosing with SOF + RBV 
with no interruption of study drug administration.  Subjects rolling 
over from the PK Lead-in will not be required to perform 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 will be reviewed to confirm 
the appropriateness of the evaluated SOF 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: Will be initiated sequentially by cohort after 
confirmation of age-appropriate SOF dosage levels. Subjects who 
participated 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.  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.
Children aged 3 to < 12 years and adolescents aged 12 to < 18 years 
with GT-2 or GT-3 infection and evidence of HCV RNA ≥1000 
IU/mL at study entry (those who were dosed in the PK Lead-in Phase
will have met this criteria prior to enrollment) will be evaluated. 
Subjects enrolled in the study will receive the following regimen:

GT-2 subjects: SOF + RBV for 12 weeks

GT-3 subjects: SOF + RBV for 24 weeks
The study will enroll both treatment-naïve and treatment-experienced 
pediatric subjects, with up to 20 subjects allowed to be treatment 
experienced. Approximately 100 total subjects, including subjects 
that participate in the PK Lead-in Phase, will be enrolled in Treatment
Phase as follows

Group 1: Approximately 50 adolescent subjects (12 to < 18 years 
of age)

Group 2: Approximately 50 pediatric subjects (3 to < 12 years of 
age)


Sofosbuvir 
Protocol GS-US-334-1112 
Gilead Sciences, Inc. 
Substudy and 
Long-Te1m 
Follow-Up Study: 
Diagnosis and Main 
Eligibility Criteria: 
CONFIDENTIAL 
Final 
Amendment4 
The following defmitions 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 dming 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, 12 (and Weeks 16, 20, and 24 for GT-3) dming 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 
encomaged to discuss treatment with standard-of-care (SOC) therapy 
with their healthcare provider. 
Pharmacogenomics (PG) Substudy 
PD 
Long-Term Follow-up 
Subjects who attain SVR24 or those who do not attain SVR24 and do 
not initiate experimental or approved anti-HCV therapy will be 
followed eve1y 6 months for assessments of growth, quality of life, 
and long-tenn viral suppression (if applicable) in a separate protocol 
(GS-US-334-1113). This follow-up will continue for 5 years. 
Chronic HCV-infected, treatment-naive and up to 20 subjects may 
be treatment experienced, male and female subjects aged 3 to < 18. 
Inclusion Criteria: 
• 
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 perf01m ed prior to the Day 1 visit with evidence 
of chronic HCV infection 
• 
Infection with HCV GT-2 or GT-3 as dete1mined at Screening 
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
HCV RNA ≥1000 IU/mL at Screening 

For the PK Lead-in Phase: subjects in cohort 1 (age 12 to 
<18 years of age) must weigh ≥ 45kg

Agree to use 2 forms of highly effective contraception, as 
referenced in Appendix 5, for the duration of the study and for 
6 months (for female subjects) or 7 months (for male subjects)
after the last dose of study medication if age, cultural, and sexual 
activity status appropriate (eg: if sexually active; does not pertain 
to pre-pubertal subjects). Females of childbearing potential
(as defined in Appendix 5) must have a negative pregnancy test at 
Screening and Day 1.
Exclusion Criteria:

Hematologic or biochemical parameters at screening outside the
protocol-specified requirements

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)

Chronic use of systemic immunosuppressive agents or
immunomodulatory agents

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.

See Sections 4.2 and 4.3 of the protocol for full eligibility criteria.


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Amendment 4
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Study Procedures/
Frequency:
PK Lead-in Phase: 
Screening assessments will be completed within 28 days of the Day 1
visit. 
Screening assessments will include: physical examination, vital signs
(including height and weight), concomitant medications, safety 
laboratory tests, coagulation tests, HCV RNA, serology (HIV, HAV, 
HCV, HBV), alpha-1 anti-trypsin, serum β-human chorionic 
gonadotropin hCG (females of childbearing potential only), thyroid 
stimulating hormone, HbA1c, IL28B genotyping, alpha fetoprotein, 
urinalysis, and urine drug screen.
Study Visits will occur at Screening, Day 1, Day 3, and Day 7.
On-Treatment assessments include adverse events (AEs), 
concomitant medications, physical examination, bone age assessment, 
vital signs, height, weight, Tanner Pubertal Stage assessment, safety 
laboratory tests, HCV RNA, viral sequencing sampling, urine 
pregnancy tests (females of child bearing potential only), pregnancy 
prevention counseling and urinalysis. Coagulation will be performed 
at Day 1 and Day 7. SOF swallowability assessment with placebo will 
be performed at screening up to Day 1 to assess a subject’s ability to 
swallow the 400 mg or 100 mg SOF tablet (only subjects 
administered SOF in tablet form).
Subjects (up to 10 subjects) enrolled in the PK Lead-in Phase will 
participate in an intensive PK evaluation on Day 7. Following 
completion of the Day 7 intensive PK visit, subjects will then return 
for scheduled study visits outlined in the Treatment Phase and 
continue dosing with SOF + RBV with no interruption of study drug 
administration.  Subjects will be administered a dosing diary with 
instructions.
Treatment Phase: 
Screening assessments will be completed within 28 days of the Day 1 
visit. For subjects continuing from the PK Lead-in, screening for 
Treatment Phase will not be required.
Screening assessments will include physical examination, vital signs
(including height and weight), concomitant medications, safety 
laboratory tests, coagulation tests, HCV RNA, serology (HIV, HAV, 
HCV, HBV), alpha-1 anti-trypsin serum β-human chorionic
gonadotropin hCG (females of childbearing potential only), thyroid
stimulating hormone, AbA1c, IL28B genotyping, alpha fetoprotein, 
urinalysis, and urine drug screen.

GT-2 Subjects: Study visits for GT-2 subjects will occur at 
screening, Day 1, and the end of Weeks 1, 2, 4, 8, and 12. 


Sofosbuvir 
Protocol GS-US-334-1112 
Final 
Gilead Sciences, Inc. 
Amendment 4 
Test Product, Dose, 
and Mode of 
Administration: 
CONFIDENTIAL 
• 
GT-3 Subjects: Study visits for GT-3 subjects will occur at 
screening, Day 1, and the end ofWeeks 1, 2, 4, 8, 12, 16, 20, 
and 24. 
All Treatment Phase subjects will then retum for follow-up visits at 4, 
12 and 24 weeks after discontinuation of therapy. 
On-u·eatment assessments will include adverse events, concomitant 
medications, physical examination, vital signs (including height and 
weight), safety laborat01y tests, coagulation tests, HCV RNA, PK 
samples, and urine pregnancy tests (females of childbearing potential 
only). Tanner Pube1ial Stage assessment will be perf01m ed at Day 1, 
end of u·eatment, post-u·eatment Week 12 and post-u·eatment 
24-week; parental heights will be recorded at screening. The Bone 
Age Assessment will be perfonned at Day 1 and post-u·eatment Week 
24 visit. If available, results from liver biopsies will be collected at 
screening. SOF swallowability assessment with placebo will be 
perf01m ed at screening up to Day 1 to assess a subject's ability to 
swallow a 400 mg or 100 mg SOF tablet For subjects continuing from 
the PK Lead-in, the screening, Day 1 and Week 1 visits of the 
Treatment Phase will not be required. Post-u·eahnent assessments will 
include adverse events, concomitant medications, vital signs, safety 
laborat01y tests, HCV RNA, and urine pregnancy tests (females of 
childbearing potential only). Samples for viral RNA 
sequencing/phenotyping will be collected at Day 1 and eve1y visit 
thereafter. 
Palatability of SOF oral granules will be assessed at Day 1, as 
applicable. 
PD 
PKLead-in: 
(Coh01i 1) SOF 400 mg tablets will be administered once daily along 
with RBV weight-based dosing. Subjects detennined lmable to 
swallow the placebo for 400 mg SOF tablet (by SOF Placebo 
swallowability assessment at Screening or at any time during the 
study) will be re-assigned to 4 x 100 mg tablets daily. 
Intensive PK and safety results fi:om the PK Lead-In of each Coh01i 
will be reviewed to confnm the appropriateness of the evaluated SOF 
dose for the Treatment Phase of that Coh01i as well as to dete1mine 
the age-appropriate dose to be evaluated in the PK Lead-in of the next 
Coh01i. 
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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.
RBV Weight-Based Dosing (All age groups):
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.
65-80 (143 – 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 SOF. The evening dose of RBV will be taken 
with food.
Reference Therapy:
None


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Amendment 4
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Evaluation Criteria:
Safety:
AEs, laboratory tests, and Tanner Pubertal Stage assessments will be 
collected throughout the study. 
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, steady-state PK of SOF and its major 
metabolites GS-566500 and GS-331007 will be assessed at Day 7.
For Cohorts 1 and 2, plasma samples will be collected for PK 
analyses following dosing of study drugs on Day 7 at the following 
time points: 0 (predose), 0.5, 1, 2, 3, 4, 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), 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 SOF, 
GS-566500 and GS-331007 and/or ribavirin will be assessed.
The effect of age and SOF dose on PK (SOF and GS-331007) will be 
explored. 
Statistical Methods:
For the PK Lead-in, plasma PK parameters Cmax, Tmax, Clast, Tlast, Ctau, 
AUCtau, and t1/2 will be estimated.  The PK parameters will be 
summarized by cohort. The effect of age and SOF dose on PK 
(SOF and GS-331007) 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 age group, by GT and by overall. Primary efficacy 
endpoint is SVR12 in all enrolled and treated subjects and will be 
summarized by age group, by genotype, by overall and by age group 
and GT.  Point estimate and its 95% confidence interval will be 
provided.  
In addition, SVR12 will be compared with historical SVR12 rate of 
80% from pegylated interferon + ribavirin for pediatric GT-2 and 
GT-3 subjects {20280}, using two-sided exact one-sample binomial 
test at the 0.05 significance level.  
Secondary efficacy endpoints are SVR4, SVR24, breakthrough and 
relapse.


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Amendment 4
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Palatability of SOF oral granules will be summarized using 
descriptive statistics by appropriate age group, by genotype, by 
overall and by age group and genotype.
Subgroup analysis on SVR12 will be performed by treatment 
experience (treatment-naive vs. experienced) and 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). 
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.
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 age group, by GT, by 
overall and by age group and GT.
With approximately 50 subjects enrolled into each age group of 
Treatment Phase, a two-sided 95.0% confidence interval of the 
SVR12 rate will extend at most 11.1% in both directions from the 
observed SVR12 rate, assuming the expected SVR12 rate is 80%. In 
addition, a sample size of 100 subjects will provide over 80% power 
to detect an 11% improvement in SVR12 rate from 80% to 91% using 
two-sided one-sample binomial test at significance level of 0.05.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


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Gilead Sciences, Inc.
Amendment 4
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
β-hCG
β-human chorionic gonadotropin
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)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BW
body weight
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)
CMH
Cochran-Mantel-Haenszel
COPD
Chronic obstructive pulmonary disease
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
Emax
maximal effect
EU
European Union
EVR
Early virologic response
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor


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Amendment 4
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
GFR
glomerular filtration rate
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
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
IV
Intravenous
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDH
Lactase dehydrogenase
LLN
lower limit of the normal range
LLOD
Lower limit of detection
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


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Amendment 4
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
PI
Protease inhibitor
PK
Pharmacokinetic
RBC
Red blood cell count 
RBV
Ribavirin
RDRP
RNA-dependent RNA polymerase
RNA
ribonucleic acid
RVR
rapid virologic response 
SADR
Serious adverse drug reaction
SAE
serious adverse event
SD
Standard deviation
SOC
Standard of Care
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TND
Target not detected
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 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 standard of care 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.
Sofosbuvir
Sovaldi™(Sofosbuvir) is a potent nucleotide analogue that inhibits HCV RNA replication in 
vitro and has demonstrated high rates of sustained viral response (SVR) when given with RBV
+/- PEG to subjects with chronic GT- 1, 2, 3 or 4 HCV infection {27503}, {23275}, {24713}, 
{24715}.  Sovaldi™has been approved in the United States by the Food and Drug Administration 
(FDA) for the treatment of HCV infection GT- 1, 2, 3 and 4 including treatment naïve and 
experienced patients and HIV/HCV co-infected patients.  Sovaldi™is also approved in EU, 
Canada and Turkey.
For further information on the clinical pharmacology, virology, safety and efficacy of SOF, 
please refer to the current version of the Investigator’s Brochure and the local prescribing 
information.
1.2.1.
Summary of Additional Clinical Experience with Sofosbuvir
A phase 1 study (GS-US-334-1111) was conducted to evaluate the relative bioavailability of, and 
effect of food on Sofosbuvir oral granules in healthy adult subjects to support the use of this 
formulation in subjects unable to swallow the tablet formulations.  The preliminary results of this 
study are presented below.
1.2.1.1.
GS-US-334-1111 Study Design
Study GS-US-334-1111 is a single dose, randomized, 3-period crossover phase 1 study 
conducted in healthy adult subjects.  Subjects were administered 400 mg SOF in the following 
treatments in a randomized order: 1 x 400 mg SOF (adult formulation) in the fasted state, 
8 x 50 mg SOF granules in capsules in the fasted state, and 8 x 50 mg SOF granules in capsules 
after a standardized high-fat meal.  Prior to administration the SOF granules were removed from 
the capsules and administered orally with water.  18 healthy subjects were enrolled and 
completed all treatment periods of this study.


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Amendment4 
1.2.1.2. 
GS-US-3 34-1111 Preliminruy Phan nacokinetic Results 
Preliminruy PK results ru·e available for all 18 subjects. Statistical comparisons of the primaty 
PK parruneters AUCinr, AUC1ast, and Cmax for SOF, its intennediate metabolite GS-566500, and 
the primruy circulating metabolite GS-331007 which is considered the primruy analyte of interest 
for PK studies ru·e presented below. Statistical compru·isons include the %GMR and 90%Cls of 
exposures achieved after administration of 8 x 50 mg SOF granules in capsules fasted 
(Granules Fasted) relative to 1 x 400 mg SOF tablet fasted (Tablet Fasted), and 8 x 50 mg SOF 
granules in capsules fed (Granules Fed) relative to 8 x 50 mg SOF granules in capsules fasted 
(Granules Fasted) (Table 1-1). Bioequivalence of the pediatric granule f01mulation and the adult 
tablet fonnulation was concluded as a result of the 90%Cls of the %GMRs for GS-331 007 
AUC1ast, AUCinf, and Cmax (protocol specified primaty endpoints) being contained within the 
predefmed boundaries of 80-125%. Additionally, administration of the pediatric granule 
f01mulation after a high-fat meal or fasted resulted in bioequivalent exposures of GS-331007 as 
the 90%Cls of the %GMRs for GS-331 007 AUC1ast and AUCinf (protocol specified primru-y 
endj)oints were contained within the redefined bmmdat·ies of 80-125%. PPD 
Table 1-1. 
Parameter (N=18) 
SOF 
AUCinf 
AUCtast 
Cmax 
GS-566500 
AUCinf 
AUCtast 
cmax 
GS-331007 
AUCinf 
AUCtast 
cmax 
GS-US-334-1111: Statistical Comparison of SOF, GS-566500, and 
GS-331 007 PK Parameters 
o/oGMR (90%CI) 
Granules Fasted/Tablet Fasted 
Granules Fed/Granules Fasted 
100 (86.0, 117) 
168 (144, 195) 
100 (85.8, 117) 
167 (143, 195) 
83.6 (64.5, 108) 
90.9 (70.2, 118) 
96.2 (85.1, 109) 
165 (144, 195) 
94.5 (82.3, 109) 
166 (145, 191) 
91.8 (90.2, 105) 
128 (112, 146) 
104 (97.9, 111) 
87.9 (82.5, 93.6) 
104 (97.6, 112) 
86.3 (80.7, 92.7) 
106 (95.6, 117) 
60.3 (54.5, 66.8) 
Note: %GMR and 90%Cls are presented to 3 significant digits 
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1.2.1.3.
GS-US-334-1111 Preliminary Conclusions
As assessed by GS-331007, the new sofosbuvir (8 x 50 mg) granule formulation was 
bioequivalent to the existing sofosbuvir 1 x 400 mg tablet formulation under fasted conditions.  
The sofosbuvir (8 x 50 mg) granule formulation is recommended to be administered without 
regard to food.
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.
1.4.
Rationale for the Current Study
This clinical study is designed to evaluate the efficacy and safety of treatment with SOF + RBV
for adolescents and children with GT-2 and GT-3 chronic HCV infection. 
Currently PEG and weight-based RBV are considered the standard of care for the treatment of 
HCV infection in children. However, this PEG and RBV regimen is long in duration, relatively 
toxic, and not well tolerated. Thus, there continues to be a need for new treatments for HCV that 
combine potent and sustained efficacy with improved tolerability and safety. Therapy that 
provides shorter duration and improved efficacy with an all-oral regimen would be a significant 
advancement over current options in pediatric patients.
The main aim for the treatment of pediatric patients with HCV is to eliminate the need to use 
PEG regimens. In this way, pediatric patients are able to avoid the necessity of weekly injections, 
which can be traumatic and burdensome, and also to significantly reduce the serious adverse 
events seen on administration of PEG regimens. 
Sovaldi (sofosbuvir 400 mg tablet) is approved in 35 countries worldwide in combination with 
other medicinal products, for the treatment of adults with chronic hepatitis C infection. SOF in
combination with RBV would provide an all-oral, IFN-free regimen with a shorter treatment 
duration (12 - 24 weeks of SOF treatment versus standard-of-care 24 to 48 weeks of treatment)
and would offer another important option in the treatment of HCV infection in the pediatric 
population.


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Phase 3 data demonstrates that high SVR12 rates in subjects with GT-2 HCV infection can be 
achieved with 12 weeks treatment with SOF+RBV, however, these studies suggest that patients 
with GT-3 infection may benefit from a longer treatment duration (i.e. 24 weeks) with 
SOF + RBV. Optimal duration of SOF + RBV, for GT-3 subjects, was established in FISSION 
and VALENCE.  Increasing treatment duration from 12 to 24 weeks increased SVR12 from 
61 to 93% in non-cirrhotics and from 34 to 92% in cirrhotics.
1.5.
Rationale for Dose Selection of SOF
SOF 400 mg, once daily, when dosed in combination with RBV with or without PEG has 
demonstrated broad genotypic efficacy and favorable safety profile in over 3300 HCV-infected 
adult subjects across multiple patient populations in Phase 2 and 3 trials. This dose is the 
marketed dose of SOF for the treatment of HCV-infection in adults.
Selection of doses of SOF for adolescents and younger age groups will target systemic exposures 
similar to those observed in adults at the marketed dose, taking into account body weight/body 
surface area, the potential ontogenic changes in hepatically expressed carboxylesterase 1 (CES1) 
and Cathepsin A (CatA) enzymes, and the results obtained in older age groups.  Available data 
suggest comparable hepatic expression of CES1 in adolescents and adults, with modestly 
decreased expression in children.  As such, the adult clinical dose, 400mg, will be evaluated in 
adolescents (12 to <18 years old) {20288}.  Safety and PK data in the adolescent group
(Cohort 1) in the PK Lead-in, will inform dose selection for the younger age groups in addition 
to body weight/body surface area. 
Age-appropriate formulations of SOF (a smaller, 100 mg strength tablet and a granule
formulation) that offer an important option in the treatment of HCV infection in the pediatric 
population will be evaluated in children below 12 years of age or children who are unable to 
swallow the adult solid-dose 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 standard of care 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. 
SOF has demonstrated efficient inhibition of viral replication in in vitro and in vivo studies. 
Available clinical data indicate SOF has a favorable safety profile and is well tolerated. SOF in 


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combination with RBV is likely to provide significant therapeutic benefit in the treatment of 
HCV infection in pediatric patients compared to currently available therapies in the following 
areas:

Expected improved efficacy in a pediatric population compared to the current standard of 
care

Expected improvement in safety and tolerability in relation to either adverse reactions or 
potential medication errors in the pediatric population compared to the current standard of 
care

Improved dosing scheme or method of administration (oral compared to subcutaneously 
administration and reduced treatment duration) leading to improved safety, efficacy,
tolerability, and compliance

Expected availability of a clinically relevant age-appropriate formulation

Different mechanism of action with potential advantage for the pediatric population in terms 
of improved efficacy and safety

Expected improvement in quality of life (e.g., minimized duration of therapy and avoidance 
of IFN-related adverse events that affect patient quality of life such as flulike syndrome and 
depression)
Additionally, the study sponsor will perform an ongoing review of safety data during the conduct 
of the study.


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2. 
OBJECTIVES 
The prima1y objective of the PK Lead-in of this study is: 
Final 
Amendment4 
• 
To evaluate the steady state phrumacokinetics (PK) and confmn the dose of SOF in HCV-
infected pediatric subjects 
The secondruy objective of the PK Lead-in of this study is: 
• 
To evaluate the safety and tolerability of 7 days of dosing of SOF + RBV in HCV -infected 
pediatric subjects 
The primary objectives of the Treatment Phase of this study are: 
• 
To evaluate the safety and tolerability of SOF + RBV for 12 or 24 weeks in HCV infected 
pediatric subjects with GT-2 or GT-3, respectively 
The secondruy objectives of the Treatment Phase of this study ru·e: 
• 
To dete1mine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects sepru·ately, as assessed by the proportion of subjects with SVR 
12 weeks after completion of treatment (SVR12) 
• 
To dete1mine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects separately, as assessed by the prop01tion 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 SOF during treatment and after completion 
of treatment 
• 
To evaluate the palatability ofSOF oral granules at Day 1, as applicable. 
The explorat01y objective of this study is: 
• 
PD 
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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 SOF + 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 SOF dose by analyzing 
PK, safety, and antiviral activity of SOF + RBV through 7 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 GT-2 or GT-3 HCV infection and evidence of HCV RNA ≥1000 IU/mL at study entry will 
be evaluated. Subjects must be treatment naïve to participate in the PK Lead-in Phase. 
Three cohorts of up to 10 subjects each will be sequentially enrolled: 

Cohort 1:  12 to < 18 years old weighing ≥45kg

Cohort 2:  6 to < 12 years old 

Cohort 3:  3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive SOF (400 mg adult tablet or 4 x 100 mg 
tablets if determined necessary based on SOF swallowability assessment) + RBV for 7 days with 
intensive PK conducted on Day 7. 
Following completion of study treatment in the PK Lead-in of Cohort 1 and pending PK and 
safety results, the PK Lead-in of Cohort 2 will initiate and receive study treatment 
(age appropriate dose and formulation). 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 7 of PK Lead-in.  They will continue dosing with 
SOF + RBV 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.
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 


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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 
GT-2 or GT-3 infection and evidence of 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:

GT-2 subjects: SOF + RBV for 12 weeks

GT-3 subjects: SOF + RBV for 24 weeks
The study will enroll both treatment-naïve and treatment–experienced pediatric subjects, with up 
to 20 subjects allowed to be treatment experienced. Approximately 100 total subjects, including 
subjects from the PK Lead-in Phase, will be enrolled in the Treatment Phase as follows:

Group 1: Approximately 50 adolescent subjects (12 to < 18 years of age)

Group 2: Approximately 50 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 standard-of-care (SOC) therapy with their healthcare provider.


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Figure 3-1.
Study Schema
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 7.
Subjects (up to 10 subjects per cohort) enrolled in the PK Lead-in Phase will participate in an 
intensive PK evaluation on Day 7. Subjects will be administered a dosing diary with 
instructions.  
Following completion of the Day 7 intensive PK visit, subjects will then return for scheduled 
study visits outlined in the Treatment Phase and continue dosing with SOF + RBV 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.


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3.2.2.
Treatment Phase
Screening assessments will be completed within 28 days of the Day 1 visit. For subjects 
continuing from the PK Lead-in Phase, screening, Day 1 and Week 1 of the Treatment Phase will 
not be required.

GT-2 Subjects: Study visits for GT-2 subjects will occur at screening, Day 1, and the end of
weeks 1, 2, 4, 8, and 12. 

GT-3 Subjects: Study visits for GT-3 subjects will occur at screening, Day 1, and the end of
weeks 1, 2, 4, 8, 12, 16, 20, and 24. 
All Treatment Phase 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).


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3.4. 
Treatment Discontinuations Criteria 
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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 defmed in Section 7 of the protocol, 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 imp01tant to detennine 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, regulat01y agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC). 
3.5. 
Discontinuations 
Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an Early Tennination visit as described in the Section 6.4.7. 
Subjects who pennanently discontinue all study dmgs for any reason including safety and/or 
tolerability concems prior to completion of the assigned dosing period will be followed 
according to the post-u·eatment study assessments described in Section 6.5. 
3.6. 
Pharmacogenomic Substudy 
PD 
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 eve1y 6 months for 
assessments of growth, quality of life, and long-te1m viral suppression (if applicable) in a 
separate protocol (GS-US-334-1113). This follow-up will continue for 5 years. 
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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.
Subjects with known or suspected study drug non-adherence will not be considered to meet the 
definition of virologic breakthrough, relapse or non-responder. 
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
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.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 100 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 (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: all subjects must be treatment naïve 
5. 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 Baseline/Day 1.
6. 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
7. Infection with HCV GT-2 or GT-3 as determined at Screening
8. HCV RNA ≥1000 IU/mL at Screening
9. Adequate hematologic function (absolute neutrophil count 1,500/mm3; hemoglobin 
12 g/dL for males and 11g/dL for females.)
10. Negative serum -HCG pregnancy test (for females of childbearing potential only, as defined 
in Appendix 5)
11. 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


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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. 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)
4. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)
5. -fetoprotein 50 ng/mL
6. Serum creatinine > 1.5 mg/dL
7. Estimated glomerular filtration rate 90 mL/min/1.73m2, as calculated by the Schwartz 
Formula
8. Evidence of hepatocellular carcinoma (HCC) or other malignancy (with the exception of 
certain resolved skin cancers)
9. Co-infection with HIV, acute HAV, or HBV
10. Significant cardiovascular, pulmonary or neurological disease
11. Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of 
orally administered medications
12. History of solid organ or bone marrow transplantation
13. Chronic daily non-steroidal anti-inflammatory drug therapy
14. Systemic corticosteroid use for 5 days (pulmonary/nasal administration is permitted)
15. Investigational agents taken within the past 28 days (except with the expressed approval of 
the Sponsor)
16. Clinically-relevant alcohol or drug abuse within 12 months of screening.  A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator
17. Known hypersensitivity to the study drugs, the metabolites or formulation excipients
18. 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
19. Use of any prohibited concomitant medications as described in Section 5.6 within 28 days of 
the Day 1 visit


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
Not applicable.
5.2.
Sofosbuvir
5.2.1.
Description and Handling
5.2.1.1.
Formulations
SOF tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets debossed with “GSI” on 
one side and “7977” on the other side. In addition to the active ingredient, SOF tablets contain 
the following inactive ingredients: mannitol, microcrystalline cellulose, croscarmellose sodium, 
colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, 
talc, and yellow iron oxide.
Placebo tablets for Swallowability Assessment, 400 mg, are yellow, capsule-shaped, film-coated 
tablets debossed with “GSI” on one side and “7977” on the other side. The tablets contain 
mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, and yellow iron oxide.
SOF tablets, 100 mg, are yellow, round, film-coated, plain-faced tablets. In addition to the active 
ingredient, SOF tablets contain the following inactive ingredients: mannitol, microcrystalline 
cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl
alcohol, titanium dioxide, macrogol, talc, and yellow iron oxide.
Placebo tablets for Swallowability Assessment, 100 mg, are yellow, round, film-coated, 
plain-faced tablets. The tablets contain lactose monohydrate, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, 
and yellow iron oxide.
SOF oral granules, 50 mg, are encapsulated in a two-piece, clear, hard gelatin capsule. In 
addition to the active ingredient, SOF capsules contain the following inactive ingredients: 
gelatin, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl 
cellulose, sodium stearyl fumarate, colloidal silicon dioxide, hypromellose, macrogol, amino 
methacrylate copolymer, stearic acid, sodium lauryl sulfate, and talc.
5.2.1.2.
Packaging and Labeling
SOF 400 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains either 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.


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Placebo tablets for Swallowability Assessment, 400 mg, are packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 30 tablets and a silica gel desiccant canister or 
sachet and polyester packing material. Each bottle is enclosed with a white, continuous thread, 
child-resistant screw cap with an induction-sealed, aluminum-faced liner.
SOF 100 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 28 tablets and a 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 for Swallowability Assessment, 100 mg, are packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 28 tablets and polyester packing material. 
Each bottle is enclosed with a white, continuous thread, child-resistant screw cap with an 
induction-sealed, aluminum-faced liner.
SOF capsules, 50 mg, which contain SOF oral granules, are packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 28 capsules and is enclosed with a white, 
continuous thread, child-resistant polypropylene screw cap with an induction-sealed and 
aluminum faced liner.
SOF bottles to be distributed to centers in the US, EU and the rest of the countries will 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.
Placebo tablets for Swallowability Assessment, 100 mg and 400 mg, bottles 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.
5.2.2.
Storage and Handling
SOF tablet, 100 mg and 400 mg, and capsule (containing granules) bottles should be stored at 
controlled room temperature until required for administration. Controlled room temperature is 
defined as 25 C (77 F); excursions are permitted between 15 C and 30 C (59 F to 86 F).
Placebo tablets for Swallowability Assessment, 100 mg and 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).  
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling SOF.


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Sufficient quantities of SOF tablets, SOF capsules containing granules 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 SOF
PK Lead-in: (Cohort 1) SOF 400 mg tablets will be administered once daily along with RBV 
weight-based dosing. Subjects determined unable to swallow the placebo for the 400 mg SOF 
tablet (by SOF Placebo swallowability assessment at Screening up to Day 1) will be re-assigned 
to 4 x 100 mg tablets daily.  Subjects unable to swallow tablets will be re-assigned to 8 x 50 mg 
capsules containing granules.  Subjects who weigh < 45 kg will be excluded.  
Intensive PK and safety results from the PK Lead-In of each Cohort will be reviewed to confirm 
the appropriateness of the evaluated SOF 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.  
5.3.
Ribavirin 
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.


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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).
5.3.2.
Dosage and Administration of RBV
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 (143 – 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 SOF. The evening dose of RBV will be 
taken with food.
RBV will be supplied by Gilead Sciences for all subjects.


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5.4.
Co-administration of SOF and RBV
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:

SOF

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 medication at the correct time, it may be taken later in the day; 
however, no more than 400 mg dose of SOF 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.  
5.5.
Study Drug Compliance
Subjects will be instructed to return any unused SOF and RBV in the original container on Day 7 
(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 of Screening, up to and including the date of the 
visit four weeks after discontinuation of study treatment, need to be recorded in the source 
documents and eCRFs. All concomitant medications should be recorded in the source 
documents.
The following medications are prohibited from 28 days prior to the Day 1 visit through the end 
of treatment:

Erythropoiesis-stimulating agents (ESAs); including but not limited to Procrit®, Aranesp®
and Epogen®

Granulocyte colony stimulating factor (GCSF)

Chronic systemic immunosuppressants including corticosteroids (prednisone equivalent of 
> 10 mg/day for > 2 weeks), azathioprine, or monoclonal antibodies (e.g., infliximab)

Investigational agents or devices for any indication


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
Drugs disallowed per prescribing information of REBETOL®

Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters i.e. P-gp) with study drug(s) may result in pharmacokinetic interactions resulting 
in decreases in exposure of study drug(s). Representative medications which are excluded 
from 21 days prior to Day 1 through the end of treatment are listed below:
Drug
Agents Disallowed
Concomitant use with study drug may 
potentially result in changes of study 
drug concentration as listed below
Anticonvulsants
Phenobarbital, Phenytoin, Carbamazepine, 
Oxcarbazepine
Decrease in concentration of study drug
Antimycobacterials
Rifampin, rifabutine, rifapentine
Decrease in concentration of study drug
Herbal/Natural 
Supplements
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
Decrease in concentration of study drug
Medications for disease conditions excluded from the protocol (e.g., HIV-1 infection, active 
cancer, transplantation) are not listed under this Concomitant Medication section and are 
disallowed in the study.


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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 (i.e., height of parents, if known)
Liver biopsy results (if available)

Complete physical examination 

Vital signs (temperature, blood pressure, pulse, respiratory rate), body weight and height


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
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 SOF swallowability assessment (for subjects administered SOF in tablet form only)
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for the Day 1 visit assessments.


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6.3. 
PK Lead-in: Treatment Assessments 
6.3.1. 
Day l 
Final 
Amendment 4 
After confnmation of eligibility has been evaluated, the following tests and procedmes must be 
completed prior to emollment and dosing/dispensing on Day 1: 
• 
Perf01m complete physical examination 
• 
Tanner Pubertal Stage Assessment 
• 
Vital signs, including body weight and height measmements 
• 
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 
prui icipants (Subjects 12 to < 18 yeru·s of age and subjects < 12 years of age at the discretion 
of the Investigator based on subject's pube1i al status) 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (ru·chive) 
_ 
PD 
• 
Obtain mine samples for the following procedmes: 
-
Urinalysis 
-
~-hCG pregnancy test for females of childberu·ing potential only 
• 
Subject completes quality of life smvey: Subject is to review questionnaire with a 
parent/guardian and write/mru·k answers directly onto the questionnaire. 
CONFIDENTIAL 
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6.3.1.1.
Drug Administration

Dispense study drugs as directed by the IWRS

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 all study drugs

Perform SOF swallowability assessment (for subjects administered SOF in tablet form only if 
not previously completed at screening).  Observe the subject taking the first dose of study 
drugs (with 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 parent/guardian

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

Review subject dosing diary
6.3.3.
Day 7 – Intensive PK 
The Day 7 Intensive PK visit should occur on the protocol-specified visit date based on the 
Day 1 visit. For the purposes of scheduling, the Day 7 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).


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Subjects should come in a fasted state for the Day 7 Intensive PK visit (i.e., no food or drink 
except water at least 8 hours prior to the Day 7 Intensive PK visit). Subjects and/or 
parents/guardians should be instructed that the Day 7 dose of SOF+RBV must not be taken until 
the evaluations listed below are completed. 
If the subject has already dosed prior to the Day 7 clinic visit or is not in a fasted state, the Day 7
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 8, 9, or 10) 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 7 visit, the Day 7 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 7 intensive PK visit no sooner than 3 days following compliant dosing and no later than 
Day 11 (i.e., return on Day 10 or Day 11).  If dosing non-compliance is due to an AE, 
consultation with the Gilead Medical Monitor is required regarding the potential of rescheduling 
the Day 7 intensive PK visit.
In both scenarios described above, the subject and/or parents/guardians should be reminded not 
to take the SOF + RBV prior to arriving at the clinic on the day of the re-scheduled intensive PK 
visit. All Day 7 intensive PK assessments listed below should be completed when the subject 
returns.
The following evaluations are to be completed at the Day 7 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 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 
Coagulation tests


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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 
SOF + RBV per dosing requirements.
Post-dose blood samples will be collected as follows: 

For Cohorts 1 and 2:  0.5, 1, 2, 3, 4, 8, and 12 hours post-dose (with predose also 
serving as t= 24).

For Cohort 3 only: 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 7 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


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Amendment4 
• 
Pregnancy prevention cmmseling including partner pregnancy prevention for male 
pmi icipants (Subjects 12 to < 18 years of age and subjects <12 years of age at the discretion 
of the Investigator based on subject's pube1ial status). 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (m·chive) 
_ 
PD 
• 
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 
pm·ent/gum·dian and write/mm·k answers directly onto the questionnaire. 
• 
Perf01m SOF swallowability assessment (for subjects administered SOF in tablet f01m only if 
not previously completed at screening). 
• 
For subjects receiving SOF oral granules, following dmg adminisu·ation assess palatability 
at Day 1, as applicable 
6.4.1.1. 
Dmg Adminisu·ation 
• 
Dispense study mugs as directed by the IWRS 
• 
Instiuct the subject on the appropriate RBV dose after weight-based dosage is calculated 
using Day 1 weight 
• 
Instiuct the subject on the packaging, storage and adminisu·ation of all study mugs 
• 
Observe the subject taking the first dose of study dmgs (with food) and record the time of 
first dose 
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6.4.2.
Weeks 1 and 2 (3 days)
Subjects who participated in the PK Lead-in will start study visits in 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

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 


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
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 drugs at these visits)

Dispense study drugs as directed by the IWRS
6.4.4.
Week 12 (3 days)

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 (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. (GT-2 Subjects 
only)

Review medication compliance with subject and/or parent/guardian.


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
Dispense study drugs as directed by the IWRS (GT-3 Subjects Only)

GT-2 Subjects should return all bottles and kits at the Week 12 Visit
6.4.5.
Week 16 and 20 (3 days) – GT-3 Subjects 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 drugs at these visits)

Dispense study drugs as directed by the IWRS
6.4.6.
Week 24 (3 days) – GT-3 Subjects 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)


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
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.

GT-3 Subjects should return all bottles and kits at the Week 24 Visit
6.4.7.
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.
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 (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)


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
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 kits at the Early Termination Visit
All subjects should complete Post-Treatment assessments after early termination, as described in 
Section 6.5.
All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
experimental or approved anti-HCV therapy will be followed every 6 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.
6.5.
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: 


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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 (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) 
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 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

Perform Tanner Pubertal Stage assessment

Obtain blood samples for 
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only


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
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)

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

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)

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.
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 
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, 


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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 right 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: 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.
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.  Perform Tanner Pubertal Stage assessment 
for subjects until Tanner Stage 5 has been reached. Date of first menses will be documented.  
6.6.5.
Height & Weight Measurement with Percentiles
Height and weight measurement will be collected at all study visits.  Percentiles will be 
calculated by Gilead using the CDC reference charts and tables by age and gender for height and 
weight.  


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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 the bone age from x-ray.
6.6.7.
Swallowability Assessment
A SOF 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 for the 400 mg SOF 
tablet. This will confirm the swallowability of the 400 mg tablet size. If, a subject is unable to 
swallow the 400 mg tablet size he/she will repeat the assessment with a placebo for the 100 mg 
SOF tablet.    If unable to take the 100 mg SOF tablet, the subject will be dispensed the SOF oral 
granule formulation.
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.
6.6.9.
Body Mass Index (BMI)
BMI is calculated by the following equation.
BMI = weight (pounds) 703           or            weight in kilograms
   (height in inches)2                                (height in meters)2
6.6.10.
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)]


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6.6.11.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each visit for viral sequence analysis. Unused 
samples may be archived.
6.6.12.
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. If required by 
local regulations, additional pregnancy tests beyond 6 months may be added. In the event of a 
positive urine pregnancy result, subjects will be instructed to stop study drugs immediately and 
return to the clinic as soon as possible for a serum pregnancy test.
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.
6.6.13.
Quality of Life Survey (PedsQL™)
The PedsQL ™ Pediatric Quality of Life Inventory V4.0 Short Form (SF15) will be completed 
in Treatment Phase of the study at Day 1, End of Treatment (Week 12 for GT-2 subjects, 
Week 24 for GT-3 subjects, or at 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 will be administered to the subject for the current age group at the time 
of survey administration.  
6.6.14.
SOF Granule Palatability Assessment
A palatability assessment for the SOF granules will be performed in Treatment Phase of the 
study at Day 1 to subjects receiving the granules.


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7.
TOXICITY MANAGEMENT
7.1.
Modification of Dose/Schedule Due to Toxicity
Dose reduction of RBV 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/day 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
Dose reduction in pediatric patients 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 SOF
The Gilead Medical Monitor should be consulted prior to dose discontinuation of SOF unless the 
investigator believes that immediate action is warranted to ensure the continued safety of the 
subject.
Administration of SOF may be discontinued due to a clinical or laboratory event. There is no 
option for SOF dose reduction. If SOF is stopped for toxicity, it should not be restarted, RBV 
should be stopped and the subject should complete an Early Termination Visit.
Subjects who meet any of the following laboratory criteria must stop treatment with SOF and 
RBV:

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 

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event or lab abnormality assessed as related to treatment with SOF


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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)

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

Persistent or significant disability/incapacity


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
A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is 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 subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the 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.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting.


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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 
All SAEs, regardless of causal relationship, that occur 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 
from screening onwards.
All AEs, regardless of causal relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP 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 post-treatment follow up 
period.
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 this time and the event is 
deemed relevant to the use of IMP, he/she should promptly document and report the event 
directly to Gilead DSPH. Gilead DSPH contact information is as follows: Email: 
Safety_FC@gilead.com or Fax: +1 (650) 522-5477.  All AEs and SAEs will be recorded in the 
CRF/eCRF database within the timelines outlined in the CRF/eCRF completion guideline.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by 
emailing or faxing the report form within 24 hours of the investigator’s knowledge of the 
event to the attention of the designated CRO Pharmacovigilance Representative.


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Electronic Serious Adverse Event (eSAE) Repmiing Process 
• 
All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit the SAE 
infonnation to Gilead DSPH within 24 homs of the investigator's knowledge of the event. 
Detailed instructions can be fmmd in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE infonnation electr·onically, i.e., the 
eCRF database is not ftmctioning, record the SAE on the paper serious adverse event 
repmiing fmm and submit within 24 homs as described above. 
• 
As soon as it is possible to do so, any SAE repmi ed via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repmied via a paper fonn because the eCRF database has been locked, no 
ftnther action is necessruy. 
Conta.ct infonnation is as follows: 
Gilead Sciences, Dmg Safety and 
Public Health: 
PRA Intem ational 
Phrum acovigilance Representative: 
Gilead Sciences, Medical Monitor: 
Fax: 
E-mail: 
Fax: 
E-mail: 
Name: 
Telephone: 
Mobile: 
+ 1 650 522-5477 
Safety _FC@gilead.com 
+1 888 772 6919 (North America); 
+49 621 8782 181 (Rest of World) 
CHOSafety@praintl.com 
Bittoo Kanwar, MD 
PO 
PPD 
Fax: 
PPD 
E-mail: 
t-'t-'U 
• 
For fatal or life-threatening events, copies of hospital case repmi s, autopsy repmis, and other 
documents ru·e also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occm without personal subject identification, 
maintaining the tr·aceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensm e the timely completion of accm ate safety 
repmis. 
Any medications necessruy for tr·eatlnent 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 
repmi fo1m. 
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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. 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, 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 the CRO Pharmacovigilance Representative using the 
pregnancy report form within 24 hours of becoming aware of the pregnancy.
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 8.1.1 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 CRO Pharmacovigilance Representative 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 drugs 
must also be reported and relevant information should be submitted to the CRO 
Pharmacovigilance Representative 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.


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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 the CRO Pharmacovigilance Representative within 24 hours of the investigator 
becoming aware of the situation. These reports must consist of situations that involve study IMP
and/or Gilead concomitant medications but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a non-
Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of contraindicated medications 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 prima1y objective ofPK Lead-in Phase of this study is: 
Final 
Amendment4 
• 
To evaluate the steady state phrumacokinetics (PK) and confmn the dose of SOF in 
HCV -infected pediatric subjects 
The secondruy objective of PK Lead-in of this study is: 
• 
To evaluate the safety and tolerability of7 days of dosing ofSOF + RBV in HCV-infected 
pediatric subjects 
The primru·y objectives of Treatment Phase of this study are: 
• 
To evaluate the safety and tolerability of SOF + RBV for 12 or 24 weeks in HCV -infected 
pediatric subjects with GT-2 or GT-3, respectively 
The secondruy objectives of Treatment Phase of this study ru·e: 
• 
To dete1mine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects sepru·ately, as assessed by the proportion of subjects with SVR 
12 weeks after completion of treatment (SVR12) 
• 
To dete1mine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects sepru·ately, 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 SOF during treatment and after completion 
of treatment 
• 
To evaluate the palatability of SOF oral granules at Day 1, as applicable. 
The explorat01y objective ofthis study is: 
• 
PD 
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9.1.2.
Primary Endpoints
For the PK Lead-in Phase, AUCtau of GS-331007 is considered as the primary PK parameter for 
determining the appropriate SOF dose.
For Treatment Phase, the primary safety endpoint is any AE leading to permanent 
discontinuation of study drug (s). The primary efficacy endpoint is SVR12. 
9.1.3.
Secondary Endpoints
For the PK Lead-in Phase, the secondary PK endpoints include AUCtau, Cmax, AUClast, Tmax, Clast, 
Tlast, Ctau and t1/2for GS-331007 and SOF as appropriate. AEs leading to permanent 
discontinuation of study drug(s) will be evaluated as a secondary safety endpoint.
For Treatment Phase, secondary efficacy endpoints include SVR4, SVR24, breakthrough and 
relapse. Additional efficacy evaluations may include HCV RNA change from Day 1; ALT 
normalization; viral kinetic parameters, and palatability of SOF oral granules.
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 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 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.


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
If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the pre-dose value and the change from pre-dose values.
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pre-treatment 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 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 SOF and metabolites (GS-566500 and GS-331007) 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 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).


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To evaluate the exposures of GS-331007 achieved in pediatric subjects of this study are similar 
to the exposures observed in adult subjects, GS-331007 exposure data from this study will be 
compared to the integrated adult data by carrying out an analysis of variance (ANOVA) for 
log-transformed AUCtau of GS-331007 as the primary endpoint while Cmax of GS-331007 as 
secondary endpoints. 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%. Individual 
patient management will be performed by maintaining exposures comparable to adults.  AUCtau
less than the 2.5th percentile of adult values may require dose adjustment as appropriate.
The effect of age and SOF dose on PK (SOF and GS-331007) will be assessed.
9.5.
Safety Analysis
Safety analysis will be performed for PK Lead-in and overall study Treatment Phaserespectively. 
Safety data will be summarized by age group, by GT, by overall and by age group and GT.
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.
Palatability of SOF oral granules
Palatability of SOF oral granules will be summarized using descriptive statistics by appropriate 
age group, by genotype, by overall and by age group and genotype.
9.5.3.
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. 


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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,

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.
9.5.4.
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.
9.5.5.
Other Safety Evaluations
9.5.5.1.
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.


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Efficacy Analysis 
Final 
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Efficacy will be evaluated using scheduled assessments of HCV RNA perf01med using CO BAS® 
TaqMan® HCV Test, v2.0 for use with the High Pure System. 
Efficacy analysis will be perf01med by age group, by GT, by overall, and by age group and GT 
for Treatment Phase. 
All continuous endpoints will be summarized using an 8-number surnmruy (n, mean, standru·d 
deviation, median, Ql, Q3, minimum, maximum). All categorical endpoints will be surnmru·ized 
by number and percentage of subjects who meet the endpoint definition. 
9.6.1. 
Primary Efficacy Analysis 
The primru·y efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
treatment) in the F AS population. Point estimate and its 95% confidence interval will be 
provided. 
9.6.2. 
Secondary Efficacy Analysis 
The prima1y efficacy endpoint of SVR12 will be compru·ed with historical SVR12 rate of 80% 
from pegylated interferon + ribavirin for pediatric GT2 and 3 subjects {20280}, using two-sided 
exact one-srunple bin01nial test at the 0.05 significance level. 
The prop01tion of subjects with HCV RNA below LLOQ over time (including SVR endpoints 
SVR4 and SVR24) will be presented in Treatment Phase in tabular and graphical fonn. 
Descriptive surnmru·ies and listings will be provided for additional efficacy evaluations including 
sennn HCV RNA actual values and change from baseline, proportion of subjects with virologic 
failures, and other endpoints of interest including AL T n01malization. 
PD 
9.6.3. 
Subgroup Analysis 
Subgroup analysis on SVR12 will be perf01med by treatment experience (treatment-naive vs. 
experienced), and by treatment experience and GT. Other clinically relevant subgroup analyses 
may be conducted as appropriate (i.e., assuming that adequate numbers of subjects in these 
subsets ru·e available for analysis). 
Details on efficacy analyses will be described in the statistical analysis plan. 
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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.
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 50 subjects enrolled into each age group of Treatment Phase, a two-sided 
95.0% confidence interval of the SVR12 rate will extend at most 11.1% in both directions from 
the observed SVR12 rate, assuming the expected SVR12 rate is 80%. In addition, a sample size 
of 100 subjects will provide over 80% power to detect a 11% improvement in SVR12 rate from 
80% to 91% using two-sided one-sample binomial test at significance level of 0.05.


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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 Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. 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 subinvestigators 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 
subinvestigator. The investigator and subinvestigator 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.


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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);

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.


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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 subinvestigator (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 prerandomization screening period if a CRF was initiated). If a subject 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.


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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 competent 
authority, IRB or IEC in accordance with local requirements. Approval must be obtained before 
changes can be implemented.
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.


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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.
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
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Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. 
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McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et 
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15572
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
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Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
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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.
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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.
20280
Schwarz KB, Gonzalez-Peralta RP, Murray KF, Molleston JP, Haber BA, Jonas 
MM, et al. The combination of ribavirin and peginterferon is superior to 
peginterferon and placebo for children and adolescents with chronic hepatitis C. 
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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.


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Final
Gilead Sciences, Inc.
Amendment 4
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20285
Wirth S. Current treatment options and response rates in children with chronic 
hepatitis C. World J Gastroenterol 2012;18 (2):99-104.
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.
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.
23275
Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. 
Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J 
Med 2013;368 (1):34-44.
24713
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, 
Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients 
without treatment options. N Engl J Med 2013;368 (20):1867-77.
24715
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et 
al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J 
Med 2013;368 (20):1878-87.
27503
SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing Information. Gilead 
Sciences, Inc. Foster City, CA. December 2013.  


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Protocol GS-US-334-1112
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Amendment 4
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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


Sofosbuvir 
Protocol GS-US-334-1112 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
. .<\mendment 4 
A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Arm Study to Investigate the 
Safety and Efficacy of Sofosbuvir + Ribavirin in Adolescents and Children with Genotype 2 
or 3 Chronic HCV Infection 
GS-US-334-1112, Protocol Amendment 4, 12 November 2014 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PPD 
Bittoo Kanwar, MD (Printed) 
Medical Monitor 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 82 
12 November 2014 


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Amendment 4
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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 7
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
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
SOF Swallowability Assessment
X
Xh
Quality of Life Survey
Xi
Review of Study 
Medication Compliance
X
X
Study Drug Dispensingb
X


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Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 7
(+ 3 days)
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X
X
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
Subject Dosing Diary
X
X
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
Palatability Assessment of Oral GranulesJ
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
PPD


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Protocol GS-US-334-1112
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Amendment 4
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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 drugs on Day 7 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 8, 
and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 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 (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).
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
Palatability of SOF oral granules will be assessed at Day 1, applicable.
PPD


Sofosbuvir
Protocol GS-US-334-1112
Final
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Amendment 4
CONFIDENTIAL
Page 86
12 November 2014
Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningc
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12g
16g
20g
24g
Early 
Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Complete Physical Examination
X
X
X
X
X
Symptom-Directed Physical Examination
X
X
X
X
X
X
Tanner Pubertal Stage Assessment
X
X
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 Counselingh
X
X
X
X
SOF Swallowability Assessment
X
Xj
Quality of Life Surveye
X
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
X
X
X
Study Drug Dispensingb
X
X
X
Xi
Xi
Xi
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
Viral Sequencing d
X
X
X
X
X
X
X
X
X
X


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 4
CONFIDENTIAL
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12 November 2014
Screeningc
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12g
16g
20g
24g
Early 
Termination
Serum or Urine Pregnancy Testing
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
X
X
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
Palatability Assessment of Oral Granulesk
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, 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 at Day 1, Week 12 (only GT-2 subjects), Week 24 (only GT-3 subjects) and Early Termination 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
GT-2 subjects will complete through the Week 12 visit; GT-3 subjects will complete through the Week 24 visit. 
h
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).
i
Study Drug Dispensing at the Week 12, Week 16, and Week 20 visit for GT-3 subjects only
j
Swallowability can occur at Day 1 if not completed during screening.
k
Palatability of SOF oral granules will be assessed at Day 1, applicable.
PPD
PPD


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Protocol GS-US-334-1112
Final
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Amendment 4
CONFIDENTIAL
Page 88
12 November 2014
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
Xd
Xd
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment 
X
X
Bone Age Assessment
X
Pregnancy Prevention Counseling e
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Testc
X
X
X
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
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.
d
At Post Treatment Week 12 and 24, only SAEs will be captured
e
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).


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 4
CONFIDENTIAL
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12 November 2014
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18June2012
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


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 4
CONFIDENTIAL
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12 November 2014
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
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
Infant, 2 – 7 Days
1250 to 1500/mm3
1.25 to 1.50 GI/L
1000 to 1250/mm3
1.00 to < 1.25 GI/L
750 to 1000/mm3
0.75 to < 1.00 GI/L
750/mm3
< 0.75 GI/L
Infant, 1 Day
4000 to 5000/mm3
4.00 to 5.00 GI/L
3000 to 4000/mm3
3.00 to < 4.00 GI/L
1500 to 3000/mm3
1.50 to < 3.00 GI/L
1500/mm3
< 1.50 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


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Protocol GS-US-334-1112
Final
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Amendment 4
CONFIDENTIAL
Page 91
12 November 2014
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0% 


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Protocol GS-US-334-1112
Final
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Amendment 4
CONFIDENTIAL
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
146  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 4
CONFIDENTIAL
Page 93
12 November 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4  mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


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Protocol GS-US-334-1112
Final
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Amendment 4
CONFIDENTIAL
Page 94
12 November 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63  to LLN mmol/L
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.14 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 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol/L to LLN
57 to 87 μmol/L
27 to 57 μmol/L
27 μmol/L


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Creatinine 
1.50 to 2.00 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol/L
177 to 265 μmol/L
265 to 530 μmol/L
530 μmol/L
Bicarbonate
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
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L
LDL
(Fasting)
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
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


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Amendment 4
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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


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Protocol GS-US-334-1112
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Amendment 4
CONFIDENTIAL
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12 November 2014
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 
Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to Dipstick 
Hematuria.
With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for the 
AE.


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Amendment 4
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(e.g., 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 
(e.g., 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 
(e.g., tamponade) OR Urgent 
intervention indicated


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


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Amendment 4
CONFIDENTIAL
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12 November 2014
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70% to 80%
FEV1 or peak flow 50% to 69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak flow 
25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in affected 
eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in affected 
eye(s)


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


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Amendment 4
CONFIDENTIAL
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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 [e.g., tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (e.g., 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 
(e.g., sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(e.g., 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 
(e.g., hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake


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


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


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Amendment 4
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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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Final
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Amendment 4
CONFIDENTIAL
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12 November 2014
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (e.g., 
status epilepticus), or difficult 
to control (e.g., refractory 
epilepsy)
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase 
from Previous Level of 
Control to Any of These 
Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (e.g., 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (e.g., 
status epilepticus), or difficult 
to control (e.g., refractory 
epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 5–20 
minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated 
with a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic self-
care functions


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Amendment 4
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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 [e.g., 
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 (e.g., upper 
arm/thigh)
Erythema OR Induration 
OR Edema involving 
50% surface area of the 
extremity segment (e.g., 
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 (e.g., 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 
(e.g., 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 
(e.g., 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 
(e.g., myxedema coma)
Lipoatrophy (e.g., 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 (e.g., stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing life-
threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic antiμbial 
treatment indicated AND 
Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening 
consequences (e.g., septic 
shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc


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Appendix 4.
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. 


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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 sofosbuvir demonstrated no adverse effect on fertility or embryo-
fetal development. However, there are no clinical studies of sofosbuvir 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 randomization. They must also agree to one of 
the following from 3 weeks prior to Day 1 until 6 months after last dose of RBV:

Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) is not permitted.
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 the last dose of RBV:
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent
tubal sterilization
vasectomy in male partner
implants of levonorgestrel


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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 Baseline 
until 7 months after the last dose of 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.
Male subjects must agree to refrain from sperm donation for at least 7 months after the last dose 
of 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. 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.

Prot_001.pdf: 
Study Title: 
Sponsor: 
IND No.: 
EudraCT Number: 
Indication: 
Protocol ID: 
Gilead Sciences Medical 
Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Aim 
Study to Investigate the Safety and Efficacy of 
Sofosbuvir + Ribavirin in Adolescents and Children with 
Genotype 2 or 3 Chronic HCV Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
106,739 
TBD 
Hepatitis C Vims Infection 
GS-US-334-1112 
Name: 
Telephone: 
Mobile: 
Fax: 
E-mail: 
Original: 
Luisa Stamm, MD, PhD 
~:~ 
PD 
t-'U 
Alnendment: 
20 December 2013 
10 Febmmy 2014 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pmi iculm·ly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Institutional Review Bom·d or Independent Ethics Committee. The inf01mation is 
only to be used by you in connection with authorized clinical studies of the investigational 
dmg described in the protocol. You will not disclose any of the infonnation to others without 
written authorization from Gilead Sciences, Inc., except to the extent necessmy to obtain 
inf01med consent from those persons to whom the dmg may be administered. 


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TABLE OF CONTENTS
TABLE OF CONTENTS .......................................................................................................................................2
LIST OF IN-TEXT FIGURES ...............................................................................................................................4
PROTOCOL SYNOPSIS .......................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................14
1.
INTRODUCTION .......................................................................................................................................17
1.1.
Background.....................................................................................................................................17
1.2.
Sofosbuvir.......................................................................................................................................18
1.3.
Ribavirin (RBV)..............................................................................................................................19
1.4.
Rationale for the Current Study ......................................................................................................19
1.5.
Rationale for Dose Selection of SOF ..............................................................................................20
1.6.
Overall Risk/Benefit Assessment....................................................................................................20
2.
OBJECTIVES..............................................................................................................................................22
3.
STUDY DESIGN ........................................................................................................................................23
3.1.
Treatment Plan and Regimen..........................................................................................................23
3.1.1.
Part A ............................................................................................................................23
3.1.2.
Part B ............................................................................................................................24
3.2.
Visit Schedule .................................................................................................................................25
3.2.1.
Part A ............................................................................................................................25
3.2.2.
Part B ............................................................................................................................26
3.3.
Virologic Response-Based Stopping Criteria..................................................................................26
3.4.
Treatment Discontinuations Criteria...............................................................................................27
3.5.
Discontinuations .............................................................................................................................27
3.6.
Pharmacogenomic Substudy...........................................................................................................27
3.7.
Long-Term Follow-Up....................................................................................................................27
4.
SUBJECT POPULATION...........................................................................................................................28
4.1.
Number of Subjects and Subject Selection .....................................................................................28
4.2.
Inclusion Criteria ............................................................................................................................28
4.3.
Exclusion Criteria ...........................................................................................................................29
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ....................................................................................31
5.1.
Randomization and Blinding...........................................................................................................31
5.2.
Sofosbuvir.......................................................................................................................................31
5.2.1.
Description and Handling..............................................................................................31
5.2.2.
Storage and Handling....................................................................................................32
5.2.3.
Dosage and Administration of SOF ..............................................................................32
5.3.
Ribavirin .........................................................................................................................................33
5.3.1.
Description and Handling of RBV................................................................................33
5.3.2.
Dosage and Administration of RBV .............................................................................33
5.4.
Co-administration of SOF and RBV...............................................................................................34
5.5.
Study Drug Compliance..................................................................................................................34
5.6.
Prior and Concomitant Medications................................................................................................34
6.
STUDY PROCEDURES .............................................................................................................................36
6.1.
Subject Enrollment..........................................................................................................................36
6.2.
Screening Assessments ...................................................................................................................36
6.2.1.
Screening Visit (Day –28 to Day 0)..............................................................................36


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6.3.
Part A: Treatment Assessments ......................................................................................................38
6.3.1.
Day 1 Visit ....................................................................................................................38
6.3.2.
Day 3.............................................................................................................................39
6.3.3.
Day 7 – Intensive PK ....................................................................................................39
6.4.
Part B: Treatment Assessments.......................................................................................................41
6.4.1.
Day 1 Visit ....................................................................................................................41
6.4.2.
Weeks 1 and 2 (3 days)..............................................................................................42
6.4.3.
Weeks 4 and 8 (3 days)..............................................................................................43
6.4.4.
Week 12 (3 days) .......................................................................................................43
6.4.5.
Week 16 and 20 (3 days) – GT-3 Subjects only.........................................................44
6.4.6.
Week 24(3 days) – GT-3 Subjects only .....................................................................45
6.4.7.
Unscheduled Visit/Early Termination Visit ..................................................................46
6.5.
Post-Treatment Assessments...........................................................................................................47
6.5.1.
4-Week Post-Treatment Visit (5 days).......................................................................47
6.5.2.
12-Week Post-Treatment Visit (5 days).....................................................................48
6.5.3.
24-Week Post-Treatment Visit (5 days).....................................................................49
6.6.
Procedures and Specifications.........................................................................................................49
6.6.1.
Clinical Laboratory Analytes ........................................................................................49
6.6.2.
Medical History.............................................................................................................50
6.6.3.
Complete Physical Examination ...................................................................................50
6.6.4.
Tanner Pubertal Stage Assessment................................................................................50
6.6.5.
Swallowability Assessment...........................................................................................50
6.6.6.
Vital Signs.....................................................................................................................50
6.6.7.
Body Mass Index (BMI) ...............................................................................................51
6.6.8.
Viral Sequencing (Archive) ..........................................................................................51
6.6.9.
Pregnancy Testing.........................................................................................................51
6.6.10.
Quality of Life Survey (PedsQL™)................................................................................51
7.
TOXICITY MANAGEMENT.....................................................................................................................52
7.1.
Modification of Dose/Schedule Due to Toxicity ............................................................................52
7.1.1.
RBV Dose Adjustments ................................................................................................52
7.2.
Subject Stopping Rules for SOF .....................................................................................................52
8.
ADVERSE EVENTS MANAGEMENT.....................................................................................................53
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events..........................53
8.1.1.
Adverse Events..............................................................................................................53
8.1.2.
Serious Adverse Events.................................................................................................53
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events..............................................................54
8.2.
Assessment of Adverse Events and Serious Adverse Events..........................................................54
8.2.1.
Assessment of Causality for Study Drugs and Procedures............................................54
8.2.2.
Assessment of Severity .................................................................................................55
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events ...............................................................................................................................55
8.4.
Gilead Reporting Requirements......................................................................................................57
8.5.
Special Situations Reports ..............................................................................................................57
8.5.1.
Definitions of Special Situations...................................................................................57
8.5.2.
Instructions for Reporting Special Situations................................................................58
9.
STATISTICAL CONSIDERATIONS.........................................................................................................60
9.1.
Analysis Objectives and Endpoints.................................................................................................60
9.1.1.
Analysis Objectives.......................................................................................................60
9.1.2.
Primary Endpoint ..........................................................................................................61


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9.1.3.
Secondary Endpoints.....................................................................................................61
9.2.
Analysis Conventions .....................................................................................................................61
9.2.1.
Analysis Sets.................................................................................................................61
9.2.2.
Data Handling Conventions ..........................................................................................62
9.2.3.
Interim Analysis............................................................................................................63
9.3.
Demographic Data and Baseline Characteristics ............................................................................63
9.4.
Pharmacokinetic Analysis...............................................................................................................64
9.5.
Efficacy Analysis............................................................................................................................64
9.5.1.
Primary Analysis...........................................................................................................64
9.5.2.
Secondary Analysis.......................................................................................................64
9.5.3.
Subgroup Analysis ........................................................................................................65
9.6.
Safety Analysis ...............................................................................................................................65
9.6.1.
Extent of Exposure........................................................................................................65
9.6.2.
Adverse Events..............................................................................................................65
9.6.3.
Laboratory Evaluations .................................................................................................66
9.6.4.
Other Safety Evaluations...............................................................................................66
9.7.
Data Monitoring Committee ...........................................................................................................67
9.8.
Sample Size.....................................................................................................................................67
10.
RESPONSIBILITIES ..................................................................................................................................68
10.1.
Investigator Responsibilities ...........................................................................................................68
10.1.1.
Good Clinical Practice ..................................................................................................68
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) Approval..............................................................................................................68
10.1.3.
Informed Consent/Assent..............................................................................................69
10.1.4.
Confidentiality ..............................................................................................................69
10.1.5.
Study Files and Retention of Records...........................................................................69
10.1.6.
Case Report Forms........................................................................................................71
10.1.7.
Drug Accountability......................................................................................................71
10.1.8.
Inspections ....................................................................................................................71
10.1.9.
Protocol Compliance.....................................................................................................71
10.2.
Sponsor Responsibilities.................................................................................................................72
10.2.1.
Protocol Modifications..................................................................................................72
10.2.2.
Study Report and Publications ......................................................................................72
10.3.
Joint Investigator/Sponsor Responsibilities ....................................................................................72
10.3.1.
Access to Information for Monitoring...........................................................................72
10.3.2.
Access to Information for Auditing or Inspections .......................................................73
10.3.3.
Study Discontinuation...................................................................................................73
11.
REFERENCES ............................................................................................................................................74
12.
APPENDICES .............................................................................................................................................76
Appendix 1.
Investigator Signature Page...........................................................................................77
Appendix 2.
Study Procedures Table.................................................................................................78
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities .............................................................................................83
Appendix 4.
Tanner Stages..............................................................................................................106
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements ................................................................107
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema................................................................................................................25


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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, Single-Arm 
Study to Investigate the Safety and Efficacy of 
Sofosbuvir + Ribavirin in Adolescents and Children with 
Genotype 2 or 3 Chronic HCV Infection
IND Number:
EudraCT Number:
106,739
TBD
Study Centers:
Approximately 50 sites in the United States, Europe, Russia, 
Australia, and New Zealand
Number of Subjects:
Approximately 100 subjects
Target Population:
Adolescents and children (aged 3 to < 18) with chronic hepatitis C 
virus (HCV) infection
Treatment Duration:
Part A – 7 days
Part B – 12 or 24 weeks
Objectives:
The primary objective of Part A of this study is:
To evaluate the steady state pharmacokinetics (PK) and confirm 
the dose of sofosbuvir (SOF) in HCV-infected pediatric subjects
The secondary objective of Part A of this study is:
To evaluate the safety and tolerability of 7 days of dosing of SOF 
in HCV-infected pediatric subjects
The primary objectives of Part B of this study are:
To evaluate the safety and tolerability of SOF + ribavirin (RBV)
for 12 or 24 weeks in HCV-infected pediatric subjects with 
genotype 2 or 3, respectively
To determine the antiviral efficacy of SOF+RBV treatment in 
genotype 2 and genotype 3 HCV-infected subjects separately, as 
assessed by the proportion of subjects with SVR 12 weeks after 
completion of treatment (SVR12)


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Study Design: 
CONFIDENTIAL 
The seconda!y objectives ofPrui B of this study ru·e: 
Final 
Amendment 1 
To detennine the antiviral efficacy of SOF+RBV u·eatment in 
genotype 2 and genotype 3 HCV -infected subjects sepru·ately, as 
assessed by the prop01iion of subjects with SVR 4 and 24 weeks 
after completion ofu·eatment (SVR4 and SVR24) 
To evaluate the kinetics of circulating HCV RNA dming u·eatment 
and after completion of u·eatment 
To evaluate the emergence of viral resistance to SOF dming 
u·eatment and after completion of u·eatment 
The explorat01y objective of this study is: 
PO 
Open-label, multi-coh01i, two-pati study evaluating the PK, safety, 
and antiviral activity ofSOF in chronic HCV-infected pediau·ic 
subjects. 
The study will be divided into 2 parts as follows: 
Part A: Pati A (PK lead-in) will evaluate and/or confitm age 
appropriate SOF doses by analyzing PK, safety, and antiviral 
activity of SOF through 7 days of dosing for each of three cohorts. 
Children aged 3 to 6, children aged 6 to < 12 yeru·s and adolescents 
aged 12 to < 18 yeru·s with genotype (GT) 2 or 3 HCV infection 
and evidence ofHCV RNA > 1000 IU/mL at study ently will be 
evaluated. Subjects must be u·eatment naive for Prui A. 
Three coh01is of up to 10 subjects each will be sequentially 
emolled: 
Cohort 1: 12 to < 18 yeru·s old weighing ~ 45kg 
Coh01i 2: 6 to < 12 yeru·s old 
Coh01i 3: 3 to < 6 yeru·s old 
The study will start with Coh01i 1. Subjects will receive SOF 
( 400-mg adult tablet or 4 x 1 00-mg tablets if detennined necessruy 
based on SOF swallowability assessment) for 7 days with intensive 
PK conducted on Day 7. 
Subjects in each coh01i (Coh01is 1, 2 and 3) will immediately 
emoll in Prui B as they complete Day 7 of Prui A. They will begin 
dosing with SOF + RBV with no intenuption of study dmg 
adminisu·ation. Subjects rolling over from Prui A will not be 
required to perfonn laborat01y assessments on Prui B Day 1. 
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Following completion of study treatment in Cohort 1 (Part A) and 
pending PK and safety results from Cohort 1 (Part A), Cohort 2
will initiate and receive study treatment (age-appropriate 
formulation). Following completion of study treatment in Cohort 2
(Part A) and pending PK and safety results from Cohort 2 (Part A), 
Cohort 3 will receive study treatment (age-appropriate 
formulation). 
Part B: Part B will be initiated by dose cohort after confirmation 
of age-appropriate SOF dosage levels. Subjects who participated in 
Part A will immediately rollover into Part B (Day 1), with no 
interruption of study drug administration:
Children aged 3 to < 12 years and adolescents aged 12 to 
< 18 years with GT-2 or GT-3 infection and evidence of HCV 
RNA > 1000 IU/mL at study entry (those who were dosed in 
Part A will have met this criteria prior to enrollment) will be 
evaluated. 
Subjects enrolled in Part B will receive the following regimen.
GT-2 subjects: SOF + RBV for 12 weeks
GT-3 subjects: SOF + RBV for 24 weeks
The study will enroll both treatment-naïve and 
treatment-experienced pediatric subjects, with up to 20 subjects 
allowed to be treatment experienced. Approximately 100 total 
subjects, including subjects from Part A, will be enrolled in Part B 
as follows
Group 1: Approximately 50 adolescent subjects (12 to < 18 years 
of age)
Group 2: Approximately 50 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)


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Substudy and 
Long-Te1m 
Follow-Up Study: 
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Amendment 1 
The study schedule contains the following visits: Screening, Day 1, 
Weeks 1, 2, 4, 8, 12 (and Weeks 16, 20, and 24 for GT-3) 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. 
Pharmacogenomics (PG) Substudy 
PO 
Long-Term Follow-up 
Subjects who attain SVR24 or those who do not attain SVR24 and 
do not initiate experimental or approved anti-HCV therapy will be 
followed eve1y 6 months for assessments of growth, quality of life, 
and long-te1m viral suppression (if applicable) in a separate 
protocol (GS-US-334-1113). This follow-up will continue for 
5 years. 
Diagnosis and Main Chronic HCV-infected, treatment-naive and up to 20 subjects may 
Eligibility Criteria: 
be treatment experienced, male and female subjects aged 3 to < 18. 
CONFIDENTIAL 
Inclusion Criteria: 
1) 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 perfonned prior to the Day 1 visit with 
evidence of chronic HCV infection 
Infection with HCV GT 2 or 3 as dete1mined at Screening 
HCV RNA~ 1000 IU/mL at Screening 
Part A only: subjects in coh01i 1 (age 12 to <18 years of age) must 
weigh ~ 45kg 
Agree to use 2 fonns of highly effective contraception, as 
referenced in Appendix 5, for the duration of the study and for 6 
months (for female subjects) or 7 months (for male subjects) after 
the last dose of study medication if age, cultural, and sexual 
activity status appropriate ( eg: if sexually active; does not pertain 
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to pre-pubertal subjects). Females of childbearing potential (as 
defined in Appendix 5) must have a negative pregnancy test at 
Screening and Day 1.
Exclusion Criteria:
Hematologic or biochemical parameters at screening outside the
protocol-specified requirements
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 
(eg, hemochromatosis, Wilson’s disease, alpha-1 antitrypsin 
deficiency)
Chronic use of systemic immunosuppressive agents or
immunomodulatory agents
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.
See Sections 4.2 and 4.3 of the protocol for full eligibility criteria.
Study Procedures/
Frequency:
Part A: 
Screening assessments will be completed within 28 days of the 
Day 1 visit. 
Screening assessments will include: physical examination, vital 
signs (including height and weight), Tanner Pubertal Stage 
assessment, concomitant medications, safety laboratory tests, 
coagulation tests, HCV RNA, serology (HIV, HAV, HCV, HBV), 
alpha-1 anti-trypsin, serum β-human chorionic gonadotropin hCG 
(females of childbearing potential only), thyroid stimulating 
hormone, HbA1c, IL28B genotyping, alpha fetoprotein, urinalysis, 
and urine drug screen.
Study Visits will occur at Screening, Day 1, Day 3, and Day 7
On-Treatment assessments include adverse events (AEs), 
concomitant medications, physical examination, vital signs, height, 
weight, safety laboratory tests, HCV RNA, viral sequencing 
sampling, urine pregnancy tests (females of child bearing potential 
only), and urinalysis. Coagulation will be performed at Day 1 and 


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Day 7. SOF swallowability assessment will be performed on Day 1 
for a subject’s ability to swallow the 400 mg SOF tablet (only
subjects administered SOF in tablet form).
Subjects (up to 10 subjects) enrolled in Part A will participate in an 
intensive PK evaluation on Day 7. Following completion of the 
Day 7 intensive PK visit, subjects will then return for scheduled 
study visits outlined in Part B and begin dosing with SOF + RBV
with no interruption of study drug administration.  Subjects will be 
administered a dosing diary with instructions.
Part B: 
Screening assessments will be completed within 28 days of the 
Day 1 visit. For subjects continuing from Part A, screening for 
Part B will not be required.
Screening assessments will include physical examination, vital 
signs, concomitant medications, safety laboratory tests, HCV 
RNA, serology (HIV, HAV, HCV, HBV), alpha-1 anti-trypsin 
serum β-human chorionic gonadotropin hCG (females of 
childbearing potential only), thyroid stimulating hormone, IL28B 
genotyping, urinalysis, and urine drug screen.
GT-2 Subjects: Study visits for GT-2 subjects will occur at 
screening, Day 1, and the end of Weeks 1, 2, 4, 8, and 12. 
GT-3 Subjects: Study visits for GT-3 subjects will occur at 
screening, Day 1, and the end of Weeks 1, 2, 4, 8, 12, 16, 20, and 
24. 
All Part B subjects will then return for follow-up visits at 4, 12 and 
24 weeks after discontinuation of therapy. 
On-treatment assessments will include adverse events, concomitant 
medications, physical examination, vital signs (including height 
and weight), safety laboratory tests, coagulation tests, HCV RNA, 
PK samples, and urine pregnancy tests (females of childbearing 
potential only). Rates of growth (height and weight percentiles) 
and Tanner Pubertal Stage assessment will be assessed at Day 1, 
end of treatment, post-treatment Week 12 and at the end of the 
24-week follow-up phase; parental heights will be recorded at 
Day 1. When available, results from liver biopsies performed 
within 2 years prior to screening will be collected at Day 1. SOF 
swallowability assessment will be performed on Day 1 for a 
subject’s ability to swallow the 400 mg SOF tablet (all subjects
administered SOF in tablet form).  Subjects rolling over from Part 
A will not be required to perform laboratory assessments on Part B 
Day 1. Post-treatment assessments will include adverse events, 
concomitant medications, vital signs, safety laboratory tests, HCV 
RNA, and urine pregnancy tests (females of childbearing potential 


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Test Product, Dose, 
and Mode of 
Administration: 
CONFIDENTIAL 
Final 
Amendment 1 
only). Samples for viral RNA sequencing/phenotyping will be 
collected at Day 1 and eve1y visit thereafter. 
Part A: (Coh01i 1) SOF 400-mg tablets will be administered once 
daily. Subjects detennined lmable to swallow the 400-mg tablet 
(by SOF swallowability assessment at Day 1 or at any time during 
the study) will be re-assigned to 4 x 1 00-mg tablets daily. Subjects 
who weigh <45 kg are excluded from this age group in Pati A. 
Subjects must be treatment naive for Part A. 
Patt B: SOF 400-mg tablets will be administered once daily for 
subjects who weigh ~ 45 kg. Subjects detennined unable to 
swallow the 400-mg tablet (by SOF assessment at Day 1 or at any 
time during the study) will be re-assigned to 4 x 100-mg tablets 
daily. For subjects in this age group who weigh < 45 kg, PK data 
from pati A will be used to detennine the appropriate dose of SOF 
to be administered. 
Subjects who patiicipated in Prui A will continue the assigned dose 
in Prut B. 
RBV Weight-Based Dosing (All age groups): 
The RBV dose is: 
15 mg/kg divided BID for subjects with weight below 50 kg 
400 mg BID for subjects weighing ~ 50 to less than 65 kg 
400 mg q AM and 600 mg q PM (i.e., 1,000 mg Total Daily Dose) 
for subjects weighing ~ 65 kg to less than 75 kg 
600 mg BID for subjects with weights greater than 75 kg. 
The moming dose of RBV will be taken with an age-appropriate 
dose of SOF with food. The evening dose of RBV will be taken 
with food. 
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Reference Therapy:
None
Evaluation Criteria:
Safety:
AEs, laboratory tests, and Tanner Pubertal Stage assessments will 
be collected throughout the study. 
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV 
RNA performed using COBAS® AmpliPrep/COBAS® TaqMan®
HCV Test.
PK:
For subjects in Part A, steady-state PK of SOF and its major 
metabolites GS-566500 and GS-331007 will be assessed at Day 7.
For Cohorts 1 and 2, plasma samples will be collected for PK 
analyses following dosing of study drugs on Day 7 at the following 
time points: 0 (predose), 0.5, 1, 2, 3, 4, 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), 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 subjects in Part B, a single PK blood sample will be collected 
at all visits while on treatment for all subjects. The PK of SOF, 
GS-566500 and GS-331007 and/or ribavirin will be assessed.
The effect of age and SOF dose on PK (SOF and GS-331007) will
be explored. 
Statistical Methods:
For Part A, plasma PK parameters Cmax, Tmax, Clast, Tlast, 
CtauAUCtau, and T1/2 will be estimated.The PK parameters will be 
summarized by cohort. The effect of age and SOF dose on PK 
(SOF and GS-331007) will be explored.
For Part B, the primary efficacy endpoint is SVR12 in all enrolled 
and treated subjects. Secondary endpoints are SVR4, SVR24, 
breakthrough and relapse. Efficacy endpoints will be summarized 
by age group and genotype.  Point estimate and its 95% confidence 
interval will be provided. 


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Subgroup analysis on SVR12 will be performed by treatment 
experience (treatment-naive vs. experienced) and by treatment 
experience and genotype. 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). 
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.
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 treatment group.
With approximately 50 subjects enrolled into each age group of 
Part B, a two-sided 95.0% confidence interval of the SVR12 rate 
will extend at most 11.1% in both directions from the observed 
SVR12 rate, assuming the expected SVR12 rate is 80%.
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
β-hCG
β-human chorionic gonadotropin
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)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BW
body weight
CLcr
creatinine clearance
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)
CMH
Cochran-Mantel-Haenszel
COPD
Chronic obstructive pulmonary disease
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
Emax
maximal effect
EU
European Union
EVR
Early virologic response
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
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
IV
Intravenous
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDH
Lactase dehydrogenase
LLN
lower limit of the normal range
LLOD
Lower limit of detection
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


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
QD
once daily (use only in tables)
QTcF
QT interval corrected using Fridericia’ formula
RBC
Red blood cell count 
RBV
Ribavirin
RDRP
RNA-dependent RNA polymerase
RNA
ribonucleic acid
RVR
rapid virologic response 
SADR
Serious adverse drug reaction
SAE
serious adverse event
SD
Standard deviation
SOC
Standard of Care
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TND
Target not detected
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 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 standard of care 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.
Novel anti-hepatitis C treatments under study are directed against a variety of molecular 
targets, which include the virally encoded RNA-dependent RNA polymerase (RDRP, NS5B) 
and proteases (NS2 and NS3). Some of the most consistently effective antivirals have been 
nucleoside/tide analogs. These compounds share characteristics with the natural nucleoside 
substrates found in the cell, and once phosphorylated to the nucleoside-triphosphate, cause 
termination of the newly encoded viral genome.
SOF is a novel nucleotide analogue that inhibits HCV RNA replication in vitro and has 
demonstrated efficient inhibition of viral replication in in vitro and in vivo studies. 
Furthermore, even in subjects who did experience off-treatment viral breakthrough, 
population sequencing revealed no treatment-emergent S282T mutations. No adverse effects 
on the nervous, cardiovascular, or respiratory systems have been observed, and no specific 
target organs of toxicity have been identified in long-term toxicology studies. Available 
clinical data indicate SOF has a favorable safety profile and is well tolerated.
Based on its observed safety and efficacy in adult patients with HCV, SOF has the potential 
to be a safe, tolerable, and effective treatment for HCV infection in the pediatric population.
1.2.
Sofosbuvir
Sovaldi™(Sofosbuvir) is a potent nucleotide analogue that inhibits HCV RNA replication in 
vitro and has demonstrated high rates of sustained viral response (SVR) when given with 
RBV +/- PEG to subjects with chronic GT- 1, 2, 3 or 4 HCV infection {27503}, {23275}, 
{24713}, {24715}.  Sovaldi™has been approved in the United States by the Food and Drug 
Administration (FDA) for the treatment of HCV infection GT- 1, 2, 3 and 4 including 
treatment naïve and experienced patients and HIV/HCV co-infected patients.
For further information on the clinical pharmacology, virology, safety and efficacy of SOF, 
please refer to the current version of the Investigator’s Brochure and US prescribing 
information.  


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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.
1.4.
Rationale for the Current Study
This clinical study is designed to evaluate the efficacy and safety of treatment with 
SOF+RBV for adolescents and children with GT-2 and GT-3 chronic HCV infection. 
Currently PEG and weight-based RBV are considered the standard of care for the treatment 
of HCV infection in children. However, this PEG and RBV regimen is long in duration, 
relatively toxic, and not well tolerated. Thus, there continues to be a need for new treatments 
for HCV that combine potent and sustained efficacy with improved tolerability and safety. 
Therapy that provides shorter duration and improved efficacy with an all-oral regimen would 
be a significant advancement over current options in pediatric patients.
The main aim for the treatment of pediatric patients with HCV is to eliminate the need to use 
IFN-based regimens. In this way, pediatric patients are able to avoid the necessity of weekly 
injections, which can be traumatic and burdensome, and also to significantly reduce the 
serious adverse events seen on administration of IFN-based regimens. 
SOF is a promising candidate to combine with RBV based on its acceptable safety profile 
and its antiviral activity.  Clinical trials from adult studies have demonstrated the antiviral 
efficacy, potency, and safety of SOF in subjects with HCV infection. SOF in combination 
with RBV would provide an all-oral, IFN-free regimen with a shorter treatment duration 
(12 - 24 weeks of SOF treatment versus standard-of-care 24 to 48 weeks of treatment) and 
would offer another important option in the treatment of HCV infection in the pediatric 
population.
While emerging Phase 3 data demonstrate high SVR12 rates in subjects with GT- 2 HCV 
infection, these studies suggest that patients with GT- 3 infection may benefit from a longer 
treatment duration with SOF+RBV. Optimal duration of SOF+RBV, for genotype 3 subjects,
was established in FISSION and VALENCE.  Increasing treatment duration from 12 to 
24 weeks increased SVR12 from 61 to 93% in non-cirrhotics and from 34 to 92% in 
cirrhotics.


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1.5.
Rationale for Dose Selection of SOF
SOF 400 mg, once daily, when dosed in combination with RBV with or without PEG has 
demonstrated broad genotypic efficacy and favorable safety profile in over 
3300 HCV-infected subjects across multiple patient populations in Phase 2 and 3 trials. This 
dose is the marketed dose of SOF for the treatment of HCV-infection.
Selection of doses of SOF for adolescents and younger age groups will target systemic 
exposures similar to those observed in adults at the marketed dose, taking into account body 
weight/body surface area, the potential ontogenic changes in hepatically expressed 
carboxylesterase 1 (CES1) and Cathepsin A (CatA) enzymes, and the results obtained in 
older age groups.  Available data suggest comparable hepatic expression of CES1 in 
adolescents and adults, with modestly decreased expression in children.  As such, the adult 
clinical dose, 400mg, will be evaluated in adolescents {20288}.  Safety and PK data in the 
adolescent group (Cohort 1) in Part A, will inform dose selection for the younger age groups 
in addition to body weight/body surface area. 
Age-appropriate formulations of SOF that offer an important option in the treatment of HCV 
infection in the pediatric population are planned for evaluation in children below 6 years of 
age or children who are unable to swallow a solid-dose 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 standard of care 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. 
SOF has demonstrated efficient inhibition of viral replication in in vitro and in vivo studies. 
Available clinical data indicate SOF has a favorable safety profile and is well tolerated. SOF 
in combination with RBV is likely to provide significant therapeutic benefit in the treatment 
of HCV infection in pediatric patients compared to currently available therapies in the 
following areas:

Expected improved efficacy in a pediatric population compared to the current standard of 
care

Expected improvement in safety and tolerability in relation to either adverse reactions or 
potential medication errors in the pediatric population compared to the current standard 
of care


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
Improved dosing scheme or method of administration (oral compared to subcutaneously 
administration and reduced treatment duration) leading to improved safety, efficacy,
tolerability, and compliance

Expected availability of a clinically relevant age-appropriate formulation

Different mechanism of action with potential advantage for the pediatric population in 
terms of improved efficacy and safety

Expected improvement in quality of life (eg, minimized duration of therapy and
avoidance of IFN-related adverse events that affect patient quality of life such as flulike
syndrome and depression)
Additionally, the study sponsor will perform an ongoing review of safety data during the 
conduct of the study.


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2. 
OBJECTIVES 
The prima1y objective of Part A of this study is: 
Final 
Amendment 1 
• 
To evaluate the steady state phrumacokinetics (PK) and confmn the dose of SOF in 
HCV -infected pediatric subjects 
The secondruy objective of Part A of this study is: 
• 
To evaluate the safety and tolerability of 7 days of dosing of SOF in HCV -infected 
pediatric subjects 
The primary objectives of Prui B of this study are: 
• 
To evaluate the safety and tolerability of SOF + ribavirin (RBV) for 12 or 24 weeks in 
HCV infected pediatric subjects with GT- 2 or 3, respectively 
• 
To dete1mine the antiviral efficacy of SOF+RBV treatment in GT- 2 and GT- 3 
HCV-infected subjects separately, as assessed by the prop01iion of subjects with SVR 
12 weeks after completion of treatment (SVR12) 
The secondruy objectives of Prui B of this study ru·e: 
• 
To dete1mine the antiviral efficacy of SOF+RBV treatment in genotype 2 and genotype 3 
HCV-infected subjects separately, as assessed by the prop01iion 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 SOF during treatment and after 
completion of treatment 
The explorat01y objective ofthis study is: 
• 
PD 
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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 SOF in chronic HCV-infected pediatric subjects.
3.1.1.
Part A
Part A (PK lead-in) will evaluate and/or confirm age appropriate SOF doses by analyzing 
PK, safety, and antiviral activity of SOF through 7 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 
genotype (GT) 2 or 3 HCV infection and evidence of HCV RNA > 1000 IU/mL at study 
entry will be evaluated. Subjects must be treatment naïve for Part A. Three cohorts of up to 
10 subjects each will be sequentially enrolled: 

Cohort 1:  12 to < 18 years old weighing ≤45kg

Cohort 2:  6 to < 12 years old 

Cohort 3:  3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive SOF (400-mg adult tablet or 
4 x 100-mg tablets if determined necessary based on SOF swallowability assessment) for 
7 days with intensive PK conducted on Day 7. A SOF swallowability assessment will be 
administered on Day 1 in which subjects will be observed taking the first 400-mg SOF tablet 
to confirm the swallowability of the 400-mg tablet size in adolescents aged 12 to < 18 years. 
If, at Day 1 or any time during the study, a subject is unable to continue with the 400-mg 
tablet size he/she will be re-assigned to 4 x 100mg SOF tablets.  If unable to take the 100mg 
SOF tablet, enrollment of subject will be deferred until the granule formulation being 
developed is available.
Following completion of study treatment in Cohort 1 (Part A) and pending PK and safety 
results from Cohort 1 (Part A), Cohort 2 will initiate and receive study treatment (age 
appropriate formulation). Following completion of study treatment in Cohort 2 (Part A)  and 
pending PK and safety results from Cohort 2 (Part A), Cohort 3 will receive study treatment 
(age-appropriate formulation). 
Subjects in each cohort (Cohorts 1, 2 and 3) will immediately enroll in Part B as they 
complete Day 7 of Part A.  On completion of Day 7 of Part A; subjects (aged 3 to < 18 years) 
will immediately enroll in Part B. They will begin dosing with SOF + RBV with no 
interruption of study drug administration.  Subjects rolling over from Part A will not be 
required to perform additional laboratory assessments on Part B Day 1.


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3.1.2.
Part B
Part B will be initiated by cohort after confirmation of age-appropriate SOF dosage levels. 
Subjects who participated in Part A will immediately rollover into Part B (Day 1), with no 
interruption of study drug administration:
Children aged 3 to < 12 years (Group 2) and adolescents aged 12 to < 18 years (Group 1) 
with GT-2 or GT-3 infection and evidence of HCV RNA > 1000 IU/mL at study entry (those 
who were dosed in Part A will have met this criteria prior to enrollment) will be evaluated.
Subjects enrolled in Part B will receive the following regimen.

GT-2 subjects: SOF + RBV for 12 weeks

GT-3 subjects: SOF + RBV for 24 weeks
The study will enroll both treatment-naïve and treatment–experienced pediatric subjects, with 
up to 20 subjects allowed to be treatment experienced. Approximately 100 total subjects, 
including subjects from Part A, will be enrolled in Part B as follows:

Group 1: Approximately 50 adolescent subjects (12 to < 18 years of age)

Group 2: Approximately 50 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 standard-of-care (SOC) therapy with their healthcare provider.


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Figure 3-1.
Study Schema
3.2.
Visit Schedule
3.2.1.
Part A
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 7.
Subjects (up to 10 subjects) enrolled in Part A will participate in an intensive PK evaluation 
on Day 7. Subjects will be administered a dosing diary with instructions.  
Following completion of the Day 7 intensive PK visit, subjects will then return for scheduled 
study visits outlined in Part B and begin dosing with SOF + RBV with no interruption of 
study drug administration.  Subjects rolling over from Part A will not be required to perform 
laboratory assessments on Part B Day 1.


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3.2.2.
Part B
Screening assessments will be completed within 28 days of the Day 1 visit. For subjects 
continuing from Part A, screening for Part B will not be required.

GT-2 Subjects: Study visits for GT-2 subjects will occur at screening, Day 1, and the 
end of weeks 1, 2, 4, 8, and 12. 

GT-3 Subjects: Study visits for GT-3 subjects will occur at screening, Day 1, and the 
end of weeks 1, 2, 4, 8, 12, 16, 20, and 24. 
All Part B 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).


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3.4. 
Treatment Discontinuations Criteria 
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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 defmed in Section 7 of the protocol, 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 imp01iant to detennine 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, regulat01y agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC). 
3.5. 
Discontinuations 
Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an Early Tennination visit as described in the Section 6.4.7. 
Subjects who pennanently discontinue all study dmgs for any reason including safety and/or 
tolerability concems prior to completion of the assigned dosing period will be followed 
according to the post-u·eatment study assessments described in Section 6.5. 
3.6. 
Pharmacogenomic Substudy 
PD 
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 eve1y 6 months for 
assessments of growth, quality of life, and long-te1m viral suppression (if applicable) in a 
separate protocol (GS-US-334-1113). This follow-up will continue for 5 years. 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 100 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
2. 3 years to < 18 years of age (consent of parent or legal guardian required)
3. Part A only: subjects in Cohort 1 (age 12 to <18 years of age) must weigh 45 kg, and be 
treatment naïve.
4. Chronic HCV infection documented by either:
c) 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
d) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV 
infection
5. Infection with HCV GT 2 or 3 as determined at Screening
6. HCV RNA ≥1000 IU/mL at Screening
7. Adequate hematologic function (absolute neutrophil count 1,500/mm3; 
hemoglobin 10.0 g/dL)
8. Negative serum -HCG pregnancy test (for females of childbearing potential only, as 
defined in Appendix 5)
9. 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


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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. 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)
4. Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)
5. -fetoprotein 50 ng/mL
6. Serum creatinine > 1.5 mg/dL
7. Evidence of hepatocellular carcinoma (HCC)
8. Co-infection with HIV, acute HAV, or HBV
9. Significant cardiovascular, pulmonary or neurological disease
10. Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption 
of orally administered medications
11. History of solid organ or bone marrow transplantation
12. Chronic daily non-steroidal anti-inflammatory drug therapy
13. Systemic corticosteroid use for 5 days (pulmonary/nasal administration is permitted)
14. Investigational agents (except with the expressed approval of the Sponsor)
15. 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
16. Known hypersensitivity to the study drugs, the metabolites or formulation excipients


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17. 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
18. Use of any prohibited concomitant medications as described in Section 5.6 within 
28 days of the Day 1 visit


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
Not applicable.
5.2.
Sofosbuvir
5.2.1.
Description and Handling
5.2.1.1.
Formulation:
SOF tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets debossed with “GSI” on 
one side and “7977” on the other side. In addition to the active ingredient, SOF tablets 
contain the following inactive ingredients: mannitol, microcrystalline cellulose, 
croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, 
titanium dioxide, macrogol, talc, and yellow iron oxide.
SOF tablets, 100 mg, are yellow, round, film-coated, plain-faced tablets. In addition to the 
active ingredient, SOF tablets contain the following inactive ingredients: mannitol, 
microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium 
stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, and yellow iron oxide.
The formulation of SOF Oral Granules will be based on the PK results obtained from cohorts 
1 and/or 2 of this study. The formulation strength, composition, will be available and 
reflected in a protocol amendment implemented prior to dosing subjects who are unable to 
swallow tablets.
5.2.1.2.
Packaging and Labeling
SOF 400 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 30 tablets and a silica gel desiccant canister or sachet and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant screw cap 
with an induction-sealed, aluminum-faced liner.
SOF 100 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 28 tablets and a 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 SOF Oral Granules will be based on the chosen formulation 
which will be dependent on the PK results obtained from cohorts 1 and/or 2 of this study. 
The packaging and labeling will be available and reflected in a protocol amendment 
implemented prior to dosing subjects who are unable to swallow tablets.
SOF bottles to be distributed to centers in the US, EU and the rest of the countries will be 
labeled to meet all applicable requirements of the US Food and Drug Administration (FDA) 


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and Annex 13 of Good Manufacturing Practices: Manufacture of investigational medicinal 
products (July 2010) and/or other local regulations as applicable.
5.2.2.
Storage and Handling
SOF tablets should be stored at controlled room temperature until required for 
administration. Controlled room temperature is defined as 25 C (77 F); excursions are 
permitted between 15 C and 30 C (59 F to 86 F).
The storage and handling of the SOF Oral Granules will be based on the formulation chosen 
dependent on the PK results obtained from cohorts 1 and/or 2 of this study. 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 study drug and to ensure proper product 
identification, the drug product should not be stored in a container other than the container in 
which they are supplied. Consideration should be given to handling, preparation, and 
disposal through measures that minimize drug contact with the body. Appropriate 
precautions should be followed to avoid direct eye contact or exposure through inhalation 
when handling SOF.
Sufficient quantities of SOF tablets and SOF Oral Granules will be shipped to the 
investigator or qualified designee from Gilead Sciences Materials & Logistics (or its 
designee).
5.2.3.
Dosage and Administration of SOF
Part A: SOF 400-mg tablets will be administered once daily. Subjects determined unable to 
swallow the 400-mg tablet, by SOF swallowability assessment at Day 1 or any time during 
the study, will be re-assigned to 4 x 100-mg tablets daily.
Part B: SOF 400-mg tablets will be administered once daily for subjects who weigh ≥45 kg. 
Subjects determined unable to swallow the 400-mg tablet (by SOF assessment at Day 1 or at 
any time during the study) will be re-assigned to 4 x 100-mg tablets daily. For subjects in this 
age group who weigh < 45 kg, PK data from part A will be used to determine the appropriate 
dose of SOF to be administered. 
Subjects who participated in Part A will continue the assigned dose in Part B.
An additional age-appropriate formulation for SOF Oral Granular is currently under 
development. The dosage strength for this formulation will be dependent on the PK results 
obtained from cohorts 1 and/or 2 of this study. The formulation strength, composition, and 
dosing administration will be available and reflected in a protocol amendment implemented 
prior to dosing subjects who are unable to swallow tablets.


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5.3.
Ribavirin 
5.3.1.
Description and Handling of RBV
5.3.1.1.
Formulation 
RBV tablets, 200 mg, are blue, capsule-shaped, film-coated tablets debossed with “3RP” on 
one side and “200” on the other side. In addition to the active ingredient, RBV tablets contain 
the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, 
croscarmellose sodium, povidone, magnesium stearate, polyvinyl alcohol), titanium dioxide, 
macrogol, talc and FD&C blue #2.
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 tablets are packaged in white, HDPE bottles. Each bottle contains 168 tablets and 
rayon coil packing material and is enclosed with a white, continuous thread, child-resistant 
screw cap with an induction-sealed, aluminum-faced liner. 
The RBV oral solution is packaged in 4-oz amber glass bottles (100 mL/bottle) with 
child-resistant closures.
RBV bottles to be distributed to centers in the US, EU and the rest of the countries will 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 (July 2010) and/or other local regulations as applicable.
5.3.1.3.
Storage and Handling
RBV tablets should be stored at 25 C (77 F); excursions are permitted between 15 and 
30 C (59 and 86 F).
RBV oral solution should be stored between 2-8°C (36-46°F) or at 25°C (77°F); excursions 
permitted to 15-30°C (59-86°F).
5.3.2.
Dosage and Administration of RBV
RBV dose will be administered by weight as follows:

Below 50 kg: RBV 15 mg/kg divided BID 

50 kg to < 65 kg : RBV 400 mg BID 

65 kg to < 75 kg: RBV 400 mg in the morning and 600 mg in the evening


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
Greater than or equal to 75 kg: 600 mg BID 
The morning dose of RBV will be taken with SOF and food. The evening dose of RBV will 
be taken with food.
RBV tablets will be supplied by Gilead Sciences for all subjects.
5.4.
Co-administration of SOF and RBV
In Part B 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 with food as follows:

SOF

Weight-based RBV (as per Section 5.3.2).
For evening doses, subjects will be instructed to take study drug with food as follows:

Weight-based RBV (as per Section 5.3.2).
If a subject forgets to take the medication at the correct time, it may be taken later in the day; 
however, no more than 400 mg dose of SOF 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.  
5.5.
Study Drug Compliance
Subjects will be instructed to return any unused SOF and RBV in the original container on 
Day 7 (Part A) and/or at study treatment visits every 4 weeks (Part B).  
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 of Screening, up to and including the date of 
the visit four weeks after discontinuation of study treatment, need to be recorded in the 
source documents and eCRFs. All concomitant medications should be recorded in the source 
documents.
The following medications are prohibited from 28 days prior to the Day 1 visit through the 
end of treatment:

Erythropoiesis-stimulating agents (ESAs); including but not limited to Procrit®, Aranesp®
and Epogen®


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
Granulocyte colony stimulating factor (GCSF)

Chronic systemic immunosuppressants including 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®

Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters i.e. P-gp) with study drug(s) may result in pharmacokinetic interactions 
resulting in decreases in exposure of study drug(s). Representative medications which are 
excluded from 21 days prior to Day 1 through the end of treatment are listed below:
Drug
Agents Disallowed
Concomitant use with study drug may 
potentially result in changes of study 
drug concentration as listed below
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Decrease in concentration of study drug
Antimycobacterials
Rifampin, rifabutine, rifapentine
Decrease in concentration of study drug
Herbal/Natural 
Supplements
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-
to (or Xiao-Shai-Hu-Tang)
Decrease in concentration of study drug
Medications for disease conditions excluded from the protocol (e.g., HIV-1 infection, active 
cancer, transplantation) are not listed under this Concomitant Medication section and are 
disallowed in the study.


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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 
genotype testing or for extenuating circumstances.
Subjects who participated in Part A will not require an additional screening visit or perform 
any additional laboratory assessments prior to starting Part B.
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 (i.e., height and weight of parents, if known)
— Liver biopsy results within 2 years of Screening (if available)

Complete physical examination 


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(Part A only) Perform Tanner Pubertal Stage assessment for subjects ≥ 6 years of age at 
the time of the visit, until Tanner Stage 5 has been reached. Date of first menses will be 
documented

Vital signs (temperature, blood pressure, pulse, respiratory rate), body weight and height

Obtain blood samples for tests as listed in Section 6.6.1:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Determination of HCV viral genotype 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
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to 
the clinic for the Day 1 visit assessments.


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6.3.
Part A: Treatment Assessments 
6.3.1.
Day 1 Visit
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

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)

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
6.3.1.1.
Drug Administration

Dispense study drugs as directed by the IWRS

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 all study drugs

Perform SOF swallowability assessment (for subjects administered SOF in tablet form 
only)


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
Observe the subject taking the first dose of study drugs (with 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 parent/guardian

Obtain blood samples for:
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing (archive)

Review subject dosing diary
6.3.3.
Day 7 – Intensive PK 
The Day 7 Intensive PK visit should occur on the protocol-specified visit date based on the 
Day 1 visit. For the purposes of scheduling, the Day 7 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 7 Intensive PK visit (i.e., no food or drink 
except water at least 8 hours prior to the Day 7 Intensive PK visit). Subjects and/or 
parents/guardians should be instructed that the Day 7 dose of SOF must not be taken until the 
evaluations listed below are completed. 
If the subject has already dosed prior to the Day 7 clinic visit or is not in a fasted state, the 
Day 7 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 8, 9, or 10) for the 
intensive PK visit. Appropriate study drug re-dispensation must be performed in this case.


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If dosing non-compliance is identified as per subject dosing diary and pill count on or prior to 
the Day 7 visit, the Day 7 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 7 intensive PK visit no sooner than 3 days following compliant dosing and 
no later than Day 11 (i.e., return on Day 10 or Day 11).  If dosing non-compliance is due to 
an AE, consultation with the Gilead Medical Monitor is required regarding the potential of 
rescheduling the Day 7 intensive PK visit.
In both scenarios described above, the subject and/or parents/guardians should be reminded 
not to take the SOF prior to arriving at the clinic on the day of the re-scheduled intensive PK 
visit. All Day 7 intensive PK assessments listed below should be completed when the subject 
returns.
The following evaluations are to be completed at the Day 7 Intensive PK visit:

Perform a symptom-directed physical examination as needed

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Perform study drug accountability 

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 
— HCV RNA
— Viral sequencing (archive)


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
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 
SOF per dosing requirements.
— Post-dose blood samples will be collected as follows: 

For Cohorts 1 and 2:  0.5, 1, 2, 3, 4, 8, and 12 hours post-dose (with predose also 
serving as t= 24).

For Cohort 3 only: 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 7 intensive PK visit subjects will then continue to the Day 1 visit in 
Part B described in Section 6.4.1
6.4.
Part B: Treatment Assessments 
6.4.1.
Day 1 Visit
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

Vital signs, including body weight and height

Review of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only). Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA


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• 
Perf01m SOF swallowability assessment (for subjects administered SOF in tablet f01m 
only and who have not ah·eady completed the assessment in Pali A) 
• 
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. 
6.4.1.1. 
Dmg Administration 
• 
Dispense study <hugs as directed by the IWRS 
• 
Instmct the subject on the appropriate RBV dose after weight-based dosage is calculated 
using Day 1 weight 
• 
Instmct the subject on the packaging, storage and a<hninistration of all study <hugs 
• 
Observe the subject taking the first dose of study dm gs (with food) and record the time of 
first dose 
• 
Perf01m SOF swallowability assessment (for subjects administered SOF in tablet f01m 
only) 
6.4.2. 
Weeks 1 and 2 (± 3 days) 
The following procedures/assessments are to be completed at these visits: 
• 
Vital signs, including body weight and height 
• 
Perf01m symptom-directed physical examination 
• 
Assessment of AEs and concomitant medications 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemis1:Iy 
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— 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

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 drugs at these visits)

Dispense study drugs as directed by the IWRS
6.4.4.
Week 12 (3 days)

Perform complete physical examination

Tanner Staging Assessment


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
Vital signs, including body weight and height

Assess Rates of Growth (percentiles)

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)

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. (GT-2 Subjects 
only)

Review medication compliance with subject and/or parent/guardian.

Dispense study drugs as directed by the IWRS (GT-3 Subjects Only)

GT-2 Subjects should return all bottles and kits at the Week 12 Visit
6.4.5.
Week 16 and 20 (3 days) – GT-3 Subjects only

Vital signs, including body weight and height

Perform symptom-directed physical examination

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 drugs at these visits)

Dispense study drugs as directed by the IWRS
6.4.6.
Week 24(3 days) – GT-3 Subjects only

Perform complete physical examination

Tanner Staging Assessment

Vital signs, including body weight and height

Assess Rates of Growth (percentiles)

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)

Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA


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— 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.

GT-3 Subjects should return all bottles and kits at the Week 24 Visit
6.4.7.
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.
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

Assess Rates of Growth (percentiles)

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)

Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA


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— 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 kits at the Early Termination Visit
All subjects should complete Post-Treatment assessments after early termination, as 
described in Section 6.5.
Subjects who do not attain SVR24 and do not initiate experimental or approved anti-HCV 
therapy will be followed every 6 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.
6.5.
Post-Treatment Assessments
6.5.1.
4-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for: 
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing (archive)


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
Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age 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 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

Perform symptom-directed physical examination

Perform Tanner Pubertal Stage assessment for subjects ≥ 6 years of age at the time of the 
visit, until Tanner Stage 5 has been reached. Date of first menses will be documented.

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 (Subjects 12 to < 18 years of age only)

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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6.5.3.
24-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height

Perform symptom-directed physical examination

Tanner Pubertal Stage Assessment & Rates of growth

Obtain blood samples for 
— HCV RNA
— Viral sequencing (archive)

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.

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)
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 
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 and creatine kinase (CK).
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 genotype and subtype will be determined using the Siemens VERSANT®


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HCV Genotype INNO-LiPA 2.0 Assay. Gilead reserves the right to use alternate assays for 
HCV RNA and HCV genotype should the above assays become unavailable.
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 right 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: 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.
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
6.6.5.
Swallowability Assessment
On Day 1 of Part A or Part B (as applicable) a SOF swallowability assessment will be 
administered.  Subjects who have indicated at Screening that they can take pills will be 
observed taking the first 400-mg SOF tablet.  This will confirm the swallowability of the 
400-mg tablet size. If, at Day 1 or any time during the study, a subject is unable to continue 
with the 400-mg tablet size he/she will be re-assigned to 4 x 100mg SOF tablets.  If unable to 
take the 100mg SOF tablet, enrollment of the subject will be deferred until the granule 
formulation is available.
6.6.6.
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:


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Subject should sit for 5 minutes with feet flat on the floor and measurement arm 
supported so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an 
appropriately sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or 
to the nearest whole number on an automatic device.
6.6.7.
Body Mass Index (BMI)
BMI is calculated by the following equation.
BMI = weight (pounds) 703           or            weight in kilograms
   (height in inches)2                                (height in meters)2
6.6.8.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each visit for viral sequence analysis. Unused 
samples may be archived.
6.6.9.
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. If required 
by local regulations, additional pregnancy tests beyond 6 months may be added. In the event 
of a positive urine pregnancy result, subjects will be instructed to stop study drugs 
immediately and return to the clinic as soon as possible for a serum pregnancy test.
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.
6.6.10.
Quality of Life Survey (PedsQL™)
The PedsQL ™  Pediatric Quality of Life Inventory V4.0 Short Form (SF15) will be 
completed in Part B of the study at Day 1, End of Treatment (Week 12 for GT-2 subjects, 
Week 24 for GT-3 subjects, or at 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 will be administered to the subject 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
7.1.1.
RBV Dose Adjustments
No formal RBV dose reduction guidelines exist for pediatric subjects. Prior to RBV dose 
adjustments, the Gilead Medical Monitor should be consulted.
7.2.
Subject Stopping Rules for SOF
The Gilead Medical Monitor should be consulted prior to dose discontinuation of SOF unless 
the investigator believes that immediate action is warranted to ensure the continued safety of 
the subject.
Administration of SOF may be discontinued due to a clinical or laboratory event. There is no 
option for SOF dose reduction. If SOF is stopped for toxicity, it should not be restarted, RBV 
should be stopped and the subject should complete an Early Termination Visit.
Subjects who meet any of the following laboratory criteria should stop treatment with SOF
and RBV:

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 

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event or lab abnormality assessed as related to treatment with SOF


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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)

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.)


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
In-patient hospitalization or prolongation of existing hospitalization

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 (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 8.1.1 and 8.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
8.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event
information and assessments.
8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to 
IMP therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the 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 (eg., 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 
All SAEs, regardless of causal relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required 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 from screening onwards.
All AEs, regardless of causal relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP 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 post-treatment follow 
up period.
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 this time 
and the event is deemed relevant to the use of IMP, he/she should promptly document and 
report the event directly to Gilead DSPH. Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com or Fax: +1 (650) 522-5477.  All AEs and SAEs will be
recorded in the CRF/eCRF database within the timelines outlined in the CRF/eCRF 
completion guideline.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by 
emailing or faxing the report form within 24 hours of the investigator’s knowledge of the 
event to the attention of the designated CRO Pharmacovigilance Representative.


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Electronic Serious Adverse Event (eSAE) Repmiing Process 
• 
All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines 
outlined in the CRF/eCRF completion guideline. 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit the SAE 
infonnation to Gilead DSPH within 24 homs of the investigator's knowledge of the 
event. Detailed instructions can be fmmd in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE infonnation electr·onically, ie, the 
eCRF database is not ftmctioning, record the SAE on the paper serious adverse event 
repmiing fmm and submit within 24 homs as described above. 
• 
As soon as it is possible to do so, any SAE repmi ed via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repmied via a paper fonn because the eCRF database has been 
locked, no ftnther action is necessruy. 
Conta.ct infonnation is as follows: 
Gilead Sciences, 
Dmg Safety and 
Public Health: 
PRA Intemational 
Phrum acovigilance 
Representative: 
Gilead Sciences, 
Medical Monitor: 
Fax: 
E-mail: 
Fax: 
E-mail: 
Nrune: 
Phone: 
Mobile: 
Fax: 
E-mail: 
+ 1 650 522-5477 
Safety _FC@gilead.com 
+1 888 772 6919 (Nmih America); 
+49 621 8782 181 (Rest of World) 
CHOSafety@praintl.com 
Luisa Stamm, MD, PhD 
PO 
PPD 
PPD 
t-'t-'U 
• 
For fatal or life-threatening events, copies of hospital case repmis, autopsy repmis, and 
other documents ru·e also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occm without personal subject identification, 
maintaining the tr·aceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensme the timely completion of accmate 
safety repmis. 
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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.
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. 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, and 
pregnancy reports regardless of an associated AE.  Also includes reports of adverse reactions 
in infants following exposure from breastfeeding, and reports of adverse reactions associated 
with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following maternal or paternal exposure 
to the medicinal product. 
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 


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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.  
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 (ie, signs the informed consent) and throughout the 
study, including the post-treatment follow-up period, to the CRO Pharmacovigilance 
Representative using the pregnancy report form within 24 hours of becoming aware of the 
pregnancy.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate 
a pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as 
an SAE. The underlying medical reason for this procedure should be recorded as the AE
term.
A spontaneous abortion is always considered to be an SAE and will be reported as described 
in Sections 8.1.1 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 CRO Pharmacovigilance Representative 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 drugs 
must also be reported and relevant information should be submitted to the CRO 
Pharmacovigilance Representative 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).


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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 the CRO Pharmacovigilance Representative within 24 hours of the investigator 
becoming aware of the situation. These reports must consist of situations that involve study 
IMP, but do not apply to concomitant medications. Except for situations that result in AEs, 
special situations involving concomitant medications will not be reported. Any inappropriate 
use of contraindicated medications 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 prima1y objective ofPa1t A of this study is: 
Final 
Amendment 1 
• 
To evaluate the steady state phrumacokinetics (PK) and confnm the dose of SOF in 
HCV -infected pediatric subjects 
The secondruy objective ofPmt A of this study is: 
• 
To evaluate the safety and tolerability of 7 days of dosing of SOF in HCV -infected 
pediatric subjects 
The primm·y objectives of Pmt B of this study m·e: 
• 
To evaluate the safety and tolerability of SOF + RBV for 12 or 24 weeks in 
HCV-infected pediatric subjects with genotype 2 or 3, respectively 
• 
To dete1mine the antiviral efficacy of SOF+RBV treatment in genotype 2 and genotype 3 
HCV-infected subjects sepm·ately, as assessed by the proportion of subjects with SVR 
12 weeks after completion oftreatment (SVR12) 
The secondmy objectives of Pmt B of this study are: 
• 
To dete1mine the antiviral efficacy of SOF+RBV treatment in genotype 2 and genotype 3 
HCV-infected subjects sepm·ately, 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 SOF during treatment and after 
completion of treatment 
The explorat01y objective of this study is: 
• 
PD 
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9.1.2.
Primary Endpoint
In Part A, AUCtau of GS-331007 is considered as the primary PK parameter for determining 
the appropriate SOF dose.
For Part B, the primary efficacy endpoint is SVR12. Safety endpoint is any AE leading to 
permanent discontinuation of study drug(s).
9.1.3.
Secondary Endpoints
In Part A, the secondary PK endpoints include AUCtau, Cmax, AUClast, Tmax, Clast, Tlast, Ctau
and t1/2for GS-331007 and SOF as appropriate. AEs leading to permanent discontinuation of 
study drug(s) will be evaluated as a secondary safety endpoint.
For Part B, secondary efficacy endpoints include SVR4, SVR24, end-of-treatment response, 
breakthrough and relapse. Additional efficacy evaluations may include HCV RNA change 
from Day 1; ALT normalization; viral kinetic parameters; and changes in patient reported 
outcomes based on the Quality of Life survey to assess the effect of treatment on quality of 
life.
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 part A 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 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 SOF or GS-331007 are 
available. The PK analysis set will be used for analysis of general PK and single sample 
plasma concentrations.


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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. 


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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.
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 Part A and Part B 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 genotype, prior treatment experience, and additional endpoints as 
necessary.


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9.4.
Pharmacokinetic Analysis
PK analysis will be performed for Part A using the intensive PK analysis set. The 
concentration data of SOF and metabolites (GS-566500 and GS-331007) 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 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 the exposures of GS-331007 achieved in pediatric subjects of this study are 
similar to the exposures observed in historical control subjects, GS-331007 exposure data 
from this study will be compared to the integrated historical control data by carrying out an 
analysis of variance (ANOVA) for log-transformed AUCtau of GS-331007 as the primary 
endpoint while Cmax of GS-331007 will be evaluated as secondary endpoints. 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%. Individual patient management 
will be performed by maintaining exposures comparable to adults.  AUCtau less than the 
2.5th percentile of adult values may require dose adjustment as appropriate.
The effect of age and SOF dose on PK (SOF and GS-331007) will be assessed.
9.5.
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 age group and genotype for Part B.
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.
9.5.1.
Primary Analysis
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
treatment) in the FAS population. The primary analysis will be performed after all enrolled
subjects have been followed through 12 weeks post-treatment or discontinued from study.
9.5.2.
Secondary Analysis
The proportion of subjects with HCV RNA below LLOQ over time (including SVR 
endpoints) will be presented by age group and genotype in Part B in tabular and graphical 
form. 


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Descriptive summaries and listings will be provided for additional efficacy evaluations 
including senun HCV RNA actual values and change from baseline, prop01iion of subjects 
with virologic failmes, and other endpoints of interest including ALT nonnalization. 
PD 
9.5.3. 
Subgroup Analysis 
Subgroup analysis on SVR12 will be perf01med by treatment experience (treatment-naive 
vs. experienced), and by treatment experience and genotype. 
Details on efficacy analyses will be described in the statistical analysis plan. 
9.6. 
Safety Analysis 
Safety analysis will be perf01med for Pmi A and Pati B respectively. 
Safety will be evaluated by assessment of clinical laborat01y tests, physical examinations, 
vital signs measmements, and by the documentation of AEs. 
All safety data collected while on or after the first dose of study dmg administration up to 
30 days after the last dose of study dmg will be summarized by coh01i according to the study 
dmg received. 
Safety endpoints will be analyzed by the number and percent of subjects with events or 
abn01malities for categorical values or 8-number summmy (n, mean, standai·d deviation, 
median, Ql, Q3, minimum, maximum) for continuous data .. 
9.6.1. 
Extent of Exposure 
A subject's extent of exposme to study dmg will be generated from the study dmg 
administration page of the CRF. Exposme data will be summm·ized. 
9.6.2. 
Adverse Events 
Clinical and laborat01y AEs will be coded using the Medical Dictionmy for Regulat01y 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Tenn (HLGT), 
High-Level Tetm (HLT), Prefened Tetm (PT), and Lower-Level Tetm (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 fust dose of study dmg up to the date of last dose of study dmg 
plus 30 days. 
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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,

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.
9.6.3.
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 by age group and overall.
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.
9.6.4.
Other Safety Evaluations
9.6.4.1.
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.


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9.6.4.2.
Quality of Life Analysis
The data from PedsQL ™  Pediatric Quality of Life survey will be summarized by visit and 
age group and overall.
9.7.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of 
the study and perform interim reviews of safety and PK data 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.
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.
9.8.
Sample Size
With approximately 50 subjects enrolled into each age group of Part B, a two-sided 95.0% 
confidence interval of the SVR12 rate will extend at most 11.1% in both directions from the 
observed SVR12 rate, assuming the expected SVR12 rate is 80%.


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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 Harmonisation (ICH) guidelines, or with the laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the study subject. 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 subinvestigators 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 subinvestigator. The investigator and subinvestigator 
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.


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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.


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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);

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 10 years for purposes of this study.


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10.1.6.
Case Report Forms
For each subject enrolled, a CRF (or eCRF) must be completed and signed by the principal 
investigator or subinvestigator (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 prerandomization screening period if a CRF was initiated). If a subject 
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.


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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 or IEC in accordance with local requirements. Approval must be obtained before 
changes can be implemented.
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.


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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.
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
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.
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.


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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.
23275
Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. 
Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J 
Med 2013;368 (1):34-44.
24713
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, 
Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without 
treatment options. N Engl J Med 2013;368 (20):1867-77.
24715
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et 
al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 
2013;368 (20):1878-87.
27503
SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing Information. Gilead 
Sciences, Inc. Foster City, CA. December 2013.  


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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, Single-Arm Study to Investigate the 
Safety and Efficacy of Sofosbuvir + Ribavirin in Adolescents and Children with 
Genotype 2 or 3 Chronic HCV Infection 
GS-US-334-1112, Protocol Amendment 1, 10 February 2014 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Luisa Stamm, MD, PhD (Printed) 
Medical Monitor 
IV 
Fe-b 
2..0\4-
Date 
PO 
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 Scjences, Inc. I will discuss this material with them to 
ensure that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 77 
10 February 2014 


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Appendix 2.
Study Procedures Table
Appendix Table 1.
Part A: Screening and On-Treatment Study Visits
Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 7
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Complete Physical Examination
X
X
Symptom-directed Physical Examination
X
X
Tanner Pubertal Stage Assessment
X
Vital Signsa
X
X
X
X
AEs and Concomitant Medications
X
X
X
X
Pregnancy Prevention Counselingf
X
SOF Swallowability Assessment
X
Review of Study 
Medication Compliance
X
Study Drug Dispensingb
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 7
(+ 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
Subject Dosing Diary
X
X
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 height, weight, blood pressure, pulse, respiratory rate and temperature
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 drugs on Day 7 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 8, 
and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 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 (subjects 12 to < 18 years of age only).


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Appendix Table 2.
Part B: Screening and On-Treatment Study Visits
Screeningc
Day 1c
Visit identified by on-treatment study week
1
2
4
8
12
16g
20g
24g
Early 
Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Complete Physical Examination
X
X
X
X
X
Symptom-Directed Physical Examination
X
X
X
X
X
X
Tanner Pubertal Stage Assessment & 
Rates of growthh
X
X
X
X
Vital Signsa
X
X
X
X
X
X
X
X
X
X
X
AEs and Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention Counselingi
X
X
X
X
SOF Swallowability Assessment
X
Quality of Life Surveye
X
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
X
X
X
Study Drug Dispensingb
X
X
X
X
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
Viral Sequencing e
X
X
X
X
X
X
X
X
X
X


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Screeningc
Day 1c
Visit identified by on-treatment study week
1
2
4
8
12
16g
20g
24g
Early 
Termination
Serum or Urine Pregnancy Testing
X
X
X
X
X
X
X
X
X
Single PK
X
X
X
X
X
X
X
X
X
Urinalysis, Urine Drug Test
X
HCV Genotyping, IL28B
X
HCV antibody, HIV 1/2 antibody, HBs 
antigen, HAV antibody
X
HbA1c
X
TSH
X
X
X
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
a
Vital signs include height, weight, blood pressure, pulse, respiratory rate and temperature
b
The IWRS will provide direction on the specifics of each subject’s study drug dispensing.
c
Subjects rolling over from Part A will not be required to repeat screening and eligibility assessments on Part B.  Subjects enrolling into Part B must completed Day 1 
assessments prior to dosing.  
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 at Day 1, 12, and 24/ET 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.
f
g
GT-2 subjects will complete through the Week 12 visit; GT-3 subjects will complete through the Week 24 visit. 
h
Performed at Day 1 and End of Treatment 
i
Including partner pregnancy prevention for male participants (subjects 12 to < 18 years of age only).
PPD
PPD


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Appendix Table 3.
Part B: 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
Xd
Xd
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment & Rates of 
Growth
X
X
Pregnancy Prevention Counseling e
X
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Testc
X
X
X
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
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.
d
All SAEs, including deaths, regardless of cause or relationship, must be reported after patient signs the informed consent through the end of the study
e
Including partner pregnancy prevention for male participants (subjects 12 to < 18 years of age only).


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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18June2012
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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 1
CONFIDENTIAL
Page 84
10 February 2014
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
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
Infant, 2 – 7 Days
1250 to 1500/mm3
1.25 to 1.50 GI/L
1000 to 1250/mm3
1.00 to < 1.25 GI/L
750 to 1000/mm3
0.75 to < 1.00 GI/L
750/mm3
< 0.75 GI/L
Infant, 1 Day
4000 to 5000/mm3
4.00 to 5.00 GI/L
3000 to 4000/mm3
3.00 to < 4.00 GI/L
1500 to 3000/mm3
1.50 to < 3.00 GI/L
1500/mm3
< 1.50 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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 1
CONFIDENTIAL
Page 85
10 February 2014
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0% 


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 1
CONFIDENTIAL
Page 86
10 February 2014
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 
146  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 1
CONFIDENTIAL
Page 87
10 February 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4  mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 1
CONFIDENTIAL
Page 88
10 February 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63  to LLN mmol/L
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.14 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 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 1
CONFIDENTIAL
Page 89
10 February 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol/L to LLN
57 to 87 μmol/L
27 to 57 μmol/L
27 μmol/L
Creatinine 
1.50 to 2.00 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol/L
177 to 265 μmol/L
265 to 530 μmol/L
530 μmol/L
Bicarbonate
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
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L
LDL
(Fasting)
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
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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 1
CONFIDENTIAL
Page 90
10 February 2014
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
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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 1
CONFIDENTIAL
Page 91
10 February 2014
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.


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 1
CONFIDENTIAL
Page 92
10 February 2014
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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 1
CONFIDENTIAL
Page 93
10 February 2014
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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Amendment 1
CONFIDENTIAL
Page 94
10 February 2014
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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Amendment 1
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening consequences 
OR Aggressive intervention 
indicated [eg, tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (eg, diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening consequences 
(eg, sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock


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Amendment 1
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids)
Life-threatening consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(eg, hypotensive shock)


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


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


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


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


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


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


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


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Amendment 1
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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. 


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Amendment 1
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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1. Background
RBV 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 sofosbuvir demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of sofosbuvir 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 randomization. They must also agree 
to one of the following from 3 weeks prior to Day 1 until 6 months after last dose of RBV:

Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) is not permitted.
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 the last dose of RBV:
— intrauterine device (IUD) with a failure rate of < 1% per year
— female barrier method: cervical cap or diaphragm with spermicidal agent
— tubal sterilization
— vasectomy in male partner


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— 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 
Baseline until 7 months after the last dose of 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.
Male subjects must agree to refrain from sperm donation for at least 7 months after the last 
dose of 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. 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.

SAP_007.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Arm 
Study to Investigate the Safety and Efficacy of 
Sofosbuvir + Ribavirin in Adolescents and Children with 
Genotype 2 or 3 Chronic HCV Infection
Name of Test Drug:
Sofosbuvir
Study Number:
GS-US-334-1112
Protocol Version (Date):
Original:
20 December 2013
Amendment 1: 10 February 2014
Amendment 2: 14 March 2014
Amendment 3: 10 October 2014
Amendment 4: 12 November 2014
Amendment 5: 29 May 2015
Amendment 6: 26 February 2016
Analysis Type:
Final Analysis
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
24 May 2018
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF ABBREVIATIONS........................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS AND DEFINITIONS ............................................................................7
1.
INTRODUCTION ................................................................................................................................................8
1.1.
Study Objectives ......................................................................................................................................8
1.2.
Study Design............................................................................................................................................9
1.2.1.
PK Lead-in Phase...................................................................................................................9
1.2.2.
Treatment Phase ...................................................................................................................10
1.2.3.
Study Duration .....................................................................................................................10
1.3.
Sample Size and Power..........................................................................................................................10
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................11
2.1.
DMC Analyses.......................................................................................................................................11
2.2.
Final Analysis ........................................................................................................................................11
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................12
3.1.
Analysis Sets..........................................................................................................................................12
3.1.1.
All Enrolled Analysis Set.....................................................................................................12
3.1.2.
Full Analysis Set ..................................................................................................................12
3.1.3.
Safety Analysis Set...............................................................................................................12
3.1.4.
Pharmacokinetic Analysis Set..............................................................................................12
3.2.
Subject Grouping ...................................................................................................................................13
3.3.
Strata and Covariates..............................................................................................................................14
3.4.
Examination of Subject Subsets.............................................................................................................14
3.5.
Missing Data and Outliers......................................................................................................................14
3.5.1.
Missing Data ........................................................................................................................14
3.5.2.
Outliers.................................................................................................................................15
3.6.
Data Handling Conventions and Transformations .................................................................................15
3.7.
Visit Windows........................................................................................................................................17
3.7.1.
Definition of Study Day .......................................................................................................17
3.7.2.
Analysis Windows................................................................................................................18
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis 
Window................................................................................................................................19
4.
SUBJECT DISPOSITION ..................................................................................................................................20
4.1.
Subject Enrollment and Disposition.......................................................................................................20
4.2.
Extent of Exposure.................................................................................................................................21
4.2.1.
Durations of Exposure to Study Regimen and Individual Study Drug.................................21
4.2.2.
Adherence to Study Drug.....................................................................................................22
4.3.
Protocol Deviations................................................................................................................................24
5.
BASELINE CHARACTERISTICS....................................................................................................................25
5.1.
Demographics ........................................................................................................................................25
5.2.
Other Baseline Characteristics ...............................................................................................................25
5.3.
Swallowability Assessment....................................................................................................................26
5.4.
Palatability of SOF Oral Granules..........................................................................................................26
5.5.
Medical History......................................................................................................................................26


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6.
EFFICACY ANALYSES ...................................................................................................................................27
6.1.
Key Efficacy Endpoint...........................................................................................................................27
6.1.1.
Definition of the Key Efficacy Endpoint..............................................................................27
6.1.2.
Statistical Hypothesis for the Key Efficacy Endpoint ..........................................................27
6.1.3.
Analysis Methods for the Key Efficacy Endpoint................................................................27
6.1.4.
Subgroup Analysis of the Key Efficacy Endpoint................................................................27
6.2.
Secondary Efficacy Endpoints ...............................................................................................................28
6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................28
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................29
6.3.
Exploratory Efficacy Endpoints.............................................................................................................30
6.3.1.
Definition of Exploratory Efficacy Endpoints......................................................................30
6.3.2.
Analysis Methods for Exploratory Efficacy Endpoints........................................................30
6.4.
Changes From Protocol-Specified Efficacy Analyses............................................................................30
7.
SAFETY ANALYSES........................................................................................................................................31
7.1.
Adverse Events and Deaths....................................................................................................................31
7.1.1.
Adverse Event Dictionary ....................................................................................................31
7.1.2.
Adverse Event Severity........................................................................................................31
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................31
7.1.4.
Serious Adverse Events........................................................................................................31
7.1.5.
Treatment-Emergent Adverse Events...................................................................................31
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................32
7.2.
Laboratory Evaluations ..........................................................................................................................34
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................34
7.2.2.
Graded Laboratory Values ...................................................................................................35
7.3.
Vital Signs..............................................................................................................................................36
7.4.
Body Weight, Height and BMI ..............................................................................................................36
7.5.
Mid-Parental Height Assessment...........................................................................................................37
7.6.
Bone Age Assessment............................................................................................................................37
7.7.
Tanner Pubertal Stage Assessment.........................................................................................................37
7.8.
Pediatric Quality of Life (PedsQL™ SF-15) Questionnaires, Including Neuropsychiatric 
Examination by Emotional Function Domain........................................................................................38
7.9.
Prior and Concomitant Medications.......................................................................................................38
7.10.
Other Safety Measures ...........................................................................................................................39
7.11.
Changes From Protocol-Specified Safety Analyses...............................................................................39
8.
PHARMACOKINETIC ANALYSES ................................................................................................................40
8.1.
PK Analysis in PK Lead-in Phase (Intensive PK Analysis)...................................................................40
8.2.
Population PK Analysis .........................................................................................................................40
9.
REFERENCES ...................................................................................................................................................41
10.
SOFTWARE.......................................................................................................................................................42
11.
SAP REVISION..................................................................................................................................................43
12.
APPENDICES ....................................................................................................................................................44
Appendix 1.
Study Procedures Table..........................................................................................................45
Appendix 2.
Tanner Stages* .......................................................................................................................51
Appendix 3.
PedsQL™ Score Calculation Algorithms...............................................................................52


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LIST OF IN-TEXT TABLES
Table 3-1.
Treatment Groups...................................................................................................................13
Table 3-2.
Subgroups for Selected Analyses in 3 to < 6 years of Age.....................................................13
Table 3-3.
Analysis Windows for On-treatment HCV RNA, Vital Signs and Safety Laboratory 
Data ........................................................................................................................................18
Table 3-4.
Analysis Windows for Posttreatment HCV RNA, Body Weight, Height, Vital Sign 
and Safety Laboratory Data....................................................................................................19


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CFR
Code of Federal Regulations
CI
confidence interval
eCRF
electronic case report form
CSR
clinical study report
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
FAS
Full Analysis Set
Gilead
Gilead Sciences, Inc.
GT
genotype
Hb
hemoglobin
HCV
hepatitis C virus
HLT
high level term
HLGT
high level group term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
LLT
lower level term
LLOQ
lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PT
preferred term
Q1
first quartile
Q3
third quartile
RBV
ribavirin
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SI (units)
International system of units
SOC
system organ class
SOF
Sofosbuvir (GS-7977)
SVR
sustained virologic response
SVRx
sustained virologic response x weeks after stopping study drug
TEAE
treatment-emergent adverse events


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TFLs
tables, figures, and listings
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization


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PHARMACOKINETIC ABBREVIATIONS AND DEFINITIONS
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination 
phase of the log plasma/serum concentration versus time curve of the drug
AUC
area under the plasma/serum concentration versus time curve
AUCtau
area under the plasma/serum concentration versus time curve over the dosing interval
CL
systemic clearance of the drug after intravenous administration
CL/F
apparent oral clearance after administration of the drug:
CL/F = Dose/AUCinf, where “Dose” is the dose of the drug
Cmax
maximum observed plasma/serum concentration of drug
Ctau
observed drug concentration at the end of the dosing interval
Emax
maximum (pharmacodynamic) effect
t½
estimate of the terminal elimination half-life of the drug in serum/plasma, calculated by dividing 
the natural log of 2 by the terminal elimination rate constant (z)
Tmax
time (observed time point) of Cmax


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-334-1112. This SAP is based on the study Protocol Amendment 6 dated 
26 February 2016 and the electronic case report form (eCRF). The SAP will be finalized before 
database finalization. Any changes made after the finalization of the SAP will be documented in 
the CSR.
1.1.
Study Objectives
The primary objectives of this study are as follows:

The primary objective of the pharmacokinetics (PK) Lead-in Phase of this study is to 
evaluate the steady state PK and confirm the dose of sofosbuvir (SOF) in hepatitis C virus 
(HCV)-infected pediatric subjects. 

The primary objective of the Treatment Phase of this study is to evaluate the safety and 
tolerability of SOF + ribavirin (RBV) for 12 or 24 weeks in HCV-infected pediatric subjects 
with genotype 2 or 3, respectively
The secondary objectives of this study are as follows:

The secondary objective of the PK Lead-in Phase of this study is to evaluate the safety and 
tolerability of 7 days of dosing of SOF + RBV in HCV-infected pediatric subjects.

The secondary objectives of the Treatment Phase of this study are:
To determine the antiviral efficacy of SOF + RBV treatment in genotypes 2 and 3 
HCV-infected subjects separately, as assessed by the proportion of subjects with 
sustained viral response 12 weeks after discontinuation of therapy (SVR12)
To determine the antiviral efficacy of SOF + RBV treatment in genotypes 2 and 3 
HCV-infected subjects separately, as assessed by the proportion of subjects with 
sustained viral response 4 and 24 weeks after discontinuation of therapy (SVR4 and 
SVR24)
To evaluate the kinetics of circulating HCV RNA during treatment and after treatment 
discontinuation
To evaluate the emergence of viral resistance to SOF during treatment and after treatment 
discontinuation
To evaluate the palatability of SOF oral granules at Day 1, as applicable
To evaluate the effect of growth and development on pediatric subjects during and after 
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The exploratory study objective is as follows:

 
1.2.
Study Design
This is an open-label, multi-cohort, two-part study evaluating the PK, safety, and efficacy of 
SOF + RBV in chronic HCV-infected pediatric subjects.
The study will enroll both treatment-naïve and treatment–experienced pediatric subjects, with up 
to 20 subjects allowed to be treatment experienced. Approximately 100 total subjects will be
enrolled as follows:

Approximately 50 adolescents aged 12 to < 18 years 

Approximately 50 children aged 3 to < 12 years
Subjects of 3 age groups will be enrolled in a sequential fashion: 12 to <18 years old, followed 
by 6 to <12 years old, and 3 to <6 years old.
Eligible subjects will receive the following regimen based on HCV genotypes:

Genotype 2 subjects: SOF + RBV for 12 weeks

Genotype 3 subjects: SOF + RBV for 24 weeks
Therefore, subjects are grouped into the treatment groups specified in Table 3-1 according to
their age groups and HCV genotypes.
The schedules of assessments for the study are provided as appendixes to the SAP (see Study 
Procedures Table, Appendix 1). 
1.2.1.
PK Lead-in Phase
The PK Lead-in Phase will evaluate and/or confirm the age appropriate SOF dose by analyzing 
PK, safety, and antiviral activity of SOF + RBV through 7 days of dosing for each cohort.
Up to 10 genotype 2 or 3, treatment-naïve pediatric eligible subjects will be sequentially enrolled 
into each of the following 3 cohorts:

Cohort 1: 12 to < 18 years old, weighing ≥ 45kg

Cohort 2: 6 to < 12 years old, weighing ≥ 17kg and <= 45kg

Cohort 3: 3 to < 6 years old
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The study will start with Cohort 1 where subjects will receive SOF (400 mg adult tablet or 
4 × 100 mg tablets if determined necessary based on SOF swallowability assessment) + RBV for 
7 days with intensive PK conducted on Day 7. 
Cohort 2 subjects will receive 200 mg SOF (2 × 100 mg tablets or 4 × 50 mg capsules if 
determined necessary based on the SOF swallowability assessment) + RBV for 7 days with 
intensive PK conducted on Day 7. 
Cohort 3 subjects weighing ≥17 kg will receive 200 mg SOF (4 × 50 mg capsules containing 
granules) + RBV for 7 days with intensive PK conducted on Day 7. Cohort 3 subjects weighing 
<17 kg will receive 150 mg SOF (3 × 50 mg capsules containing granules) + RBV for 7 days 
with intensive PK conducted on Day 7. 
Subjects enrolled in the PK Lead-in Phase will immediately enroll in the Treatment Phase as 
they completed Day 7 of the PK Lead-in Phase. Subjects continue dosing with SOF + RBV with 
no interruption of study drug administration.
1.2.2.
Treatment Phase
Additional genotypes 2 and 3 HCV-infected children will be enrolled into the Treatment Phase 
upon confirmation of the appropriateness of the dose from the PK Lead-in Phase. The Treatment 
Phase will be initiated sequentially by age cohort as defined in Cohorts 1, 2, and 3 of the PK 
Lead-in Phase. 
Subjects who participated in the PK Lead-in Phase will immediately roll over into the 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 Phase. The first visit in the 
Treatment Phase for these subjects will be the Week 2 visit. 
1.2.3.
Study Duration
The total time to complete all study visits is up to approximately 40 weeks for subjects treated 
with 12 weeks of therapy and 52 weeks for subjects treated for 24 weeks of therapy including the 
following periods:

28-day (4-week) screening period

12 or 24 week treatment period

24-week post-treatment period
1.3.
Sample Size and Power
With approximately 50 subjects enrolled into 12 to < 18 years of age group and approximately 
50 subjects enrolled into 3 to < 12 years of age group of the Treatment Phase, a 2-sided 95% 
confidence interval of the SVR12 rate will extend at most 11.1% in both directions from the 
observed SVR12 rate, assuming the expected SVR12 rate is 80%. In addition, a sample size of 
100 subjects will provide over 80% power to detect an 11% improvement in SVR12 rate from 
80% to 91% using 2-sided one-sample binomial test at significance level of 0.05.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
DMC Analyses
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety data 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.
Specific activities of the DMC will be defined by a mutually agreed charter, which will define 
DMC membership, conduct and meeting schedule.
2.2.
Final Analysis
After all subjects have completed through the post-treatment week 24 visit or have prematurely 
discontinued from the study, outstanding data queries have been resolved, and the database has 
been cleaned and finalized, the final analysis of the data will be performed.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects [n], mean, standard deviation [SD] or standard error [SE], median, first 
quartile [Q1], third quartile [Q3], minimum, and maximum will be presented.
Data collected in the study will be presented in by-subject listings for all subjects in the Safety 
Analysis Set, unless otherwise specified. All by-subject listings will be presented by subject 
identification (ID) number in ascending order, unless otherwise specified.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The number of subjects eligible for each analysis set will be 
provided. Subjects who were excluded from Safety and Full Analysis Sets will be provided in a 
by-subject listing with reasons for exclusion. 
3.1.1.
All Enrolled Analysis Set
All Enrolled Analysis Set includes all subjects enrolled in the study after screening. All analyses 
based on the All Enrolled Analysis Set will be performed according to the treatment group to 
which subjects were enrolled.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes HCV infected subjects who were enrolled into the study 
and received at least one dose of study drug. The study drugs in this study include SOF and 
RBV. Subjects are grouped within the FAS by the treatment group to which they were enrolled.
This is the primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug (i.e. SOF and 
RBV). Subjects will be grouped according to the treatment they actually received. 
This is the primary analysis set for safety analyses.
3.1.4.
Pharmacokinetic Analysis Set
PK Lead-in Phase Intensive PK Analysis Set
The PK Lead-in Phase Intensive PK Analysis Set includes all PK Lead-in Phase subjects who 
received at least one dose of study drug and for whom at least one non-missing PK concentration 
data is available from the PK Lead-in Phase intensive sampling. This is the primary analysis set 
for PK Lead-in Phase intensive PK analysis.


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Population PK Analysis Set
The Population PK Analysis Set includes all enrolled subjects who received at least one dose of 
study drug and for whom at least one non-missing PK concentration data is available from the 
PK sampling. This is the primary analysis set for the Population PK modeling and PK exposure 
analyses.
The PK Analysis Set is equivalent to Population PK Analysis Set.
3.2.
Subject Grouping
For analyses based on the All Enrolled Analysis Set or FAS, subjects will be grouped according 
to the treatment to which they were enrolled. For analyses based on the Safety Analysis Set, 
subjects will be grouped according to the actual treatment received. The actual treatment 
received is defined as the enrolled treatment except for subjects who received treatment that 
differs from the enrolled treatment for the entire treatment duration. In this case, the actual 
treatment received is defined as the treatment received for the entire treatment duration.
Specifically, efficacy and safety analyses will be performed according to age group and HCV 
genotype in the following treatment groups:
Table 3-1.
Treatment Groups
12 to < 18 Years Old
SOF(400mg)+RBV
3 to < 12 Years Old
SOF(200mg or 150mg)+RBV
GT-2 12 Weeks
(N = )
GT-3 24 Weeks
(N = )
GT-2 12 Weeks
(N = )
GT-3 24 Weeks
(N = )
6 to < 12 Years Old
SOF(200mg)+RBV
3 to < 6 Years Old
SOF(200mg or 150mg)+RBV
GT-2 12 Weeks
(N = )
GT-3 24 Weeks
(N = )
GT-2 12 Weeks
(N = )
GT-3 24 Weeks
(N = )
GT = genotype
Subjects in the 3 to < 6 years of age group will have additional selected efficacy and safety
analyses performed according to baseline weight and HCV genotype in the following subgroups:
Table 3-2.
Subgroups for Selected Analyses in 3 to < 6 years of Age
3 to < 6 Years Old
GT-2 12 Weeks
GT-3 24 Weeks
< 17 kg
SOF(150mg)+RBV
(N = )
>= 17 kg
SOF(200mg)+RBV
(N = )
< 17 kg
SOF(150mg)+RBV
(N = )
>= 17 kg
SOF(200mg)+RBV
(N = )
GT = genotype


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3.3.
Strata and Covariates
This study does not use a stratified randomization schedule for enrolling subjects. No covariates 
will be included in efficacy and safety analyses.
3.4.
Examination of Subject Subsets
The efficacy endpoint SVR12 will be analyzed for the following subsets:

sex (male, female)

race (black, non-black)

ethnicity (hispanic or latino, non-hispanic or latino)

baseline HCV RNA (< 800,000 IU/mL, ≥ 800,000 IU/mL)

baseline weight (≤ median, > median)

baseline ALT (≤1.5 × ULN, > 1.5 × ULN)

IL28B (CC, non-CC [further broken down to CT, TT])

prior HCV treatment experience (treatment naive, treatment experienced)

Interferon (IFN) eligibility (IFN-eligible, IFN-ineligible)

most recent response to prior HCV treatment (non-response, relapse/breakthrough, 
IFN-intolerant) for treatment experienced subjects

study treatment status (completed study treatment, discontinued study treatment)

adherence to study regimen (< 80%, ≥ 80%).
3.5.
Missing Data and Outliers
3.5.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. 
For missing last dosing date of study drug, imputation rules are described in Section 3.7.1. The 
handling of missing or incomplete dates for adverse event (AE) onset is described in 
Section 7.1.5.2, and for prior and concomitant medications in Section 7.9.


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For analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have the 
missing data imputed. Missing on-treatment HCV RNA will have the missing data imputed up to 
the time of the last dose (for on-treatment displays). If the study day associated with the last 
dosing date is greater than or equal to the lower bound of a visit window, and the value at the 
visit is missing, the value will be imputed. If the study day associated with the last dosing date is 
less than the lower bound of a visit window then the on-treatment value at that visit will remain 
missing. 
If a data point is missing and is preceded and followed in time by values that are “< LLOQ target 
not detected (TND)”, then the missing data point will be set to “< LLOQ TND”. If a data point is 
missing and preceded and followed by values that are “< LLOQ detected”, or preceded by 
“< LLOQ detected” and followed by “< LLOQ TND”, or preceded by “< LLOQ TND” and 
followed by “< LLOQ detected”, then the missing value will be set to “< LLOQ detected”. In 
these situations the data point will be termed a bracketed success; otherwise, the data point will 
be termed a bracketed failure (i.e. ≥LLOQ detected). If a data point is missing and is not 
bracketed, the missing data point will also be termed a failure (i.e. ≥LLOQ detected) except for 
SVR24, which will be imputed according to SVR12 status. Success for SVR12 who have no 
further HCV RNA measurements collected will be counted as a success for SVR24 due to the 
high correlation between these 2 endpoints.
For the analyses of continuous HCV RNA efficacy data, when and only when a missing HCV 
RNA value is imputed as < LLOQ TND or < LLOQ detected according to the imputation rule 
described above, the corresponding continuous value will be imputed to LLOQ - 1 IU/mL. No 
other imputation will be performed for continuous HCV RNA data.
In the analysis of the PedsQL ™Pediatric Quality of Life Inventory V4.0 Short Form (SF15) 
questionnaire, missing data at on-treatment visits and posttreatment follow-up Week 12 (FU-12) 
visit will not be imputed. Last posttreatment observation carried forward will be used for 
imputation of missing data at posttreatment follow-up Week 24 visit.
3.5.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.6.
Data Handling Conventions and Transformations
By-subject listings will be presented for all subjects in the Safety Analysis Set and sorted by 
subject ID number, visit date, and time (if applicable) unless otherwise specified. Data collected 
on log forms, such as AEs, will be presented in chronological order within subject. 
Age (in years) on the date of the first dose of study drug and sex at birth will be used for analyses 
and presentation in listings.


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If a subject was not dosed with study drug at all, then the date the informed consent was signed 
will be used instead of the first dose date of study drug. For some countries, only birth year is 
collected on the eCRF. In those cases, “01 January” will be used for the unknown birth day and 
month for the purpose of age calculation, unless age is captured on the eCRF. 
Non-PK data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed as follows:

A value that is one unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “x” (where x is considered the 
limit of quantitation). For example, if the values are reported as < 50 and < 5.0, values of 
49 and 4.9, respectively, will be used for calculation of summary statistics. An exception for 
this rule is any value reported < 1. For the values reported as < 1 or < 0.1, value of 0.9 or 
0.09 will be used for calculation of summary statistics.

A value that is one unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “> x” (where x is considered the 
limit of quantitation). Values with decimal points will follow the same logic as above.

The limit of quantitation will be used for calculation of descriptive statistics if the datum is 
reported in the form of “≤ x” or “≥ x” (where x is considered the limit of quantitation).
The COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 for use with the High Pure 
System was used to determine HCV RNA results in this study. The lower limit of quantitation 
(LLOQ) of the assay is 15 IU/mL.
When the calculated HCV RNA value is within the linear range of the assay, then the result will 
be reported as the “<< numeric value>> IU/mL”. This result will be referred to in this document 
as the numeric result or as “≥ LLOQ detected” for categorical result.
When HCV RNA is not detected, the result is reported as “No HCV RNA detected” or “target 
not detected”. This result will be referred to in this document as “< LLOQ target not detected” or 
“< LLOQ TND”.
When the HCV RNA IU/mL is less than LLOQ of the assay, the result is reported as 
“< 15 IU/mL HCV RNA detected”. This result will be referred to in this document as “< LLOQ 
detected”.
The overall category of HCV RNA < LLOQ includes “< LLOQ TND” and “< LLOQ detected.”
For numerical HCV RNA data, values below LLOQ will be set to the LLOQ – 1 IU/mL 
(i.e. 14 HCV RNA IU/mL). HCV RNA values returned as “No HCV RNA detected” will also be 
set to 14 IU/mL.
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data (eg, log10 scale) or nonparametric analysis 
methods may be used, as appropriate.


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Natural logarithm transformation will be used for plasma/blood concentrations and analysis of 
PK parameters. Plasma concentration values that are below the lower limit of quantitation (BLQ) 
will be presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated 
as 0 for determination of summary and order statistics 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 of BLQ for the time point, then the minimum value will be displayed as “BLQ.” If more 
than 25% of the subjects have a concentration data value of BLQ for a given time point, then the 
minimum and Q1 values will be displayed as “BLQ.” If more than 50% of the subjects have a 
concentration data value of BLQ for a given time point, then the minimum, Q1, and median 
values will be displayed as “BLQ.” If more than 75% of the subjects have a concentration data 
value of BLQ for a given time point, then the minimum, Q1, median, and Q3 values will be 
displayed as “BLQ.” If all subjects have concentration data values of BLQ for a given time point, 
then all order statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”.
3.7.
Visit Windows
3.7.1.
Definition of Study Day
Study day is the day relative to the date of the first dose of study drug. Study Day 1 will be 
defined as the day of first dose of study drug administration.
Study day will be calculated from the date of first dose of study drug administration and derived 
as follows:

For postdose study days: Assessment Date – First Dose Date + 1

For days prior to the first dose: Assessment Date – First Dose Date
The last dose date for an individual study drug will be the end date on study drug administration 
eCRF for the record where the “subject permanently discontinued” flag is ‘Yes’. The last dose 
date will be defined as the maximum of the last dose dates of individual study drugs in a 
treatment group.
If there are subjects for whom the date of last study drug is unknown due to the reason that the 
subject was lost to follow-up and not able to be contacted, the date of last dose will be estimated 
using the maximum of nonmissing study drug start or stop dates, visit dates and laboratory 
collection dates (posttreatment visits and unscheduled visits are not included).


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3.7.2.
Analysis Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.
In general, the baseline value will be the last nonmissing value on or prior to the first dose date 
of study drug. 
HCV RNA, vital signs, and safety laboratory data collected up to the last dose date + 2 days are 
considered to be on-treatment data and HCV RNA, vital signs and safety laboratory data 
collected after the last dose date + 2 days are considered posttreatment data. The analysis 
windows for on-treatment HCV RNA, vital signs and safety laboratory data are provided in 
Table 3-3.
Table 3-3.
Analysis Windows for On-treatment HCV RNA, Vital Signs and 
Safety Laboratory Data
Nominal Visit
SOF + RBV 12 Weeks 
SOF + RBV 24 Weeks
Nominal Day
Lower Limit
Upper Limit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
1
(none)
1
Week 1
7
2
11
7
2
11
Week 2
14
12
21
14
12
21
Week 4
28
22
42
28
22
42
Week 8
56
43
70
56
43
70
Week 12
84
71
≥ 85
84
71
98
Week 16
NA
112
99
126
Week 20
140
127
154
Week 24
168
155
≥ 169
Subjects who participated in the PK Lead-in Phase will immediately roll over into 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 Phase. These subjects will start at the 
Week 2 visit of the Treatment Phase. Week 1 records for these subjects will be chosen from 
Day 7 in the PK Lead-in Phase.
HCV RNA, vital sign, and safety laboratory data collected after the last dose date + 2 days will 
be assigned to the posttreatment follow-up (FU) visits. Visit windows will be calculated from the 
last dose date (i.e. FU Day = collection date minus the last dose date) as shown in Table 3-4.


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Table 3-4.
Analysis Windows for Posttreatment HCV RNA, Body Weight, 
Height, Vital Sign and Safety Laboratory Data
Nominal 
FUa Visit
HCV RNA, Body weight and Height
Vital Signs and Safety Laboratory Datab
Nominal FU Day
Lower Limit
Upper Limit
Nominal FU Day
Lower Limit
Upper Limit
FU-4
28
21
69
28
3
30
FU-12
84
70
146
NA
NA
NA
FU-24
168
147
210
NA
NA
NA
a
FU-x visit = posttreatment Week-x follow-up visit.
b
Vital signs (blood pressure, pulse, respiratory rate, and temperature) and safety labs will only be summarized for the FU-4
visit (up to 30 days after last dose).
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window. 
If multiple valid nonmissing numeric observations exist in an analysis window, records will be 
chosen based on the following rules if a single value is needed:

For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, average (arithmetic mean) will be used for the baseline value. 

For postbaseline visits: 
The record closest to the nominal day for that visit will be selected except for HCV RNA 
posttreatment follow-up visits, for which the latest record in the analysis window will be 
selected. 
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken, unless 
otherwise specified.
If multiple valid nonmissing categorical observations exist in a window, records will be selected
as follows:

For baseline, the last available record on or prior to the date of the first dose of study drug
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, the value with the lowest severity will be selected (eg, normal will be selected over 
abnormal).

For postbaseline visits, follow the same rules described above for postbaseline numeric 
observations, except that if there are multiple records on the same day, the most conservative 
value will be selected (eg, abnormal will be selected over normal).


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by treatment group for each country, 
investigator within a country, and overall. The summary will present the number and percentage 
of subjects in the Safety Analysis Set. For each column, the denominator for the percentage 
calculation will be the total number of subjects analyzed for that column. 
A summary of subject disposition will be provided by treatment group. This summary will 
present the number of subjects screened, the number of subjects enrolled, the number of subjects 
enrolled but never treated, and the number and percentage of subjects in each of the categories 
listed below. For the “Treated” category, the denominator for the percentage calculation will be 
the total number of subjects enrolled for each column. For all other categories, the denominator 
for the percentage calculation will be the total number of subjects in the Safety Analysis Set for 
each column. 

Treated (Safety Analysis Set) 

In FAS

In PK Analysis Set

Completed study treatment

Did not complete study treatment with reasons for premature discontinuation of study 
treatment

Completed the study

Did not complete the study with reason for premature discontinuation of study
Among subjects who completed study treatment and who discontinued study treatment, the 
number and percentage of subjects will be summarized for:

Who had no HCV posttreatment Week 4 assessment and thereafter (No HCV FU-4 and 
thereafter)

Who had HCV posttreatment Week 4 assessment but no HCV posttreatment Week 12 
assessment and thereafter (With HCV FU-4 but No FU-12 and thereafter)


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If a subject did not have any HCV RNA assessment ≥ 21 days after the last dose of any study 
drug (i.e. lower bound of FU-4 visit for HCV RNA data), the subject is categorized as having 
“No HCV FU-4 and thereafter”. If a subject had the HCV FU-4 assessment but did not have any 
HCV RNA assessment ≥ 70 days after the last dose of any study drug (i.e. lower bound of FU-12 
visit for HCV RNA data), the subject is categorized as having “With HCV FU-4 but No FU-12 
and thereafter”.
In addition, the total number of subjects who were enrolled, and the number of subjects in each 
of the disposition categories listed above will be displayed in a flowchart.
The following by-subject listings will be provided by subject ID number in ascending order to 
support the above summary tables:

Disposition for subjects who complete study treatment and study

Disposition for subjects who did not complete study treatment and/or study with reasons for 
premature discontinuation of study drug and/or study

Lot number and kit ID (if applicable)
4.2.
Extent of Exposure 
Extent of exposure to study regimen and individual study drug will be examined by assessing the 
total durations of study regimen and individual study drug exposure and the level of adherence to 
any study drug and individual study drug specified in the protocol. 
4.2.1.
Durations of Exposure to Study Regimen and Individual Study Drug
Total duration of exposure to study regimen will be defined as last dose date of any study drug 
minus first dose date of any study drug plus 1, regardless of any temporary interruptions in study 
drug administration, and will be expressed in weeks using up to 1 decimal place (e.g. 4.5 weeks).
Total duration of exposure to individual study drug will be defined as last dose date of individual 
study drug minus first dose date of individual study drug plus 1, regardless of any temporary 
interruptions in study drug administration.
The total durations of exposure to study regimen and individual study drug will be summarized 
using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) and using 
the number (i.e. cumulative counts) and percentage of subjects exposed through the following 
time periods: Baseline (Day 1), Week 1 (Day 7), Week 2 (Day 14), Week 4 (Day 28), Week 8 
(Day 56), and Week 12 (Day 84) for all subjects and additionally Week 16 (Day 112), Week 20 
(Day 140), and Week 24 (Day 168) for subjects receiving 24 weeks of treatment. Summaries will 
be provided by treatment group for the Safety Analysis Set. 


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4.2.2.
Adherence to Study Drug
The level of adherence to individual study drug will be assessed separately based on the total 
amount of individual study drug administered relative to the total amount of individual study 
drug prescribed. In this study, SOF 400 mg tablets, SOF 100 mg tablets, and SOF 50 mg 
capsules containing granules have been used. For RBV, both REBETOL capsules and 
REBETOL RBV oral solution have been used. Each capsule contains 200 mg RBV and the oral 
solution contains 40 mg RBV per mL.
Given the fact that multiple formulations of the study drug have been used in this study, the 
adherence will be calculated based on the amount of SOF (mg) or RBV (mg) by the following 
formula:
100
  
baseline
at 
Prescribed
Drug
Study 
of
Amount 
Total
  
ed
Administer
Drug
Study 
of
Amount 
Total
(%)
Adherence
of
Level








Where the presumed total amount of study drug (mg) administered to a subject will be 
determined by the data collected on the drug accountability eCRF using the following formula:







Returned
(mg)
Drug
Study 
  
of
Amount 
Total
Dispensed
(mg)
Drug
Study 
  
of
Amount 
Total
ed
Administer
(mg)
Drug
Study 
of
Amount 
Total
Note: If calculated adherence is greater than 100%, the result will be set to 100%.
The total amount of prescribed SOF (mg) for 12 weeks and 24 weeks are as follows:
Age Group and 
Body Weight 
SOF Daily Dose
Total Amount of SOF
Prescribed for 12 Weeks
Total Amount of SOF
Prescribed for 24 Weeks
12 to <18 years
any weight
400 mg/day
33600 mg
67200 mg
6 to <12 years
any weight
200 mg/day
16800 mg
33600 mg
3 to <6 years 
weighing ≥17 kg
200 mg/day
16800 mg
33600 mg
3 to < 6 years 
weighing <17 kg
150 mg/day
12600 mg
25200 mg


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RBV was prescribed by weight at baseline for all subjects. The total amount of RBV (mg)
prescribed for 12 weeks and 24 weeks is as follows:
Body Weight 
kg (lbs.)
RBV Daily 
Dose
RBV Number of Capsules
Total Amount of 
RBV Prescribed 
for 12 Weeks
Total Amount of 
RBV Prescribed 
for 24 Weeks
<47 
(<103)
15 mg/kg/day
Use Oral Solution. Divided dose in 
the morning and evening.
1,260 mg/kg
2,520 mg/kg
47-49
(103-108)
600 mg/day
1 200-mg capsules A.M.
2 200-mg capsules P.M.
252 capsules
(50400 mg) 
504 capsules
(100800 mg) 
50-65
(110 – 143)
800 mg/day
2 200-mg capsules A.M.
2 200-mg capsules P.M.
336 capsules
(67200 mg)
672 capsules
(134400 mg)
66-80
(145 – 176)
1000 mg/day
2 200-mg capsules A.M.
3 200-mg capsules P.M.
420 capsules
(84000 mg)
840 capsules
(168000 mg)
81-105 
(178-231)
1200 mg/day
3 200-mg capsules A.M.
3 200-mg capsules P.M.
504 capsules
(100800 mg)
1,008 capsules
(201600 mg)
>105
(>231)
1400 mg/day
3 200-mg capsules A.M.
4 200-mg capsules P.M.
588 capsules
(117600 mg)
1,176 capsules
(235200 mg)
Note: Subjects with a body weight greater than or equal to 47 kg may utilize the RBV oral solution if necessary.
Weight reported as a decimal number was rounded to the whole number to determine the 
prescribed RBV dosage. For example, a subject weighing 49.5 kg fell into the 50-65 kg category 
and received 800 mg/day.
Subjects who prematurely discontinue study drug for lack of efficacy (i.e. virologic failure) will 
have the total amount of study drug prescribed calculated up to the first date when virologic 
failure criteria were met. For virologic failure confirmed by 2 consecutive measurements the date 
of the first measurement will be used. If there are study drug bottles dispensed on or after the 
subject first met virologic failure criteria, these bottles will not be included in the calculation of 
adherence. If a bottle is dispensed and the bottle is returned empty, then the number of tablets 
returned will be entered as zero. If a bottle is dispensed but not returned (missing), the number of 
tablets taken from that bottle will be counted as zero.
Descriptive statistics for the level of adherence (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) with the number and percentage of subjects belonging to adherence categories 
(e.g. < 80%, ≥ 80 to < 90%, ≥ 90%) will be provided by treatment group for the Safety Analysis 
Set. No inferential statistics will be provided for duration of exposure and adherence to study 
drug. Categorical displays will be provided for the number of subjects who are at least 80% 
adherent to individual study drug and study regimen (i.e. adherence is ≥ 80% for each of the 
study drugs). No inferential statistics will be provided. 
A separate by-subject listing of study drug administration and drug accountability will be 
provided by subject ID number (in ascending order) and visit (in chronological order).


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4.3.
Protocol Deviations
A summary of important protocol deviations will be provided by the Clinical Operations group 
for subjects in the Safety Analysis Set.
Subjects who received study drug other than their enrolled treatment assignment will be listed 
with the start and stop dates that they received incorrect study treatment.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic variables (i.e. age, sex, race, and ethnicity) will be summarized by 
treatment group and total in each age group using descriptive statistics (n, mean, SD, median, 
Q1, Q3, minimum, and maximum) for age, and using the numbers and percentages of subjects 
for sex, race, and ethnicity. Age is calculated in years at the date of initial study drug 
administration. If a subject did not receive study drug after enrollment, the subject’s age will be 
calculated from the date that the subject signed the informed consent form. The summary of 
demographic data will be provided for the Safety Analysis Set.
A by-subject demographic listing will be provided by subject ID number in ascending order.
In addition, demographic variables (i.e. age, sex, race, and ethnicity) will be summarized by 
treatment group defined in Table 3-2 and total for 3 to < 6 years of age subjects.
5.2.
Other Baseline Characteristics
Other baseline characteristics include:

weight in kg

height in cm

body mass index (BMI; in kg/m2)

HCV genotype (2, 3 with both genotypes further broken down to observed subtypes)

cirrhosis (presence, absence, unknown)

IL28B (CC, CT, TT) 

baseline HCV RNA (log10 IU/mL) as a continuous variable and as categories 
(< 800,000 IU/mL, ≥ 800,000 IU/mL)

baseline ALT (U/L) as a continuous variable and as categories (≤1.5 × ULN, > 1.5 × ULN)

estimated glomerular filtration rate (eGFR) using Schwartz Formula (mL/min/1.73m2)

prior treatment experience (treatment naïve, treatment experienced)

IFN eligibility (IFN-eligible, IFN-ineligible)

most recent response to prior HCV treatment (non-response, relapse/breakthrough, 
IFN-intolerant) for treatment experienced subjects


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
mode of HCV Infection

bone age in years

Tanner Stage 
Estimated Glomerular Filtration Rate (GFR) will be calculated using Schwartz Formula 
(mL/min/1.73m2) = k L/Scr [(k is a proportionality constant, for adolescent females ≥12 years
old is 0.55; for adolescent males ≥ 12 years old is 0.70, and for children 3- <12 years old is 0.55); 
L is height in centimeters (cm); and Scr is serum creatinine (mg/dL)]
These baseline characteristics will be summarized by treatment group and total in each age group
using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for 
continuous variables and using the numbers and percentages of subjects for categorical variables. 
The summary of baseline characteristics will be provided for the Safety Analysis Set.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
In addition, baseline characteristics will be summarized by treatment group defined in Table 3-2
and total for 3 to < 6 years of age subjects.
5.3.
Swallowability Assessment
Swallowability of SOF tablets will be summarized using the numbers and percentages of 
subjects in each of the swallowability categories (as applicable) by total in 12 to < 18 years of 
age group and 6 to < 12 years of age group respectively. 
A by-subject listing of Swallowability of SOF tablets will be provided by subject ID number in 
ascending order.
5.4.
Palatability of SOF Oral Granules
Palatability of SOF oral granules will be summarized using the numbers and percentages of 
subjects who took SOF oral granules in each of palatability categories by total in each age group
(as applicable).
A by-subject listing of Palatability of SOF oral granules will be provided by subject ID number 
in ascending order.
5.5.
Medical History
General medical history (ie, conditions not specific to the disease being studied) data will be 
collected at screening and listed only. General medical history data will not be coded. A 
by-subject listing of disease-specific medical history will be provided by subject ID number 
(in ascending order) and medical history of abnormalities (in chronological order).


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6.
EFFICACY ANALYSES
6.1.
Key Efficacy Endpoint
6.1.1.
Definition of the Key Efficacy Endpoint
The key efficacy endpoint is SVR12 defined as HCV RNA < LLOQ (i.e. < 15 IU/mL) 12 weeks 
after discontinuation of all study drugs in the FAS. The COBAS® AmpliPrep/COBAS®
TaqMan® HCV Test, v2.0 for use with the High Pure System will be used to measure HCV 
RNA.
6.1.2.
Statistical Hypothesis for the Key Efficacy Endpoint
The null (H0) and alternative (H1) hypotheses used to assess the superiority of SOF + RBV 
relative to the historical SVR12 rate of 80% are as follows:
H0: SVR12 rate = 80% 
H1: SVR12 rate ≠ 80%
6.1.3.
Analysis Methods for the Key Efficacy Endpoint
A sequential test method was used to firstly perform the above statistical test in the adolescent
subjects (ie, 12 to < 18 years of age). The SVR12 rate for adolescents was compared with the 
historical SVR12 rate of 80% using a 2-sided exact 1-sample binomial test at the 0.05 
significance level. The test in adolescents was described in a separate SAP for Adolescents 
SVR12 Analysis. Only if the superiority is demonstrated in adolescents, the SVR12 rate in the 
remaining subjects (ie, children aged 3 to < 12 years) will be compared with 80% at the 0.05 
significance level.
The point estimates of SVR12 rate and 2-sided 95% exact CI based on Clopper-Pearson method 
will be provided for the SVR12 rate by treatment group and total in each age group
{Clopper 1934}.
6.1.4.
Subgroup Analysis of the Key Efficacy Endpoint
The point estimates of SVR12 rate and 2-sided 95% exact CIs based on Clopper-Pearson method 
will be provided for each treatment group within each subgroup specified in Section 3.4
{Clopper 1934}. 
A Forest plot will graphically present estimates and 95% confidence intervals of SVR12 rates for 
each treatment group within each subgroup.


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6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints include the following:

The percentage of subjects who attain SVR at 4 and 24 weeks after stopping therapy, defined 
as HCV RNA < LLOQ (i.e. < 15 IU/mL) 4 and 24 weeks after stopping treatment (SVR 4 
and SVR 24)

The percentage of subjects with HCV RNA below LLOQ by study visit

HCV RNA (log10 IU/mL) and change from baseline in HCV RNA (log10 IU/mL) through end 
of treatment (EOT)

The percentage of subjects with virologic failure as the following:
On-treatment virologic failure
HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ, while on 
treatment, confirmed with 2 consecutive values (note, second confirmation value can be 
posttreatment), or last available on-treatment measurement with no subsequent follow-up
values (i.e. breakthrough)
> 1 log10IU/mL increase in HCV RNA from nadir while on treatment, confirmed with 
2 consecutive values (note, second confirmation value can be posttreatment), or last 
available on-treatment measurement with no subsequent follow-up values (i.e. rebound)
HCV RNA persistently ≥ LLOQ through 8 weeks of treatment (i.e. nonresponse)
Relapse 
HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA 
< LLOQ at end of treatment, confirmed with 2 consecutive values or last available 
posttreatment measurement

The proportion of subjects with ALT normalization (defined as ALT > ULN at baseline and 
ALT ≤ ULN at each visit), presented by study visit.

Characterization of HCV drug resistance substitutions at baseline, during, and after therapy 
with SOF


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6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
For analyses of HCV RNA < LLOQ by visit while on treatment and during the posttreatment 
(SVR) follow-up period, subjects will be assigned a value at each visit based on the analysis visit 
windows specified in Section 3.7.2. Missing values will be imputed based on the categorical 
imputation rules described in Section 3.5.1. The 2-sided 95% exact confidence interval based on 
Clopper-Pearson method will be provided for the percentage of subjects with HCV RNA 
< LLOQ at each visit in each treatment group. The overall category for “HCV RNA < LLOQ” 
will be split into the following 2 subcategories: “< LLOQ TND” for subjects with target not 
detected and “< LLOQ detected” for subjects with < LLOQ detected in tabular displays. 
Graphs for the percentage of subjects with HCV RNA < LLOQ over time during treatment will 
be displayed.
Summary statistics will be presented for absolute values and change from baseline in HCV RNA 
(log10 IU/mL) by visit through EOT. Imputation rules described in Section 3.5.1 will be used to 
assign HCV RNA values for missing values at a visit that are bracketed by “< LLOQ TND” 
and/or “< LLOQ detected”. Otherwise, a missing = excluded analysis will be performed. Plots of 
the mean ± SD and median (Q1, Q3) of absolute values and changes from baseline in HCV RNA 
through EOT will be presented.
For the SVR12 endpoint analysis, a summary table of the number and percentage of subjects 
with SVR12, virologic failure (VF), and Other will be created. All subjects who achieve SVR12 
will be categorized as SVR12. Virologic failure will be descriptively summarized as 
“on-treatment virologic failure” and relapse (which will be broken down by study drug 
completed yes/no). Subjects who do not achieve SVR12 and do not meet criteria for VF will be 
categorized as Other. The denominator for relapse will be the number of subjects who had 
HCV RNA < LLOQ on their last observed on-treatment HCV RNA measurement; otherwise, the 
denominator will be the number of subjects in the FAS. Additional summary table will be 
provided by treatment group defined in Table 3-2 for 3 to < 6 years of age subjects.
A concordance table between SVR12 and SVR24 will be provided by treatment group and total 
in each age group. Subjects with both observed SVR12 and observed SVR24 data will be 
included for this analysis.
In addition, a summary table of the number and percentage of subjects with HCV RNA < LLOQ 
and >= LLOQ at the posttreatment follow-up visit (observed and imputed, with reasons for 
imputed) will be provided for each posttreatment follow-up visit. 95% Clopper-Pearson exact 
CIs will be presented for the overall proportion of subjects with HCV RNA < LLOQ.
Tables for ALT normalization by visit will use similar methodology to the analyses of HCV 
RNA < LLOQ, but will use a missing = excluded analysis. Only those subjects with ALT greater 
than the ULN range at baseline (defined as the last ALT value collected prior to first dose of 
study drug) will be included in the analysis of ALT normalization.
Drug resistant substitutions will be analyzed as part of the Virology Study Report.


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6.3.
Exploratory Efficacy Endpoints
6.3.1.
Definition of Exploratory Efficacy Endpoints
 
 
 
 
 
 
6.4.
Changes From Protocol-Specified Efficacy Analyses
Instead of comparing the SVR12 rate in all treated subjects (3 to < 18 years of age) against the 
historical SVR12 rate of 80% by using the 2-sided exact 1-sample binomial test at the 
0.05 significance level as specified in the protocol, a sequential test method was used to firstly 
perform the above statistical test in the adolescent subjects (12 to < 18 years of age). Only if the 
superiority is demonstrated in adolescents, the SVR12 rate in the remaining subjects 
(3 to < 12 years of age) will be compared with 80% at the 0.05 significance level. The test in 
adolescents was described in a separate SAP for Adolescents SVR12 Analysis. Details of the test 
in this Final Analysis are described in Section 6.1.3. 
PPD


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using 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 provided in the 
AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity criteria 
specified in the protocol. The severity grade of events for which the investigator did not record 
severity will be categorized as “missing” for tabular summaries and data listings and the most 
severe will be considered (for sorting purpose only) in data presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE eCRF to the 
question of “Related to Study Treatment”. Events for which the investigator did not record 
relationships to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing from that captured on the 
CRF.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAE specified in the study protocol. Serious adverse events captured and stored in the clinical 
database will be reconciled with the SAE database from the Gilead Pharmacovigilance and 
Epidemiology Department before database finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment Emergent
Treatment-emergent adverse events (TEAEs) are defined as one or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug.

Any AEs leading to premature discontinuation of study drug.


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7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete, then the month and year (or year alone if month is not 
recorded) of onset determine whether an AE is treatment emergent, as long as the AE stop date is 
not prior to the first dose date of study drug. The event is considered treatment emergent if both
of the following 2 criteria are met:

The AE onset and end dates are the same as or after the month and year (or year) of the first 
dose date of study drug

The AE onset date is the same as or before the month and year (or year) of the 30th day after
the date of the last dose of study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dose date of study drug, will be considered to be treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
A brief high-level summary of TEAEs will be provided by treatment group and by the number 
and percentage of subjects who had the following: any AE; any AE of Grade 3 or above; any AE 
of Grade 2 or above; any treatment-related AE; any treatment-related AE of Grade 3 or above; 
any treatment-related AE of Grade 2 or above; any SAE; any treatment-related SAE; any AE that 
led to premature discontinuation of any study drug; any AE that led to premature discontinuation 
of SOF; any AE that led to premature discontinuation of RBV; any AE that led to modification 
or interruption of any study drug; any AE that led to interruption of SOF; any AE that led to 
modification or interruption of RBV. All deaths (including those that are treatment emergent and 
those that are not treatment emergent) observed during the study will also be summarized and 
included in this table. Additional brief high-level summary of TEAEs will be provided by 
treatment group defined in Table 3-2 for 3 to < 6 years of age subjects.
Adverse event summaries will provide the number and percentage of subjects with TEAEs by 
SOC and PT, by treatment group based on the Safety Analysis Set as follows:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

All SAEs

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
All AEs leading to premature discontinuation of study drug

AEs leading to premature discontinuation of SOF

AEs leading to premature discontinuation of RBV

AEs leading to modification or interruption of any study drug

AEs leading to interruption of SOF

AEs leading to modification or interruption of RBV
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC and then by PT in order of descending
incidence of the pooled treatment groups within each SOC. In summaries by severity grade, the 
most severe grade will be used for those AEs that occurred more than once in an individual 
subject during the study. 
In addition to the above summary tables, TEAEs will be summarized by PT only, in order of 
descending incidence within the pooled treatment groups for:

AEs that occurred in at least 5% of subjects within any treatment group

AEs of Grade 3 or above

All treatment-related AEs

All SAEs

AEs leading to premature discontinuation of study drug

AEs leading to premature discontinuation of SOF

AEs leading to premature discontinuation of RBV

AEs leading to modification or interruption of any study drug

AEs leading to interruption of SOF

AEs leading to modification or interruption of RBV
In addition to the by-treatment summaries described above, data listings will be provided for the 
following:

All AEs (with a variable indicating whether the event is treatment emergent)

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
SAEs

Deaths

AEs leading to premature discontinuation of study drug

AEs leading to modification or interruption of any study drug
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days
for subjects who have permanently discontinued study drug or all available data at the time of the 
database snapshot for subjects those who were ongoing at the time of an interim analysis. The 
analysis will be based on values reported in conventional units. When values are below the limit 
of quantitation, they will be listed as such, and the closest imputed value will be used for the 
purpose of calculating summary statistics. For example, if “< 0.2” was recorded, a value of 0.1 
will be used for the purpose of calculating summary statistics; if “< 0.1” was recorded, a value of 
0.09 will be used for the purpose of calculating summary statistics.
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and urinalysis separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on the 
Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
flagged in the data listings, as appropriate.
No inferential statistics will be generated.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided 
by treatment group for ALT, AST, total bilirubin, alkaline phosphatase, hemoglobin, 
reticulocytes, white blood cell (WBC), neutrophils, lymphocytes, platelets, and INR as follows:

Baseline values

Values at each postbaseline analysis window

Change from baseline at each postbaseline analysis window
A baseline laboratory value will be defined as the final assessment performed on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
will be displayed to the reported number of digits; SD to the reported number of digits plus 1.
Median (Q1, Q3) of the observed values for these laboratory parameters will be plotted using a 
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In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3 (Selection of Data in the Event of Multiple Records in a Window). 
7.2.2.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
used for assigning toxicity grades to laboratory results for analysis as Grade 0, Grade 1, Grade 2, 
Grade 3, or Grade 4. Grade 0 includes all values that do not meet the criteria for an abnormality 
of at least Grade 1. Some laboratory tests have criteria for both increased and decreased levels; 
analyses for each direction (i.e. increased, decreased) will be presented separately. 
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days for subjects who permanently discontinued study drug, or all 
available data in the database snapshot for subjects who were still on treatment at the time of an 
interim analysis. If the relevant baseline laboratory value is missing, then any abnormality of at 
least Grade 1 will be considered treatment emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by analyte and treatment group; subjects will be categorized 
according to the most severe postbaseline abnormality grade for a given analyte:

Graded laboratory abnormalities

Grade 3 or above laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after last dose for the laboratory parameter of 
interest.
A by-subject listing of treatment-emergent Grade 3 or above laboratory abnormalities will be 
provided by subject ID number and visit in chronological order. This listing will include all test 
results that were collected throughout the study for the analyte of interest, with all applicable 
severity grades or abnormal flags displayed.
7.2.2.3.
On-Treatment Liver-Related Laboratory Events
The following liver-related laboratory events will be summarized using data from all the 
on-treatment postbaseline visits (up to 2 days after the last dose of any study drug):

Aspartate aminotransferase (AST) or ALT > 3 × ULN and total bilirubin > 2 × ULN


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
ALT > 5 × ULN

Total bilirubin > 2 × ULN
For the composite criterion of AST or ALT and total bilirubin, AST or ALT and total bilirubin 
must meet the specified cut-offs at a given postbaseline time point; subjects will be counted once 
when the criterion is met. The denominator will be the number of subjects in the Safety Analysis 
Set with at least 1 postbaseline value of AST or ALT and total bilirubin at the same time point. 
For individual laboratory tests, subjects will be counted once based on the most severe 
postbaseline values when the criterion is met. The denominator will be the number of subjects in 
the Safety Analysis Set with at least 1 nonmissing postbaseline value for the test. A listing will 
be provided including ALT, AST, total bilirubin, direct bilirubin, alkaline phosphatase, HCV 
RNA (log10) and yes/no flag for subjects meeting at least 1 of the 3 criteria. All the available data 
for the subjects will be listed.
7.3.
Vital Signs
Vital signs (systolic and diastolic blood pressure [mmHg], pulse [beats/min]) at each visit, and 
change from baseline at each visit will be summarized for the Safety Analysis Set using 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) by treatment 
group. The baseline value will be defined as the last available value collected on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the postbaseline value minus the baseline value.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3 (Selection of Data in the Event of Multiple Records in a Window). No 
inferential statistics will be generated.
A by-subject listing of vital signs (systolic and diastolic blood pressure [mmHg], pulse 
[beats/min], respiration [breaths/min], and body temperature [°C]) will be provided by subject ID 
number and visit in chronological order. 
7.4.
Body Weight, Height and BMI
An age- and sex-specific percentile will be derived for each weight, height and BMI measurement 
according to the downloadable SAS program available on the Centers for Disease Control (CDC) 
website using the year 2000 growth charts. Methods and SAS program published on the following 
CDC website will be applied to calculate the percentile {Centers for Disease Control and 
Prevention (CDC) 2016a, Centers for Disease Control and Prevention (CDC) 2016b}.
Body weight, height, BMI and percentiles for body weight, height, BMI at each visit, and change 
from baseline at each visit will be summarized for the Safety Analysis Set using descriptive 
statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) by treatment group. 


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In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3 (Selection of Data in the Event of Multiple Records in a Window). No 
inferential statistics will be generated.
A by-subject listing of body weight, weight percentile, height, height percentile, BMI and BMI 
percentile will be provided by subject ID number and visit in chronological order.
7.5.
Mid-Parental Height Assessment
The calculation of mid-parental height has been a standard procedure for assessing individual 
child’s future adult height since it was first described by Tanner {Tanner 1970}. Mid-parental 
height was calculated as the average of father's and mother's height. For boys, calculate the 
sex-adjusted mid-parental height by adding 2.5 inch or 6.5 cm from the mean of the parents' 
heights. For girls, subtract 2.5 inch or 6.5 cm from the mean of the parents' heights. If any one of 
parents’ heights is missing, the calculation will be excluded.
A by-subject listing of parents’ heights and derived mid-parental height will be provided by 
subject ID number in ascending order.
7.6.
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 the bone age from x-ray.
Bone age at baseline visit, FU-24 visit and change from baseline visit will be summarized for the 
Safety Analysis Set using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by treatment group. 
A by-subject listing of bone age will be provided by subject ID number in ascending order and 
visit in chronological order.
7.7.
Tanner Pubertal Stage Assessment
The Tanner stages will be used to evaluate the onset and progression of pubertal changes. 
Females will be rated for pubic hair growth and breast development, and males will be rated for 
pubic hair growth and genitalia development. The Tanner stages (Pubic Hair and Breasts for 
female; Pubic Hair and Genitalia for male) at EOT, FU-12 and FU-24 visit will be summarized 
by baseline Tanner stages using frequency count and percentage by sex overall and within each 
treatment group.


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7.8.
Pediatric Quality of Life (PedsQL™SF-15) Questionnaires, Including 
Neuropsychiatric Examination by Emotional Function Domain
The PedsQL™Pediatric Quality of Life Inventory V4.0 Short Form (SF15) will be completed at 
Day 1, EOT (Week 12 for genotype 2 subjects, Week 24 for genotype 3 subjects, or at Early
Termination, if applicable), 12-Week Post-Treatment, and 24-Week Post-Treatment visits. 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/guardian) for the current age group at the time of survey administration.
The transformed scale scores (0 to 100 scale) at baseline, EOT (Week 12 for genotype 2 subjects, 
Week 24 for genotype 3 subjects, or at Early Termination, if applicable), 12-Week Post-
Treatment, and 24-Week Post-Treatment visits and change from baseline, change from EOT to 
posttreatment will be presented for each of the 4 domains of the SF-15 (physical functioning, 
emotional functioning, social functioning, and school functioning), and the Total Score. Scoring 
of the SF15 scales will be performed as described in Scaling and Scoring of the Pediatric Quality 
of Life Inventory™ (PedsQLTM) by James W. Varni. A Wilcoxon signed rank test will be used to 
explore within treatment group changes in status from baseline to EOT (Week 12 for genotype 2 
subjects, Week 24 for genotype 3 subjects, or at Early Termination, if applicable), and from EOT 
to each of the posttreatment time points. Results (p-values) will be presented, but should be 
interpreted with caution as multiple endpoints are being tested, and the study has not been 
powered to test these exploratory endpoints. Plot of the mean ± SD of change from baseline in 
SF15 summary scores will be presented.
7.9.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version
of the World Health Organization (WHO) Drug dictionary. The medications will be categorized 
as prior or concomitant using the following definitions:

Prior medications: any medications taken and stopped prior to or on the date of first study 
drug administration

Concomitant medications: any medications taken after the date of first study drug 
administration and up to the last dosing date of study drug
Concomitant medications will be summarized by preferred name using the number and 
percentage of subjects for each treatment group. A subject reporting the same medication more 
than once will be counted only once when calculating the number and percentage of subjects 
who received that medication. The summary of concomitant medications will be ordered by 
preferred term in descending frequency. For drugs with the same frequency, sorting will be done 
alphabetically.
Summaries will be based on the Safety Analysis Set. No inferential statistics will be generated. 


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For purposes of analysis, any medication with a stop date that is on or prior to the initial study 
drug dosing date or a start date that is after the last study drug dosing date will be excluded from 
a concomitant medication summary. If a partial stop date is entered, any medication with the 
month and year (if day is missing) or year (if day and month are missing) prior to the initial 
study drug dosing date will be excluded from the concomitant medication summary. If a partial 
start date is entered, then any medication with the month and year (if day is missing) or year (if 
day and month are missing) after the study drug stop date will be excluded from the concomitant 
medication summary. Medications with completely missing dates will be included in the 
concomitant medication summary.
A summary of prior medications will not be provided.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.10.
Other Safety Measures
A data listing will be provided for subjects who become pregnant during the study.
7.11.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC ANALYSES
8.1.
PK Analysis in PK Lead-in Phase (Intensive PK Analysis)
Intensive PK Analysis will be performed using PK Lead-in Phase Intensive PK Analysis Set.
Concentrations of SOF and GS-331007 from subjects in the PK lead-in Phase over sampling 
time will be listed and summarized using descriptive statistics (n, arithmetic mean, geometric 
mean and its 95% confidence interval, coefficient of variation [%CV], SD, median, Q1, Q3, 
minimum, and maximum) by nominal time and cohort. For Cohorts 1 and 2, plasma samples will 
be collected for PK analyses following dosing of study drugs on Day 7 at the following time 
points: 0 (predose), 0.5, 1, 2, 3, 4, 8, and 12 hours postdose. For Cohort 3, plasma samples for 
PK analyses will be collected at the following time points: 0 (predose), 2, 4, 8, and 12 hours 
postdose. PK parameters from subjects in the PK lead-in Phase will be summarized (e.g; AUCtau, 
AUClast, Cmax, Tmax, Clast, Tlast, Ctau, T1/2, volume of distribution and clearance, as appropriate) by 
cohort.
To confirm the appropriateness of SOF dose for each age group, PK parameters for GS-331007 
will be compared between each age group from this study and the SOF NDA patient population 
(which includes population-PK derived PK exposure data from adult phase 2 and 3 studies) by 
carrying out an analysis of variance (ANOVA) for log-transformed AUCtau of GS-331007 as the 
primary endpoint and Cmax of GS-331007 as a secondary endpoint. Geometric Mean Ratio and 
its 90% confidence interval will be provided.
8.2.
Population PK Analysis
Population PK modeling will be applied on the combined data from both intensive PK blood 
samples collected in PK Lead-in Phase and sparse PK blood samples collected in the Treatment 
Phase to characterize the pharmacokinetics of SOF and GS-331007 using mixed-effect modeling 
techniques. Estimated PK parameters using the population PK model will be presented in a 
separate Population PK report.


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9.
REFERENCES
Centers for Disease Control and Prevention (CDC). Division of Nutrition, Physicial Activity, and 
Obesity> Nutrition: Growth Chart Training: A SAS Program for the 2000 CDC 
Growth Charts (ages 0 to <20 years). Available at: 
http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm.  2016a.
Centers for Disease Control and Prevention (CDC). Division of Nutrition, Physicial Activity, and 
Obesity> Nutrition: Growth Chart Training: Other Growth Chart Resources. 
Available at: 
http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/index.htm.  2016b.
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the Case of the 
Binomial. Dec. Biometrika 1934;26 (4):pp. 404-13.
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of disease 
in childhood 1969;44 (235):291-303.
Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Archives of 
disease in childhood 1970;45 (239):13-23.
Tanner JM, Goldstein H, Whitehouse RH. Standards for Children's Height at Ages 2-9 Years 
Allowing for Height of Parents. Archives of disease in childhood 1970;45:755-62.


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.
nQuery Advisor(R) Version 7.0. Statistical Solutions, Cork, Ireland.


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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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12.
APPENDICES
Appendix 1.
Study Procedures Table
Appendix 2.
Tanner Stages*
Appendix 3.
PedsQL™ Score Calculation Algorithms


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Appendix 1.
Study Procedures Table
Appendix Table 1.
PK Lead-in Phase: Screening and On-Treatment Study Visits
Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 7 (+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
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
SOF Swallowability Assessment
X
Xh
Quality of Life Survey
Xi
Review of Study 
Medication Compliance
X
X
Study Drug Dispensingb
X


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Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 7 (+ 3 days)
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X
X
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
Subject Dosing Diary
X
X
X
Intensive PK
Xd
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
Palatability Assessment of Oral Granulesj
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 drugs on Day 7 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 8, 
and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 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. 
PPD


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f
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). 
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
Palatability of SOF oral granules will be assessed at Day 1, applicable.
PPD


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Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningc
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12g
16g
20g
24g
Early 
Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Complete Physical Examination
X
X
X
X
X
Symptom-Directed Physical Examination
X
X
X
X
X
X
Tanner Pubertal Stage Assessment
X
X
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 Counselingh
X
X
X
X
SOF Swallowability Assessment
X
Xj
Quality of Life Surveye
X
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
X
X
X
Study Drug Dispensingb
X
X
X
Xi
Xi
Xi


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Screeningc
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12g
16g
20g
24g
Early 
Termination
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
Viral Sequencing d
X
X
X
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testing
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
X
X
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
Palatability Assessment of Oral Granulesk
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, 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 at Day 1, Week 12 (only GT-2 subjects), Week 24 (only GT-3 subjects) and Early Termination 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
GT-2 subjects will complete through the Week 12 visit; GT-3 subjects will complete through the Week 24 visit. 
h
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).
i
Study Drug Dispensing at the Week 12, Week 16, and Week 20 visit for GT-3 subjects only
j
Swallowability can occur at Day 1 if not completed during screening.
k
Palatability of SOF oral granules will be assessed at Day 1, applicable.
PPD
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
Xd
Xd
Concomitant Medications
X
Quality of Life Surveya
X
X
Tanner Pubertal Stage Assessment 
X
X
Bone Age Assessment
X
Pregnancy Prevention Counselinge
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencingb
X
X
X
Urine Pregnancy Testc
X
X
X
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
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.
d
At Post Treatment Week 12 and 24, only SAEs will be captured
e
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).


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Appendix 2.
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 {Marshall 1969, Marshall 1970}


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Appendix 3.
PedsQL™Score Calculation Algorithms
The Parent Report for Toddlers (ages 2-4) and the Child & Parent Reports for Young 
Children (ages 5-7), Children (ages 8-12) and Teens (ages 13-18) of the PedsQL™4.0 SF15 
Generic Core Scales are composed of 15 items comprising 4 dimensions.
DESCRIPTION OF THE SF15 QUESTIONNAIRE:
Dimensions
Number of Items
Cluster of Items
Reversed Scoring
Direction of Dimensions
Physical Functioning
5
1-5
1-5
Higher scores indicate 
better HRQOL
Emotional Functioning
4
1-4
1-4
Social Functioning
3
1-3
1-3
School Functioning
3
1-3
1-3
SCORING OF DIMENSIONS:
Item Scaling
5-point Likert scale from 0 (Never) to 4 (Almost always)
3-point scales: 0 (Not at all), 2 (Sometimes) and 4 (A lot) for the Young Child 
self-report
Weighting of Items
No
Extension of the Scoring 
Scale
Scores are transformed on a scale from 0 to 100
Scoring Procedure
Step 1: Transform Score
Items are reversed scored and linearly transformed to a 0-100 scale as follows:
0=100, 1=75, 2=50, 3=25, 4=0.
Step 2: Calculate Scores
Score by Dimensions:

If more than 50% of the items in the scale are missing, the scale scores should 
not be computed,

Mean score = Sum of the items over the number of items answered.
Psychosocial Health Summary Score = Sum of the items over the number of items 
answered in the Emotional, Social, and School Functioning Scales.
Physical Health Summary Score = Physical Functioning Scale Score
Total Score: Sum of all the items over the number of items answered on all the Scales.
Interpretation and 
Analysis of Missing Data
If more than 50% of the items in the scale are missing, the Scale Scores should not 
be computed.

Prot_006.pdf: 
Study Title: 
Sponsor: 
IND No.: 
EudraCT Number: 
Indication: 
Protocol ID: 
Gilead Study Director 
Gilead Sciences Medical 
Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Aim 
Study to Investigate the Safety and Efficacy of 
Sofosbuvir + Ribavirin in Adolescents and Children with 
Genotype 2 or 3 Chronic HCV Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
106739 
2014-002283-32 
Hepatitis C Vims Infection 
GS-US-334-1112 
Name: 
Telephone: 
Fax: 
E-mail: 
~
PD 
t-'U 
PD 
t-'U 
Name: 
Theo Brandt-Sarif, MD, 
Telephone: 
PPD 
Fax: 
PPD 
E-mail: 
........ u 
I 
Original: 
20 December 2013 
Alnendment 1: 
10 Febrmuy 2014 
Alnendment 2: 
14 March 2014 
Alnendment 3: 
10 October 2014 
Alnendment 4: 
12 November 2014 
Alnendment 5: 
29 May2015 
Alnendment 6: 
26 Febrmuy 2016 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pruiicularly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, yom staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from Gilead 
Sciences, Inc., except to the extent necessa1y to obtain infonned consent from those persons to 
whom the dmg may be administered. 


Sofosbuvir
Protocol GS-US-334-1112
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Amendment 6
CONFIDENTIAL
Page 2
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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.
Sofosbuvir ..............................................................................................................................................21
1.2.1.
Summary of Additional Clinical Experience with Sofosbuvir .............................................21
1.3.
Ribavirin (RBV).....................................................................................................................................24
1.4.
Rationale for the Current Study .............................................................................................................25
1.5.
Rationale for Dose Selection of SOF .....................................................................................................25
1.6.
Overall Risk/Benefit Assessment...........................................................................................................28
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 ........................................................................................................................................32
3.2.1.
PK Lead-in ...........................................................................................................................32
3.2.2.
Treatment Phase ...................................................................................................................33
3.3.
Virologic Response-Based Stopping Criteria.........................................................................................33
3.4.
Treatment Discontinuations Criteria ......................................................................................................34
3.5.
Discontinuations.....................................................................................................................................34
3.6.
Pharmacogenomic Substudy ..................................................................................................................34
3.7.
Long-Term Follow-Up...........................................................................................................................34
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 ...........................................................................................38
5.1.
Randomization and Blinding..................................................................................................................38
5.2.
Sofosbuvir ..............................................................................................................................................38
5.2.1.
Description and Handling.....................................................................................................38
5.2.2.
Storage and Handling...........................................................................................................39
5.2.3.
Dosage and Administration of SOF .....................................................................................40
5.3.
Ribavirin.................................................................................................................................................40
5.3.1.
Description and Handling of RBV .......................................................................................40
5.3.2.
Dosage and Administration of RBV.....................................................................................41
5.4.
Co-administration of SOF and RBV ......................................................................................................42
5.5.
Study Drug Compliance.........................................................................................................................42
5.6.
Prior and Concomitant Medications.......................................................................................................42


Sofosbuvir
Protocol GS-US-334-1112
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Amendment 6
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6.
STUDY PROCEDURES ....................................................................................................................................44
6.1.
Subject Enrollment.................................................................................................................................44
6.2.
Screening Assessments ..........................................................................................................................44
6.2.1.
Screening Visit (Day –28 to Day 0) .....................................................................................44
6.3.
PK Lead-in: Treatment Assessments .....................................................................................................46
6.3.1.
Day 1 ....................................................................................................................................46
6.3.2.
Day 3 ....................................................................................................................................47
6.3.3.
Day 7 – Intensive PK ...........................................................................................................47
6.4.
Treatment Phase: Treatment Assessments .............................................................................................49
6.4.1.
Day 1 ....................................................................................................................................49
6.4.2.
Weeks 1 and 2 (3 days) .....................................................................................................51
6.4.3.
Weeks 4 and 8 (3 days) .....................................................................................................51
6.4.4.
Week 12 (3 days) ..............................................................................................................52
6.4.5.
Week 16 and 20 (3 days) – GT-3 Subjects only................................................................53
6.4.6.
Week 24 (3 days) – GT-3 Subjects only ...........................................................................53
6.4.7.
Unscheduled Visit/Early Termination Visit .........................................................................54
6.5.
Post-Treatment Assessments..................................................................................................................55
6.5.1.
4-Week Post-Treatment Visit (5 days)..............................................................................55
6.5.2.
12-Week Post-Treatment Visit (5 days)............................................................................56
6.5.3.
24-Week Post-Treatment Visit (5 days)............................................................................57
6.6.
Procedures and Specifications................................................................................................................57
6.6.1.
Clinical Laboratory Analytes ...............................................................................................57
6.6.2.
Medical History....................................................................................................................58
6.6.3.
Complete Physical Examination...........................................................................................58
6.6.4.
Tanner Pubertal Stage Assessment.......................................................................................58
6.6.5.
Height & Weight Measurement............................................................................................58
6.6.6.
Bone Age Assessment..........................................................................................................59
6.6.7.
Swallowability Assessment..................................................................................................59
6.6.8.
Vital Signs............................................................................................................................59
6.6.9.
Body Mass Index (BMI).......................................................................................................59
6.6.10.
Estimated Glomerular Filtration Rate (GFR) .......................................................................59
6.6.11.
Viral Sequencing (Archive)..................................................................................................60
6.6.12.
Pregnancy Testing................................................................................................................60
6.6.13.
Quality of Life Survey (PedsQL™).......................................................................................60
6.6.14.
SOF Granule Palatability Assessment..................................................................................60
7.
TOXICITY MANAGEMENT............................................................................................................................61
7.1.
Modification of Dose/Schedule Due to Toxicity....................................................................................61
7.2.
Subject Stopping Rules for SOF ............................................................................................................61
8.
ADVERSE EVENTS MANAGEMENT ............................................................................................................62
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................62
8.1.1.
Adverse Events.....................................................................................................................62
8.1.2.
Serious Adverse Events........................................................................................................62
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................63
8.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................63
8.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................63
8.2.2.
Assessment of Severity ........................................................................................................64
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events.......................................................................................................................................64
8.4.
Gilead Reporting Requirements.............................................................................................................66
8.5.
Special Situations Reports......................................................................................................................66


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Amendment 6
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8.5.1.
Definitions of Special Situations..........................................................................................66
8.5.2.
Instructions for Reporting Special Situations.......................................................................67
9.
STATISTICAL CONSIDERATIONS................................................................................................................69
9.1.
Analysis Objectives and Endpoints........................................................................................................69
9.1.1.
Analysis Objectives..............................................................................................................69
9.1.2.
Primary Endpoints................................................................................................................70
9.1.3.
Secondary Endpoints............................................................................................................70
9.2.
Analysis Conventions.............................................................................................................................70
9.2.1.
Analysis Sets ........................................................................................................................70
9.2.2.
Data Handling Conventions .................................................................................................71
9.2.3.
Interim Analysis ...................................................................................................................72
9.3.
Demographic Data and Baseline Characteristics ...................................................................................72
9.4.
Pharmacokinetic Analysis......................................................................................................................72
9.5.
Safety Analysis.......................................................................................................................................73
9.5.1.
Extent of Exposure...............................................................................................................73
9.5.2.
Palatability of SOF oral granules .........................................................................................73
9.5.3.
Adverse Events.....................................................................................................................74
9.5.4.
Laboratory Evaluations ........................................................................................................74
9.5.5.
Other Safety Evaluations......................................................................................................75
9.6.
Efficacy Analysis ...................................................................................................................................75
9.6.1.
Primary Efficacy Analysis....................................................................................................75
9.6.2.
Secondary Efficacy Analysis................................................................................................75
9.6.3.
Subgroup Analysis ...............................................................................................................76
9.7.
Quality of Life Analysis.........................................................................................................................76
9.8.
Data Monitoring Committee ..................................................................................................................76
9.9.
Sample Size............................................................................................................................................76
10.
RESPONSIBILITIES..........................................................................................................................................77
10.1.
Investigator Responsibilities ..................................................................................................................77
10.1.1.
Good Clinical Practice..........................................................................................................77
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval...............................................................................................................................77
10.1.3.
Informed Consent/Assent.....................................................................................................78
10.1.4.
Confidentiality......................................................................................................................78
10.1.5.
Study Files and Retention of Records ..................................................................................78
10.1.6.
Case Report Forms...............................................................................................................80
10.1.7.
Drug Accountability.............................................................................................................80
10.1.8.
Inspections............................................................................................................................80
10.1.9.
Protocol Compliance............................................................................................................80
10.2.
Sponsor Responsibilities ........................................................................................................................81
10.2.1.
Protocol Modifications.........................................................................................................81
10.2.2.
Study Report and Publications .............................................................................................81
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................81
10.3.1.
Access to Information for Monitoring..................................................................................81
10.3.2.
Access to Information for Auditing or Inspections ..............................................................82
10.3.3.
Study Discontinuation..........................................................................................................82
11.
REFERENCES ...................................................................................................................................................83
12.
APPENDICES ....................................................................................................................................................85
Appendix 1.
Investigator Signature Page....................................................................................................86
Appendix 2.
Study Procedures Table..........................................................................................................87


Sofosbuvir
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Amendment 6
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Page 5
26 February 2016
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............94
Appendix 4.
Tanner Stages* .....................................................................................................................117
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................118
LIST OF IN-TEXT TABLES
Table 1-1.
GS-US-334-1111: Statistical Comparison of SOF, GS-566500, and GS-331007 PK 
Parameters ..............................................................................................................................22
Table 1-2.
Steady-state PK and Statistical Comparison of SOF and GS-331007 PK in Cohort 1 
and Cohort 2 Subjects (PK Lead-in) and Adult Subjects (Phase 2/3 Population 
Analysis).................................................................................................................................24
Table 7-1.
RBV Dose Reduction Guidelines...........................................................................................61
LIST OF IN-TEXT FIGURES
Figure 1-1.
Predicted SOF and GS-331007 AUCtau following administration of SOF 200 mg or 
SOF 150 mg to Children (3 to < 6 years of age) ....................................................................27
Figure 3-1.
Study Schema.........................................................................................................................32


Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6
CONFIDENTIAL
Page 6
26 February 2016
PROTOCOL SYNOPSIS
Gilead Sciences, Inc. 
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Arm Study 
to Investigate the Safety and Efficacy of Sofosbuvir + Ribavirin in 
Adolescents and Children with Genotype 2 or 3 Chronic HCV 
Infection
IND Number:
EudraCT Number:
106739
2014-002283-32
Study Centers:
Approximately 50 sites in the United States, Europe, Russia, 
Australia, New Zealand, Belgium and India
Number of Subjects:
Approximately 100 subjects
Target Population:
Adolescents and children (aged 3 to < 18) with chronic hepatitis C 
virus (HCV) infection
Treatment Duration:
PK Lead-in – 7 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 sofosbuvir (SOF) in HCV-infected pediatric subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety and tolerability of 7 days of dosing of SOF
+ ribavirin (RBV) in HCV-infected pediatric subjects
The primary objective of the Treatment Phase of this study is:

To evaluate the safety and tolerability of SOF + RBV for 12 or 
24 weeks in HCV-infected pediatric subjects with genotype (GT)
GT-2 or GT-3, respectively


Sofosbuvir 
Protocol GS-US-334-1112 
Gilead Sciences, Inc 
Study Design: 
CONFIDENTIAL 
FINAL 
Amendment6 
The seconda!y objectives of the Treatment Phase of this study are: 
• 
To detennine the antiviral efficacy of SOF + RBV u·eatment in 
GT-2 and GT-3 HCV-infected subjects separately, as assessed by 
the prop01iion of subjects with SVR 12 weeks after completion of 
u·eatment (SVR12) 
• 
To detennine the antiviral efficacy of SOF + RBV u·eatment in 
GT-2 and GT-3 HCV-infected subjects separately, as assessed by 
the prop01iion of subjects with SVR 4 and 24 weeks after 
completion ofu·eatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA dming u·eatment 
and after completion of u·eatment 
• 
To evaluate the emergence of viral resistance to SOF dming 
u·eatment and after completion of u·eatment 
• 
To evaluate the palatability of SOF oral granules at Day 1, as 
applicable. 
• 
To evaluate the effect of growth and development on pediau·ic 
subjects dming and after u·eatlnent 
The explorat01y objective of this study is: 
• 
PO 
Open-label, multi-coh01i, two-pati study evaluating the PK, safety, 
and antiviral activity of SOF in chronic HCV-infected pediau·ic 
subjects. 
The study will be divided into 2 parts as follows: 
PK Lead-in: Will evaluate and/or confitm age appropriate SOF doses 
by analyzing PK, safety, and antiviral activity of SOF administered in 
combination with RBV through 7 days of dosing for each of three 
coh01is. Children aged 3 to < 6, children aged 6 to < 12 years and 
adolescents aged 12 to < 18 years with genotype GT-2 or GT-3 HCV 
infection and evidence of HCV RNA :=::: 1000 IU/mL at study entry 
will be evaluated. Subjects must be u·eatment naive to patiicipate in 
the PK Lead-in Phase. 
Three coh01is of up to 10 subjects each will be sequentially enrolled: 
• 
Cohort 1: 12 to < 18 yem·s old weighing :=::: 45kg 
• 
Cohort 2: 6 to < 12 yem·s old weighing :=::: 17kg and < 45kg 
• 
Coh01i 3: 3 to < 6 yem·s old 
Page7 
26 Febmaty 2016 


Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6
CONFIDENTIAL
Page 8
26 February 2016
The study will start with Cohort 1.  Subjects will receive SOF (400 mg 
adult tablet or 4 x 100 mg tablets if determined necessary based on 
SOF swallowability assessment) + RBV for 7 days with intensive PK 
conducted on Day 7.   Cohort 2 subjects will receive 200 mg SOF 
(2 x 100 mg tablets or 4 x 50 mg capsules containing granules if 
determined necessary based on the SOF swallowability assessment) + 
RBV for 7 days with intensive PK conducted on Day 7.  Cohort 3 
subjects weighing ≥17kg will receive 200 mg SOF (4 x 50 mg 
capsules containing granules) + RBV for 7 days with intensive PK 
conducted on Day 7. Cohort 3 subjects weighing <17kg will receive 
150 mg SOF (3 x 50mg capsules containing granules) + RBV for 7 
days with intensive PK conducted on Day 7.
PK Lead-in subjects in each cohort (Cohorts 1, 2 and 3) will 
immediately enroll in the Treatment Phase as they complete Day 7 of 
the PK Lead-in Phase.  They will continue dosing with SOF + RBV 
with no interruption of study drug administration.  Subjects rolling 
over from the PK Lead-in will not be required to perform 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 will be reviewed to confirm 
the appropriateness of the evaluated SOF 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: Will be initiated sequentially by cohort after 
confirmation of age-appropriate SOF dosage levels. Subjects who 
participated 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.  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.
Children aged 3 to < 12 years and adolescents aged 12 to < 18 years 
with GT-2 or GT-3 infection and evidence of HCV RNA 
≥1000 IU/mL at study entry (those who were dosed in the PK Lead-in 
Phase will have met this criteria prior to enrollment) will be evaluated. 
Subjects enrolled in the study will receive the following regimen:

GT-2 subjects: SOF + RBV for 12 weeks

GT-3 subjects: SOF + RBV for 24 weeks


Sofosbuvir 
Protocol GS-US-334-1112 
Gilead Sciences, Inc 
Substudy and 
Long-Te1m 
Follow-Up Study: 
CONFIDENTIAL 
FINAL 
Amendment6 
The study will enroll both treatment-naive and treatment-experienced 
pediatric subjects, with up to 20 subjects allowed to be treatment 
experienced. Approximately 100 total subjects, including subjects that 
pruiicipate in the PK Lead-in Phase, will be enrolled in Treatment 
Phase as follows 
• 
Group 1: Approximately 50 adolescent subjects (12 to < 18 years 
of age) 
• 
Group 2: Approximately 50 pediatric subjects (3 to < 12 yeru·s 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 
lmdetectable 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, 12 (and Weeks 16, 20, and 24 for GT-3) 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-cru·e (SOC) therapy 
with their healthcru·e provider. 
Pharmacogenomics (PG) Substudy 
PO 
Long-Term Follow-up 
Subjects who attain SVR24 or those who do not attain SVR24 and do 
not initiate experimental or approved anti-HCV therapy will be 
followed eve1y 6 months for the first two years followed by eve1y 
12 months for assessments of growth, quality of life, and long-te1m 
viral suppression (if applicable) in a separate protocol 
(GS-US-334-1113). This follow-up will continue for 5 years. 
Page9 
26 Febmaty 2016 


Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6
CONFIDENTIAL
Page 10
26 February 2016
Diagnosis and Main 
Eligibility Criteria: 
Chronic HCV-infected, treatment-naïve and up to 20 subjects may 
be treatment experienced, male and female subjects aged 3 to < 18. 
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

a liver biopsy performed prior to the Day 1 visit with evidence of 
chronic HCV infection

Infection with HCV GT-2 or GT-3 as determined at Screening

HCV RNA ≥1000 IU/mL at Screening 

For the PK Lead-in Phase: subjects in cohort 1 (age 12 to 
<18 years of age) must weigh ≥ 45kg

For the PK Lead-in Phase:  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)

Chronic use of systemic immunosuppressive agents or
immunomodulatory agents

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.


Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6
CONFIDENTIAL
Page 11
26 February 2016

Sexually active subjects who are not willing to use two 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 height and weight), concomitant medications, SOF 
swallowability assessment (may be performed at 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 7.
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 7. SOF swallowability 
assessment with placebo will be performed (if not performed at 
screening) on Day 1 to assess a subject’s ability to swallow the 
400 mg or 100 mg SOF tablet (only subjects administered SOF in 
tablet form).
Subjects (up to 10 subjects) enrolled in the PK Lead-in Phase will 
participate in an intensive PK evaluation on Day 7. Following 
completion of the Day 7 intensive PK visit, subjects will then return 
for scheduled study visits outlined in the Treatment Phase and 
continue dosing with SOF + RBV with no interruption of study drug 
administration.  Subjects will be administered a dosing diary with 
instructions.


Sofosbuvir 
Protocol GS-US-334-1112 
Gilead Sciences, Inc 
CONFIDENTIAL 
Treatment Phase: 
FINAL 
Amendment6 
• 
GT-2 Subjects: Study visits for GT-2 subjects will occur at Day 1, 
and the end of Weeks 1, 2, 4, 8, and 12. 
• 
GT-3 Subjects: Study visits for GT-3 subjects will occur at Day 1, 
and the end of Weeks 1, 2, 4, 8, 12, 16, 20, and 24. 
All Treatment Phase subjects will then retu.m for follow-up visits at 4, 
12 and 24 weeks after discontinuation of therapy. 
On-u·eatment assessments will include physical examination, vital 
signs (including height and weight) adverse events, concomitant 
medications, pregnancy prevention cmmseling (all subjects:::: 12 years 
of age and subjects < 12 years of age at the discretion of the 
Investigator based on subject's pube1tal status), safety laborat01y tests, 
coagulation tests, HCV RNA, PK samples, a quality of life survey and 
urine pregnancy tests (females of childbearing potential only). Tanner 
Pubeiial Stage assessment will be perf01med at Day 1 and end of 
u·eatment visits; parental heights will be recorded at Day 1. The Bone 
Age Assessment will be perfonned at Day 1 visit. If available, results 
from liver biopsies will be collected at screening. SOF swallowability 
assessment with placebo will be perf01med (if not perf01med at 
screening) on Day 1 to assess a subject's ability to swallow a 400 mg 
or 100 mg SOF tablet 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 eve1y visit thereafter. 
Post-u·eatment assessments will include adverse events, concomitant 
medications, vital signs (including body weight and height), symptom-
directed physical examination, safety laborat01y tests, HCV RNA, 
Tanner Pubertal Stage assessment (only post-u·eahnent Week 12 and 
post-u·eatment Week 24), Bone Age Assessment (only post-u·eatment 
Week 24) and urine pregnancy tests as defmed in Appendix 5. 
Palatability of SOF oral granules will be assessed at Day 1, as 
applicable. 
PO 
Page 12 
26 Febmaty 2016 


Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6
CONFIDENTIAL
Page 13
26 February 2016
Test Product, Dose, 
and Mode of 
Administration:
PK Lead-in: 
(Cohort 1) SOF 400 mg tablets will be administered once daily along 
with RBV weight-based dosing. Subjects determined unable to 
swallow the placebo for 400 mg SOF tablet (by SOF Placebo 
swallowability assessment at Screening or at any time during the 
study) will be re-assigned to 4 x 100 mg tablets daily.  
(Cohort 2) SOF 200 mg (2 X 100 mg tablets) will be administered 
once daily along with RBV weight-based dosing. Subjects determined 
unable to swallow the placebo for the 100 mg SOF tablet (by SOF 
Placebo swallowability assessment at Screening or at any time during 
the study) will be re-assigned to 4 X 50 mg capsules containing 
granules. Subjects who weigh outside of the ≥ 17kg and < 45 kg 
range will be excluded
(Cohort 3) subjects weighing ≥17kg will receive 200 mg SOF 
(4 x 50mg capsules containing granules) + RBV weight-based dosing
for 7 days. Subjects who weigh <17kg will receive 150 mg SOF (3 x 
50mg capsules containing granules) + RBV weight-based dosing for 7 
days.  
Intensive PK and safety results from the PK Lead-In of each Cohort 
will be reviewed to confirm the appropriateness of the evaluated SOF 
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.


Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6
CONFIDENTIAL
Page 14
26 February 2016
RBV Weight-Based Dosing (All age groups):
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 a weight 
and/or age-appropriate dose of SOF. The evening dose of RBV will be 
taken with food.
Reference Therapy:
None
Evaluation Criteria:
Safety:
AEs, laboratory tests, physical examination, vital signs and Tanner 
Pubertal Stage assessments will be collected throughout the study. 
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, steady-state PK of SOF and its major 
metabolites GS-566500 and GS-331007 will be assessed at Day 7. For 
Cohorts 1 and 2, plasma samples will be collected for PK analyses
following dosing of study drugs on Day 7 at the following time points: 
0 (predose), 0.5, 1, 2, 3, 4, 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), 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 SOF, 
GS-566500 and GS-331007 and/or ribavirin will be assessed.
The effect of age and SOF dose on PK (SOF and GS-331007) will be 
explored. 


Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6
CONFIDENTIAL
Page 15
26 February 2016
Statistical Methods:
For the PK Lead-in, plasma PK parameters Cmax, Tmax, Clast, Tlast, Ctau, 
AUCtau, and t1/2 will be estimated.  The PK parameters will be 
summarized by cohort. The effect of age and SOF dose on PK 
(SOF and GS-331007) 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 age group, by GT and overall. The key efficacy 
endpoint is SVR12 in all enrolled and treated subjects and will be 
summarized by age group, by genotype, by overall and by age group 
and GT.  Point estimate and its 95% confidence interval will be 
provided.  
In addition, SVR12 will be compared with historical SVR12 rate of 
80% from pegylated interferon + ribavirin for pediatric GT-2 and 
GT-3 subjects {20280}, using two-sided exact one-sample binomial 
test at the 0.05 significance level.  
Secondary efficacy endpoints are SVR4, SVR24, breakthrough and 
relapse.
Palatability of SOF oral granules will be summarized using 
descriptive statistics by appropriate age group, by genotype, by overall 
and by age group and genotype.
Subgroup analysis on SVR12 will be performed by treatment 
experience (treatment-naive vs. experienced) and 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). 
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.
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 age group, by GT, by 
overall and by age group and GT.


Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6
CONFIDENTIAL
Page 16
26 February 2016
With approximately 50 subjects enrolled into each age group of 
Treatment Phase, a two-sided 95.0% confidence interval of the 
SVR12 rate will extend at most 11.1% in both directions from the 
observed SVR12 rate, assuming the expected SVR12 rate is 80%. In 
addition, a sample size of 100 subjects will provide over 80% power 
to detect an 11% improvement in SVR12 rate from 80% to 91% using 
two-sided one-sample binomial test at significance level of 0.05.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6
CONFIDENTIAL
Page 17
26 February 2016
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
β-hCG
β-human chorionic gonadotropin
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)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BW
body weight
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)
CMH
Cochran-Mantel-Haenszel
COPD
Chronic obstructive pulmonary disease
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
Emax
maximal effect
EU
European Union
EVR
Early virologic response
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor
GFR
glomerular filtration rate
GSI
Gilead Sciences, Inc.


Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6
CONFIDENTIAL
Page 18
26 February 2016
GT
Genotype (viral)
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
IV
Intravenous
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDH
Lactase dehydrogenase
LLN
lower limit of the normal range
LLOD
Lower limit of detection
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
RBC
Red blood cell count 
RBV
Ribavirin
RDRP
RNA-dependent RNA polymerase
RNA
ribonucleic acid


Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6
CONFIDENTIAL
Page 19
26 February 2016
RVR
rapid virologic response 
SADR
Serious adverse drug reaction
SAE
serious adverse event
SD
Standard deviation
SOC
Standard of Care
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TND
Target not detected
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


Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6
CONFIDENTIAL
Page 20
26 February 2016
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 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 standard of care 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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Gilead Sciences, Inc
Amendment 6
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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.
Sofosbuvir
Sovaldi™(Sofosbuvir) is a potent nucleotide analogue that inhibits HCV RNA replication in 
vitro and has demonstrated high rates of sustained viral response (SVR) when given with RBV
+/- PEG to subjects with chronic GT- 1, 2, 3 or 4 HCV infection {27503}, {23275}, {24713}, 
{24715}.  Sovaldi™has been approved in the United States by the Food and Drug Administration 
(FDA) for the treatment of HCV infection GT- 1, 2, 3 and 4 including treatment naïve and 
experienced patients and HIV/HCV co-infected patients.  Sovaldi™is also approved in EU, 
Canada and Turkey.
For further information on the clinical pharmacology, virology, safety and efficacy of SOF, 
please refer to the current version of the Investigator’s Brochure and the local prescribing 
information.
1.2.1.
Summary of Additional Clinical Experience with Sofosbuvir
A phase 1 study (GS-US-334-1111) was conducted to evaluate the relative bioavailability of, and 
effect of food on sofosbuvir oral granules in healthy adult subjects to support the use of this 
formulation in subjects unable to swallow the tablet formulations.  Study results are presented 
below.
1.2.1.1.
GS-US-334-1111 Study Design
Study GS-US-334-1111 is a single dose, randomized, 3-period crossover phase 1 study 
conducted in healthy adult subjects.  Subjects were administered 400 mg SOF in the following 
treatments in a randomized order: 1 x 400 mg SOF (adult formulation) in the fasted state, 
8 x 50 mg SOF granules in capsules in the fasted state, and 8 x 50 mg SOF granules in capsules 
after a standardized high-fat meal.  Prior to administration the SOF granules were removed from 
the capsules and administered orally with water.  18 healthy subjects were enrolled and 
completed all treatment periods of this study.


Sofosbuvir 
Protocol GS-US-334-1112 
Gilead Sciences, Inc 
1.2.1.2. 
GS-US-3 34-1111 Phannacokinetic Results 
FINAL 
Amendment6 
PK results are available for all18 subjects. Statistical comparisons of the primruy PK pru·ameters 
AUCinf, AUC1ast, and Cmax for SOF, its inte1mediate metabolite GS-566500, and the primaty 
circulating metabolite GS-331007 which is considered the primaty analyte of interest for PK 
studies m·e presented below. Statistical compm·isons include the %GMR and 90%Cis of 
exposures achieved after administration of 8 x 50 mg SOF granules in capsules fasted 
(Granules Fasted) relative to 1 x 400 mg SOF tablet fasted (Tablet Fasted), and 8 x 50 mg SOF 
granules in capsules fed (Granules Fed) relative to 8 x 50 mg SOF granules in capsules fasted 
(Granules Fasted) (Table 1-1). 
Bioequivalence of the pediatric granule fonnulation and the adult tablet f01mulation was 
concluded as a result of the 90%Cis of the %GMRs for GS-331007 AUCiast, AUCinf, and Cmax 
(protocol specified primaty endpoints) being contained within the predefmed boundaries of 
80-125%. Additionally, administration of the pediatric granule f01mulation after a high-fat meal 
or fasted resulted in bioequivalent exposures of GS-331 007 as the 90%Cis of the %GMRs for 
GS-331 007 AUC1ast and AUCinf (protocol Sj)ecified primat}' end oints were contained within the 
j)redefmed boundm·ies of 80-125%. 
PD 
Table 1-1. 
Parameter (N=18) 
SOF 
AUCinf 
AUCtast 
Cmax 
GS-566500 
AUCinf 
AUCtast 
cmax 
GS-331007 
AUCinf 
AUCtast 
cmax 
GS-US-334-1111: Statistical Comparison of SOF, GS-566500, and 
GS-331 007 PK Parameters 
o/oGMR (90%CI) 
Granules Fasted/Tablet Fasted 
Granules Fed/Granules Fasted 
100 (85.9, 117) 
167 (143, 195) 
99.8 (85.3, 117) 
167 (143, 196) 
83.6 (64.5, 108) 
90.9 (70.2, 118) 
96.2 (85.2, 109) 
165 (146, 186) 
94.6 (82.3, 109) 
166 (145, 191) 
91.8 (80.2, 105) 
128 (112, 146) 
105 (98.7, 112) 
87.2 (82.1, 92.7) 
104 (97.6, 112) 
86.2 (80.6, 92.2) 
106 (95.6, 117) 
60.3 (54.5, 66.8) 
Note: %GMR and 90%Cls are presented to 3 significant digits 
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1.2.1.3.
GS-US-334-1111 Conclusions
As assessed by GS-331007, the new sofosbuvir (8 x 50 mg) granule formulation was 
bioequivalent to the existing sofosbuvir 1 x 400 mg tablet formulation under fasted conditions.  
The sofosbuvir (8 x 50 mg) granule formulation is recommended to be administered without 
regard to food.
1.2.1.4.
GS-US-334-1112 Preliminary Pharmacokinetic and Safety Results
Preliminary data are available for Cohort 1 adolescent subjects (12 to < 18 years of age; N=10) 
and Cohort 2 pediatric subjects (6 to < 12 years of age; N=12) who enrolled in the PK Lead-in to
receive adult clinical doses of SOF 400 mg or 200 mg, respectively. Of note, 2 out of 12 subjects 
(subject 
 and 
 in Cohort 2 have erroneously received a 400 mg dose of sofosbuvir
for the duration of the PK lead-in phase (Day 1 through Week 24). 
Evaluation of PK in Cohort 2 subjects was conducted using data from all 12 subjects. SOF and 
GS-331007 exposure in subjects 
 and 
scaled to 200 mg; as well as using the data 
from 10 subjects who received a 200 mg dose of sofosbuvir; Table 1-2.
Mean exposures of SOF and GS-331007 in Cohort 1 and Cohort 2 subjects were comparable 
to observed exposures in the adult subjects in the Phase 2/3 SOF clinical program; 
thereby confirming the appropriateness of adult 400 mg dose in the adolescent population (12 to 
< 18 years of age) and 200 mg dose in pediatric patients (6 to < 12 years of age) (Table 1-2).
PPD
PPD
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Table 1-2.
Steady-state PK and Statistical Comparison of SOF and GS-331007 
PK in Cohort 1 and Cohort 2 Subjects (PK Lead-in) and Adult 
Subjects (Phase 2/3 Population Analysis)
Mean (%CV)
Adolescents: 12 to < 18 
years of age (N=10)
Phase 2/3 (N=1695)
GMR% (90% CI)
SOF*
AUC
tau (ng*hr/ml)
1170 (67.6)
1030 (36.5)
101 (83.9, 121)
C
max (ng/ml)
592 (84.1)
511 (32.5)
97.4 (79.0, 120)
GS-331007
AUC
tau (ng*hr/ml)
9110 (28.6)
7120 (30.7)
129 (110, 152)
C
max (ng/ml)
981 (43.7)
582 (36.3)
168 (137, 206)
Pediatrics: 6 to < 12 years 
of age (N=12) **
Phase 2/3 (N=1695)
GMR% (90% CI)
SOF*
AUC
tau (ng*hr/ml)
977 (52.8)
1030 (36.5)
88.7 (75.2, 105)
C
max (ng/ml)
635 (50.9)
511 (32.5)
115 (95.1, 139)
GS-331007
AUC
tau (ng*hr/ml)
6250 (25.4)
7120 (30.7)
89.2 (76.8, 104)
C
max (ng/ml)
865 (26.5)
582 (36.3)
154 (128, 185)
Data reported to 3 significant figures; *N=838 (Phase 2/3); ** Similar results were observed following exclusion of subjects  
 and 
 who received sofosbuvir 400 mg for the duration of the PK-Lead in
Safety data available for Cohort 1 adolescent subjects (N=10) who enrolled in the PK lead-in and 
received adult clinical dose of SOF 400mg resulted in no significant safety signals. Subjects in 
Cohort 2 (N= 10) who enrolled in the PK lead-in and received a dose of SOF 200mg resulted in 
no significant safety signals.  Additionally, the two Cohort 2 subjects (subject 
 and 
 
who received 400mg of SOF had no significant safety signals.  
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}.
PPD
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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.
1.4.
Rationale for the Current Study
This clinical study is designed to evaluate the efficacy and safety of treatment with SOF + RBV
for adolescents and children with GT-2 and GT-3 chronic HCV infection. 
Currently PEG and weight-based RBV are considered the standard of care for the treatment of 
HCV infection in children. However, this PEG and RBV regimen is long in duration, relatively 
toxic, and not well tolerated. Thus, there continues to be a need for new treatments for HCV that 
combine potent and sustained efficacy with improved tolerability and safety. Therapy that 
provides shorter duration and improved efficacy with an all-oral regimen would be a significant 
advancement over current options in pediatric patients.
The main aim for the treatment of pediatric patients with HCV is to eliminate the need to use 
PEG regimens. In this way, pediatric patients are able to avoid the necessity of weekly injections, 
which can be traumatic and burdensome, and also to significantly reduce the serious adverse 
events seen on administration of PEG regimens. 
Sovaldi (sofosbuvir 400 mg tablet) is approved in more than 35 countries worldwide in 
combination with other medicinal products, for the treatment of adults with chronic hepatitis C 
infection. SOF in combination with RBV would provide an all-oral, IFN-free regimen with a 
shorter treatment duration (12 - 24 weeks of SOF treatment versus standard-of-care 24 to 48 
weeks of treatment) and would offer another important option in the treatment of HCV infection 
in the pediatric population.
Phase 3 data demonstrates that high SVR12 rates in subjects with GT-2 HCV infection can be 
achieved with 12 weeks treatment with SOF + RBV, however, these studies suggest that patients 
with GT-3 infection may benefit from a longer treatment duration (i.e. 24 weeks) with 
SOF + RBV. Optimal duration of SOF + RBV, for GT-3 subjects, was established in FISSION 
and VALENCE.  Increasing treatment duration from 12 to 24 weeks increased SVR12 from 
61 to 93% in non-cirrhotics and from 34 to 92% in cirrhotics.
1.5.
Rationale for Dose Selection of SOF
SOF 400 mg, once daily, when dosed in combination with RBV with or without PEG has 
demonstrated broad genotypic efficacy and favorable safety profile in over 3300 HCV-infected 
adult subjects across multiple patient populations in Phase 2 and 3 trials. This dose is the 
marketed dose of SOF for the treatment of HCV-infection in adults.
Selection of doses of SOF for adolescents and younger age groups will target systemic exposures 
similar to those observed in adults at the marketed dose.  SOF is a substrate for efflux drug 
transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). SOF is 
extensively metabolized to the pharmacologically active nucleoside analog phosphate. The 


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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 SOF 400 mg or a lower dose, SOF 200 mg are being evaluated in 
adolescent subjects (12 to <18 years old, weighing ≥ 45 kg) or pediatric subjects (6 to < 12 years 
old, weighing  ≥ 17kg and < 45kg), respectively.  The appropriateness of these doses is 
supported by data from the PK Lead-ins which demonstrated comparable SOF and 
GS-331007 exposures in adolescent subjects who received sofosbuvir 400 mg or pediatric 
subjects (6 to < 12 years old) who received sofosbuvir 200 mg and in adult subjects in Phase 2/3
using population PK analyses.
In Cohort 3 (3 to < 6 years of age), a dose of SOF 200 mg is proposed for evaluation in children, 
weighing ≥ 17 kg, whereas a lower SOF dose of 150 mg is proposed for evaluation in children, 
weighing < 17 kg. These proposed doses were supported by scaling of adult exposures based on 
correlations between body weight and clearance capacity (liver volume/size for SOF, and renal 
capacity for GS-331007) {34882} for the expected body weight range in children (3 to < 6 years 
of age) (Figure 1-1).  Based on this scaling approach, doses of SOF 200 mg in children ≥ 17kg 
and SOF 150 mg in children < 17 kg are expected to achieve mean systemic exposures of SOF 
and GS-331007 within the range of those observed in the Phase 2/3 population. (Figure 1-1) 
Safety and PK data in children (3 to < 6 years of age) who enroll in the PK-lead in will be 
evaluated to confirm the appropriateness of the dose for this age group.


Sofosbuvir 
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Amendment 6 
Figure 1-1. 
Predicted SOF and GS-331007 AUCtau following administration of 
SOF 200 mg or SOF 150 mg to Children (3 to < 6 years of age) 
u. 
0 
C/) 
Predicted SOF exposure 
150 mg 
200 mg 
5000 ... (~_1.!,~~~. -~ ......................... (~~- ?. .~~)__ ........................... max 
~ 
"-> 
(;) 
· .. · .. · .... · · .... · · · .. · .. · .. · · 95th % ile 
\J 
0 
'0 
c 
iii' 
!:!: 
0 :I 
C/) 
0 
"TI 
........................................................ ..................... 
I 
lh %ile 
~ 
I 
I 
. 
· · .. · ...... · .. · ·r · ..... · .. · ... · ........... · .. · ......... · ........ · .... · · · ..... · .. · · nun 
I 
100 +-,-~~r-~,-~~--~,-~~r-~-r~~r-~~ 
10 
12 
14 161713 
20 
22 
24 
26 
23 
31 
32 
34 36 
31 
40 
42 
44 
weight (kg) 
o 5th percentile 
o 
Q1 
c. 
mecfian 
"' Q3 
o 95th percentile 
Predicted GS-331007 exposure 
150 mg 
200 mg 
20000 
(<17 kg) 
(~17 kg) 
................. ............................................................. .... max 
10000 
5000 
1000 ................ ' .............. ..... ......................... ..... ................. min 
10 
12 
14 
161718 
20 
22 
24 
26 
2: 
30 
32 
34 
36 
38 
40 
42 
44 
weight (kg) 
o 
5th percentile o 0 1 
t. median 
v 
Q3 
o 95th percentile 
0 
3 
~ 
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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 standard of care 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. 
SOF has demonstrated efficient inhibition of viral replication in in vitro and in vivo studies. 
Available clinical data indicate SOF has a favorable safety profile and is well tolerated. SOF in 
combination with RBV is likely to provide significant therapeutic benefit in the treatment of 
HCV infection in pediatric patients compared to currently available therapies in the following 
areas:

Expected improved efficacy in a pediatric population compared to the current standard of 
care

Expected improvement in safety and tolerability in relation to either adverse reactions or 
potential medication errors in the pediatric population compared to the current standard of 
care

Improved dosing scheme or method of administration (oral compared to subcutaneously 
administration and reduced treatment duration) leading to improved safety, efficacy,
tolerability, and compliance

Expected availability of a clinically relevant age-appropriate formulation

Different mechanism of action with potential advantage for the pediatric population in terms 
of improved efficacy and safety

Expected improvement in quality of life (e.g., minimized duration of therapy and avoidance 
of IFN-related adverse events that affect patient quality of life such as flulike syndrome and 
depression)
Additionally, the study sponsor will perform an ongoing review of safety data during the conduct 
of the study.


Sofosbuvir 
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2. 
OBJECTIVES 
The prima1y objective of the PK Lead-in of this study is: 
FINAL 
Amendment6 
• 
To evaluate the steady state phrumacokinetics (PK) and confmn the dose of SOF in 
HCV -infected pediatric subjects 
The secondruy objective of the PK Lead-in of this study is: 
• 
To evaluate the safety and tolerability of 7 days of dosing of SOF + RBV in HCV -infected 
pediatric subjects 
The primary objectives of the Treatment Phase of this study are: 
• 
To evaluate the safety and tolerability of SOF + RBV for 12 or 24 weeks in HCV infected 
pediatric subjects with GT-2 or GT-3, respectively 
The secondruy objective of the Treatment Phase of this study is: 
• 
To dete1mine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects sepru·ately, as assessed by the proportion of subjects with SVR 
12 weeks after completion of treatment (SVR12) 
• 
To detennine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects separately, as assessed by the prop01tion 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 SOF during treatment and after completion 
of treatment 
• 
To evaluate the palatability ofSOF oral granules at Day 1, as applicable. 
• 
To evaluate the effect of growth and development on pediatric subjects during and after 
treatment. 
The explorat01y objective ofthis study is: 
• 
PD 
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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 SOF + 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 SOF dose by analyzing 
PK, safety, and antiviral activity of SOF + RBV through 7 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 GT-2 or GT-3 HCV infection and evidence of HCV RNA ≥1000 IU/mL at study 
entry will be evaluated. Subjects must be treatment naïve to participate in the PK Lead-in Phase. 
Three cohorts of up to 10 subjects each will be sequentially enrolled: 

Cohort 1:  12 to < 18 years old weighing ≥45kg

Cohort 2:  6 to < 12 years old weighing ≥ 17kg and < 45 kg

Cohort 3:  3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive SOF (400 mg adult tablet or 4 x 100 mg 
tablets if determined necessary based on SOF swallowability assessment) + RBV for 7 days with 
intensive PK conducted on Day 7. 
Once Cohort 2 is opened, subjects will receive SOF 200 mg (4 x 50 mg capsules containing 
granules if determined necessary based on SOF swallowability assessment) + RBV for 7 days 
with intensive PK conducted on Day 7. Subjects who weigh outside of the ≥17kg and < 45 kg 
range will be excluded.
Once Cohort 3 is opened, subjects weighing ≥17 kg will receive 200 mg SOF (4 x 50 mg 
capsules containing granules) + RBV for 7 days with intensive PK conducted on Day 7. Cohort 3 
subjects weighing <17 kg will receive 150 mg SOF (3 X 50mg capsules containing granules) + 
RBV for 7 days with intensive PK conducted on Day 7.
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 7 of PK Lead-in.  They will continue dosing with 
SOF + RBV 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.


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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 
GT-2 or GT-3 infection and evidence of 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:

GT-2 subjects: SOF + RBV for 12 weeks

GT-3 subjects: SOF + RBV for 24 weeks
The study will enroll both treatment-naïve and treatment–experienced pediatric subjects, with up 
to 20 subjects allowed to be treatment experienced. Approximately 100 total subjects, including 
subjects from the PK Lead-in Phase, will be enrolled in the Treatment Phase as follows:

Group 1: Approximately 50 adolescent subjects (12 to < 18 years of age)

Group 2: Approximately 50 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 standard-of-care (SOC) therapy with their healthcare provider.


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Figure 3-1.
Study Schema
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 7.
Subjects (up to 10 subjects per cohort) enrolled in the PK Lead-in Phase will participate in an 
intensive PK evaluation on Day 7. Subjects will be administered a dosing diary with 
instructions.  
Following completion of the Day 7 intensive PK visit, subjects will then return for scheduled 
study visits outlined in the Treatment Phase and continue dosing with SOF + RBV 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.


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3.2.2.
Treatment Phase
Screening assessments will be completed within 28 days of the Day 1 visit. For subjects 
continuing from the PK Lead-in Phase, screening, Day 1 and Week 1 of the Treatment Phase will 
not be required.

GT-2 Subjects: Study visits for GT-2 subjects will occur at screening, Day 1, and the end of
weeks 1, 2, 4, 8, and 12. 

GT-3 Subjects: Study visits for GT-3 subjects will occur at screening, Day 1, and the end of
weeks 1, 2, 4, 8, 12, 16, 20, and 24. 
All Treatment Phase 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).


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3.4. 
Treatment Discontinuations Criteria 
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Amendment6 
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 defmed in Section 7 of the protocol, 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 imp01tant to detennine 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, regulat01y agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC). 
3.5. 
Discontinuations 
Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an Early Tennination visit as described in the Section 6.4.7. 
Subjects who pennanently discontinue all study dmgs for any reason including safety and/or 
tolerability concems prior to completion of the assigned dosing period will be followed 
according to the post-u·eatment 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 evety 6 months for the 
first 2 years followed by evety 12 months for assessments of growth, quality of life, and 
long-tetm viral suppression (if applicable) in a separate protocol (GS-US-334-1113). This 
follow-up will continue for 5 years. 
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3.8.
Breakthrough Futility Assessment
A futility assessment will be performed after the first 10 subjects in each Cohort 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.
Subjects with known or suspected study drug non-adherence will not be considered to meet the 
definition of virologic breakthrough, relapse or non-responder. 
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
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.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 100 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 (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 
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 Baseline/Day 1.
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
8. Infection with HCV GT-2 or GT-3 as determined at Screening
9. HCV RNA ≥1000 IU/mL at Screening
10. Adequate hematologic function (absolute neutrophil count 1,500/mm3; hemoglobin 
12 g/dL for males and 11g/dL for females.)
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


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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. 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)
4. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)
5. -fetoprotein 50 ng/mL
6. Serum creatinine > 1.5 mg/dL
7. Estimated glomerular filtration rate 90 mL/min/1.73m2, as calculated by the Schwartz 
Formula
8. Evidence of hepatocellular carcinoma (HCC) or other malignancy (with the exception of 
certain resolved skin cancers)
9. Co-infection with HIV, acute HAV, or HBV
10. Significant cardiovascular, pulmonary or neurological disease
11. Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of 
orally administered medications
12. History of solid organ or bone marrow transplantation
13. Chronic daily non-steroidal anti-inflammatory drug therapy
14. Systemic corticosteroid use for 5 days (pulmonary/nasal administration is permitted)
15. Investigational agents taken within the past 28 days (except with the expressed approval of 
the Sponsor)
16. Clinically-relevant alcohol or drug abuse within 12 months of screening.  A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator
17. Known hypersensitivity to the study drugs, the metabolites or formulation excipients
18. 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
19. Use of any prohibited concomitant medications as described in Section 5.6 within 28 days of 
the Day 1 visit
20. 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.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
Not applicable.
5.2.
Sofosbuvir
5.2.1.
Description and Handling
5.2.1.1.
Formulations
SOF tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets debossed with “GSI” on 
one side and “7977” on the other side. In addition to the active ingredient, SOF tablets contain 
the following inactive ingredients: mannitol, microcrystalline cellulose, croscarmellose sodium, 
colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, 
talc, and yellow iron oxide.
Placebo tablets for Swallowability Assessment, 400 mg, are yellow, capsule-shaped, film-coated 
tablets debossed with “GSI” on one side and “7977” on the other side. The tablets contain 
mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, and yellow iron oxide.
SOF tablets, 100 mg, are yellow, round, film-coated, plain-faced tablets. In addition to the active 
ingredient, SOF tablets contain the following inactive ingredients: mannitol, microcrystalline 
cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl
alcohol, titanium dioxide, macrogol, talc, and yellow iron oxide.
Placebo tablets for Swallowability Assessment, 100 mg, are yellow, round, film-coated, 
plain-faced tablets. The tablets contain lactose monohydrate, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, 
and yellow iron oxide.
SOF oral granules, 50 mg, are encapsulated in a two-piece, clear, hard gelatin capsule. In 
addition to the active ingredient, SOF capsules contain the following inactive ingredients: 
gelatin, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl 
cellulose, sodium stearyl fumarate, colloidal silicon dioxide, hypromellose, macrogol, amino 
methacrylate copolymer, stearic acid, sodium lauryl sulfate, and talc.
5.2.1.2.
Packaging and Labeling
SOF 400 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains either 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.


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Placebo tablets for Swallowability Assessment, 400 mg, are packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 30 tablets and a silica gel desiccant canister or 
sachet and polyester packing material. Each bottle is enclosed with a white, continuous thread, 
child-resistant screw cap with an induction-sealed, aluminum-faced liner.
SOF 100 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 28 tablets and a 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 for Swallowability Assessment, 100 mg, are packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 28 tablets and polyester packing material. 
Each bottle is enclosed with a white, continuous thread, child-resistant screw cap with an 
induction-sealed, aluminum-faced liner.
SOF capsules, 50 mg, which contain SOF oral granules, are packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 28 capsules and is enclosed with a white, 
continuous thread, child-resistant polypropylene screw cap with an induction-sealed and 
aluminum faced liner.
SOF bottles to be distributed to centers in the US, EU and the rest of the countries will 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.
Placebo tablets for Swallowability Assessment, 100 mg and 400 mg, bottles 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.
5.2.2.
Storage and Handling
SOF tablet, 100 mg and 400 mg, and capsule (containing granules) bottles should be stored at 
controlled room temperature until required for administration. Controlled room temperature is 
defined as 25 C (77 F); excursions are permitted between 15 C and 30 C (59 F to 86 F).
Placebo tablets for Swallowability Assessment, 100 mg and 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).  
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling SOF.


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Sufficient quantities of SOF tablets, SOF capsules containing granules 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 SOF
PK Lead-in: (Cohort 1) SOF 400 mg tablets will be administered once daily along with RBV 
weight-based dosing. Subjects determined unable to swallow the placebo for the 400 mg SOF 
tablet (by SOF Placebo swallowability assessment at Screening up to Day 1) will be re-assigned 
to 4 x 100 mg tablets daily.  Subjects unable to swallow tablets will be re-assigned to 8 x 50 mg 
capsules containing granules.  Subjects who weigh < 45 kg will be excluded.  
PK Lead-in:  (Cohort 2) SOF 200mg (2 x 100 mg tablets) will be administered once daily along 
with RBV weight-based dosing.  Subjects determined unable to swallow the placebo for the 
100 mg SOF tablet (by SOF Placebo swallowability assessment at Screening up to Day 1) will be 
re-assigned to 4 X 50 mg capsules containing granules.  Subjects who weigh outside of the 
≥17kg and < 45 kg range will be excluded
PK Lead-in: (Cohort 3) subjects weighing ≥17 kg will receive 200 mg SOF (4 x 50 mg capsules 
containing granules) + RBV weight-based dosing for 7 days. Subjects who weigh <17 kg will 
receive 150 mg SOF (3 x 50 mg capsules containing granules) + RBV weight-based dosing for 7 
days.  
Intensive PK and safety results from the PK Lead-In of each Cohort will be reviewed to confirm 
the appropriateness of the evaluated SOF 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.  
5.3.
Ribavirin 
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 


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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).
5.3.2.
Dosage and Administration of RBV
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 SOF. The evening dose of RBV will be 
taken with food.
RBV will be supplied by Gilead Sciences for all subjects.


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5.4.
Co-administration of SOF and RBV
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:

SOF

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 medication at the correct time, it may be taken later in the day; 
however, no more than the protocol specified dose of SOF 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.  
5.5.
Study Drug Compliance
Subjects will be instructed to return any unused SOF and RBV in the original container on Day 7 
(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 of Screening, up to and including the date of the 
visit four weeks after discontinuation of study treatment, need to be recorded in the source 
documents and eCRFs. All concomitant medications should be recorded in the source 
documents.
The following medications are prohibited from 28 days prior to the Day 1 visit through the end 
of treatment:

Erythropoiesis-stimulating agents (ESAs); including but not limited to Procrit®, Aranesp®
and Epogen®

Granulocyte colony stimulating factor (GCSF)

Chronic systemic immunosuppressant’s including corticosteroids (prednisone equivalent of 
> 10 mg/day for > 2 weeks), azathioprine, or monoclonal antibodies (e.g., infliximab)

Investigational agents or devices for any indication


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
Drugs disallowed per prescribing information of REBETOL®

Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters i.e. P-gp) with study drug(s) may result in pharmacokinetic interactions resulting 
in decreases in exposure of study drug(s). Representative medications which are excluded 
from 21 days prior to Day 1 through the end of treatment are listed below:
Drug
Agents Disallowed
Concomitant use with study drug may 
potentially result in changes of study 
drug concentration as listed below
Anticonvulsants
Phenobarbital, Phenytoin, Carbamazepine, 
Oxcarbazepine
Decrease in concentration of study drug
Antimycobacterials
Rifampin, rifabutine, rifapentine
Decrease in concentration of study drug
Herbal/Natural 
Supplements
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
Decrease in concentration of study drug
Medications for disease conditions excluded from the protocol (e.g., HIV-1 infection, active 
cancer, transplantation) are not listed under this Concomitant Medication section and are 
disallowed in the study.


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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 (i.e., height of parents, if known)
Liver biopsy results (if available)

Complete physical examination 

Vital signs (temperature, blood pressure, pulse, respiratory rate), body weight and height


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
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 SOF swallowability assessment (for subjects administered SOF in tablet form only)
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for the Day 1 visit assessments.


Sofosbuvir 
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6.3. 
PK Lead-in: Treatment Assessments 
6.3.1. 
Day l 
FINAL 
Amendment6 
After confnmation of eligibility has been evaluated, the following tests and procedmes must be 
completed prior to emollment and dosing/dispensing on Day 1: 
• 
Perf01m complete physical examination 
• 
Tanner Pubertal Stage Assessment 
• 
Vital signs, including body weight and height measmements 
• 
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 
prui icipants (Subjects 12 to < 18 yeru·s of age and subjects < 12 years of age at the discretion 
of the Investigator based on subject's pube1ial status) 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (ru·chive) 
_ 
PD 
• 
Obtain mine samples for the following procedmes: 
-
Urinalysis 
-
~ -hCG pregnancy test for females of childberu·ing potential only 
• 
Subject completes quality of life smvey: Subject is to review questionnaire with a 
parent/guardian and write/mru·k answers directly onto the questionnaire. 
CONFIDENTIAL 
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26 Febmaty 2016 


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6.3.1.1.
Drug Administration

Dispense study drugs as directed by the IWRS

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 all study drugs

Perform SOF swallowability assessment (for subjects administered SOF in tablet form only if
not previously completed at screening).  Observe the subject taking the first dose of study 
drugs (with 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 parent/guardian

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

Review subject dosing diary
6.3.3.
Day 7 – Intensive PK 
The Day 7 Intensive PK visit should occur on the protocol-specified visit date based on the 
Day 1 visit. For the purposes of scheduling, the Day 7 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).


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Subjects should come in a fasted state for the Day 7 Intensive PK visit (i.e., no food or drink 
except water at least 8 hours prior to the Day 7 Intensive PK visit). Subjects and/or 
parents/guardians should be instructed that the Day 7 dose of SOF+RBV must not be taken until 
the evaluations listed below are completed. 
If the subject has already dosed prior to the Day 7 clinic visit or is not in a fasted state, the Day 7
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 8, 9, or 10) 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 7 visit, the Day 7 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 7 intensive PK visit no sooner than 3 days following compliant dosing and no later than 
Day 11 (i.e., return on Day 10 or Day 11).  If dosing non-compliance is due to an AE, 
consultation with the Gilead Medical Monitor is required regarding the potential of rescheduling 
the Day 7 intensive PK visit.
In both scenarios described above, the subject and/or parents/guardians should be reminded not 
to take the SOF + RBV prior to arriving at the clinic on the day of the re-scheduled intensive PK 
visit. All Day 7 intensive PK assessments listed below should be completed when the subject 
returns.
The following evaluations are to be completed at the Day 7 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 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 
Coagulation tests


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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 
SOF + RBV per dosing requirements.
Post-dose blood samples will be collected as follows: 

For Cohorts 1 and 2:  0.5, 1, 2, 3, 4, 8, and 12 hours post-dose (with predose also 
serving as t= 24).

For Cohort 3 only: 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 7 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


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• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
pmi icipants (Subjects 12 to < 18 years of age and subjects <12 years of age at the discretion 
of the Investigator based on subject's pube1ial status). 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (m·chive) 
_ 
PD 
• 
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 
pm·ent/gum·dian and write/mark answers directly onto the questionnaire. 
• 
Perf01m SOF swallowability assessment (for subjects administered SOF in tablet f01m only if 
not previously completed at screening). 
• 
For subjects receiving SOF oral granules, following dmg adminisu·ation assess palatability 
at Day 1, as applicable 
6.4.1.1. 
Dmg Adminisu·ation 
• 
Dispense study mugs as directed by the IWRS 
• 
Instiuct the subject on the appropriate RBV dose after weight-based dosage is calculated 
using Day 1 weight 
• 
Instiuct the subject on the packaging, storage and adminisu·ation of all study dmgs 
• 
Observe the subject taking the first dose of study dmgs (with food) and record the time of 
first dose 
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6.4.2.
Weeks 1 and 2 (3 days)
Subjects who participated in the PK Lead-in will start study visits in 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

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 


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Amendment 6
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
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 drugs at these visits)

Dispense study drugs as directed by the IWRS
6.4.4.
Week 12 (3 days)

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 (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. (GT-2 Subjects 
only)

Review medication compliance with subject and/or parent/guardian.


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
Dispense study drugs as directed by the IWRS (GT-3 Subjects Only)

GT-2 Subjects should return all bottles and kits at the Week 12 Visit
6.4.5.
Week 16 and 20 (3 days) – GT-3 Subjects 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 drugs at these visits)

Dispense study drugs as directed by the IWRS
6.4.6.
Week 24 (3 days) – GT-3 Subjects 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)


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Amendment 6
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
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.

GT-3 Subjects should return all bottles and kits at the Week 24 Visit
6.4.7.
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.
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 (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)


Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6
CONFIDENTIAL
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26 February 2016

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 kits at the Early Termination Visit
All subjects should complete Post-Treatment assessments after early termination, as described in 
Section 6.5.
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


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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 (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) 
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 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

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 (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)


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Amendment 6
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
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)

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.
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 
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.


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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 right 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: Hemoglobin A1c (HbA1c), TSH (reflex Free T4), Alfa fetoprotein (AFP), 
Alpha-1 anti-trypsin (AAT), Urine drug screen (for amphetamines, cocaine, methadone, opiates).
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.
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.  Perform Tanner Pubertal Stage assessment 
for subjects until Tanner Stage 5 has been reached. 
6.6.5.
Height & Weight Measurement 
Height and weight measurement will be collected at all study visits.  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.


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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 the bone age from x-ray.
6.6.7.
Swallowability Assessment
A SOF 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 for the 400 mg SOF 
tablet. This will confirm the swallowability of the 400 mg tablet size. If, a subject is unable to 
swallow the 400 mg tablet size he/she will repeat the assessment with a placebo for the 100 mg 
SOF tablet.  If unable to take the 100 mg SOF tablet, the subject will be dispensed the SOF oral 
granule formulation.
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.
6.6.9.
Body Mass Index (BMI)
BMI is calculated by the following equation.
BMI = weight (pounds) 703           or            weight in kilograms
   (height in inches)2                                (height in meters)2
6.6.10.
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; for 
adolescent males ≥12 years old is 0.70, and for children 3- <12 years old is 0.55); L is height in 
centimeters (cm); and Scr is serum creatinine (mg/dL)]


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6.6.11.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each visit for viral sequence analysis. Unused 
samples may be archived.
6.6.12.
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. If required by 
local regulations, additional pregnancy tests beyond 6 months may be added. In the event of a 
positive urine pregnancy result, subjects will be instructed to stop study drugs immediately and 
return to the clinic as soon as possible for a serum pregnancy test.
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.
6.6.13.
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 (Week 12 for GT-2 subjects, Week 24 for GT-3 subjects, or at 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/guardian) for the current age group at the time of survey 
administration.  
6.6.14.
SOF Granule Palatability Assessment
A palatability assessment for the SOF granules will be performed at Day 1 to subjects receiving 
the granules.


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7.
TOXICITY MANAGEMENT
7.1.
Modification of Dose/Schedule Due to Toxicity
Dose reduction of RBV 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/day 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
Dose reduction in pediatric patients 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 SOF
The Gilead Medical Monitor should be consulted prior to dose discontinuation of SOF unless the 
investigator believes that immediate action is warranted to ensure the continued safety of the 
subject.
Administration of SOF may be discontinued due to a clinical or laboratory event. There is no 
option for SOF dose reduction. If SOF is stopped for toxicity, it should not be restarted, RBV 
should be stopped and the subject should complete an Early Termination Visit.
Subjects who meet any of the following laboratory criteria must stop treatment with SOF and 
RBV:

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 

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event or lab abnormality assessed as related to treatment with SOF


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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)

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

Persistent or significant disability/incapacity


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
A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is 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 subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the 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.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting.


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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 
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.
All SAEs, regardless of causal relationship, that occur 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 
from screening onwards.
All AEs, regardless of causal relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP 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 post-treatment follow up 
period.
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 this time and/or if 
patient is enrolled into the long term follow-up registry, GS-US-334-1113 study, and/or eCRF 
database has been locked and the event is deemed relevant to the use of IMP, he/she should 
promptly document and report the event directly to Gilead DSPH within 24 hours of awareness.
Gilead DSPH contact information is as follows: Email: Safety_FC@gilead.com or Fax: +1 (650) 
522-5477.  All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines 
outlined in the CRF/eCRF completion guideline.


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Serious Adverse Event Paper Repmiing Process 
FINAL 
Amendment6 
• 
All SAEs will be recorded on the serious adverse event repmi fmm and submitted by 
emailing or faxing the report fmm within 24 hours of the investigator's knowledge of the 
event to the attention of Gilead DSPH or to the designated CRO Phannacovigilance 
Representative. 
Electronic Serious Adverse Event (eSAE) Repmiing Process 
• 
All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit the SAE 
infmm ation 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 infmm ation electr·onically, i.e., the 
eCRF database is not ftmctioning, record the SAE on the paper serious adverse event 
repmiing fmm and submit within 24 hours as described above. 
• 
As soon as it is possible to do so, any SAE repmied via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been reported via a paper fonn because the eCRF database has been locked, no 
ftniher action is necessaty. 
Conta.ct infonnation is as follows: 
Gilead Sciences, Dmg Safety and 
Public Health: 
PRA Intemational 
Phrum acovigilance Representative: 
Klinera Phrum acovigilance 
Representative (India only): 
Gilead Sciences, Medical Monitor: 
CONFIDENTIAL 
Fax: 
E-mail: 
Fax: 
E-mail: 
Name: 
Phone: 
Fax: 
E-mail: 
Name: 
Telephone: 
Fax: 
E-mail: 
Page 65 
+ 1 650 522-5477 
Safety_ FC@gilead.com 
+1 888 772 6919 (Nmih America); 
+49 621 8782 181 (Rest of World 
CHOSafety@praintl.com 
Dr. Vikrrun Vora 
+91 22 25004573 (India) 
+91 22 25004588 
safetyrepmiing@klinera.com 
Theo Brandt-Sarif, MD, 
rpo 
rpo 
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
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.
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. 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 associate 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.


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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.  
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 the designated CRO Pharmacovigilance Representative using 
the pregnancy report form within 24 hours of becoming aware of the pregnancy.
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 8.1.1 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 CRO Pharmacovigilance Representative 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 drugs 
must also be reported and relevant information should be submitted to the CRO 
Pharmacovigilance Representative 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. 


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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 the designated CRO Pharmacovigilance Representative within 24 hours of the 
investigator becoming aware of the situation. These reports must consist of situations that 
involve study IMP and/or Gilead concomitant medications but do not apply to non-Gilead 
concomitant medications. 
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of contraindicated medications 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 SOF in 
HCV-infected pediatric subjects
The secondary objective of PK Lead-in of this study is:

To evaluate the safety and tolerability of 7 days of dosing of SOF + RBV in HCV-infected
pediatric subjects
The primary objective of Treatment Phase of this study is:

To evaluate the safety and tolerability of SOF + RBV for 12 or 24 weeks in HCV-infected
pediatric subjects with GT-2 or GT-3, respectively
The secondary objectives of Treatment Phase of this study are:

To determine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects separately, as assessed by the proportion of subjects with SVR 
12 weeks after completion of treatment (SVR12)

To determine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects separately, 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 SOF during treatment and after completion 
of treatment

To evaluate the palatability of SOF oral granules at Day 1, as applicable.

To evaluate the effect of growth and development of pediatric subjects during and after 
treatment.


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The explorat01y objective of this study is: 
• 
PD 
9.1.2. 
Primary Endpoints 
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For the PK Lead-in Phase, the appropriateness of the SOF dose will be assessed by evaluating 
the steady-state PK of the SOF and its metabolite GS-331007. The primruy endpoint is AUCtau 
of GS-331 007. Additional steady-state PK pru·ameters of SOF and GS-331 007 (e.g., AUC1ast, 
Cmax, Tmax, Clast, T1ast, Ctau, 'Az, CLIF, VzJF and tv, and AUCtau of SOF) will be estimated and 
summarized as described in Section 9.4. 
For Treatment Phase, the primary safety endpoint is any AE leading to pe1manent 
discontinuation of study dmg (s). The key efficacy endpoint is SVR12. 
9.1.3. 
Secondary Endpoints 
For the PK Lead-in Phase, the secondruy endpoints include antiviral activity measmements, 
including assessment ofHCV RNA. AEs leading to pe1manent discontinuation of study dmg(s) 
will be evaluated as a secondruy safety endpoint. 
For Treatment Phase, seconda1y efficacy endpoints include SVR4, SVR24, breakthrough and 
relapse. Additional efficacy evaluations may include HCV RNA change from Day 1; AL T 
n01malization; viral kinetic pru·ameters, and palatability of SOF oral granules. Seconda1y safety 
endpoints of growth and development measmements will be assessed (e.g. height, weight, and 
Tanner Stage Assessment). 
9.2. 
Analysis Conventions 
All individual subject data will be listed as measmed. All statistical summru1es and analyses will 
be perfonned using SAS® softwru·e (SAS Institute, Cruy, North Cru·olina, USA). 
9.2.1. 
Analysis Sets 
9.2.1.1. 
Phrumacokinetics (PK) Analysis Sets 
9.2.1.1.1. 
Intensive PK Analysis Set 
The intensive PK analysis set will include all PK Lead-in subjects who received at least one dose 
of study dmg and for whom at least one non-missing PK concentration data, dming the intensive 
srunpling period, reported by PK lab. The PK analysis set will be used for detailed 
phrumacokinetic analysis of SOF, and metabolites. 
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9.2.1.1.2.
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 SOF or GS-331007 are available. 
The PK analysis set will be used for analysis of general PK and single sample plasma
concentrations.
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. 


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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.
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 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 SOF and metabolites (GS-566500 and GS-331007) 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 


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summarized for 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 the exposures of GS-331007 achieved in pediatric subjects of this study are similar 
to the exposures observed in adult subjects, GS-331007 exposure data from this study will be 
compared to the integrated adult data by carrying out an analysis of variance (ANOVA) for 
log-transformed AUCtau of GS-331007 as the primary endpoint while Cmax of GS-331007 as 
secondary endpoints. 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%. Individual 
patient management will be performed by maintaining exposures comparable to adults.  AUCtau
less than the 2.5th percentile of adult values may require dose adjustment as appropriate.
The effect of age and SOF dose on PK (SOF and GS-331007) will be assessed.
9.5.
Safety Analysis
Safety analysis will be performed for PK Lead-in and overall study Treatment Phaserespectively. 
Safety data will be summarized by age group, by GT, by overall and by age group and GT.
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.
Palatability of SOF oral granules
Palatability of SOF oral granules will be summarized using descriptive statistics by appropriate 
age group, by genotype, by overall and by age group and genotype.


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9.5.3.
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,

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.
9.5.4.
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 


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data are missing, then any graded abn01mality (i.e., at least a Grade 1) will be considered 
treatment emergent. 
Alllaborat01y abn01malities will be included in the listings of laborat01y data. 
9.5.5. 
Other Safety Evaluations 
9.5.5.1. 
Tanner Pube1ial Stage Assessment 
Tanner Stages (Appendix 4) will be summarized by baseline Tanner Stage using frequency and 
percentage. 
9.6. 
Efficacy Analysis 
Efficacy will be evaluated using scheduled assessments of HCV RNA perf01med using CO BAS® 
TaqMan® HCV Test, v2.0 for use with the High Pure System. 
Efficacy analysis will be perf01med by age group, by GT, by overall, and by age group and GT 
for Treatment Phase. 
All continuous endpoints will be summarized using an 8-number summruy (n, mean, standru·d 
deviation, median, Q1, Q3, minimum, maximum). All categorical endpoints will be summru·ized 
by number and percentage of subjects who meet the endpoint defmition. 
9.6.1. 
Primary Efficacy Analysis 
The key efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
treatment) in the F AS population. Point estimate and its 95% confidence interval will be 
provided. 
9.6.2. 
Secondary Efficacy Analysis 
The key efficacy endpoint of SVR12 will be compared with historical SVR12 rate of 80% from 
pegylated interferon + ribavirin for pediatric GT2 and 3 subjects {20280}, using two-sided exact 
one-sample binomial test at the 0.05 significance level. 
The proportion of subjects with HCV RNA below LLOQ over time (including SVR endpoints 
SVR4 and SVR24) will be presented in Treatment Phase in tabular and graphical fonn. 
Descriptive summru·ies and listings will be provided for additional efficacy evaluations including 
serum HCV RNA actual values and change from baseline, prop01iion of subjects with virologic 
failmes, and other endpoints of interest including AL T n01malization. 
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Subgroup analysis on SVR12 will be perf01m ed by treatment experience (treatment-naive vs. 
experienced), and by treatment experience and 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 extemal multidisciplinruy data monitoring committee (DMC) will review the progress of the 
study and perf01m interim reviews of safety and provide recommendation to Gilead about 
whether the nature, frequency, and severity of adverse effects associated with study u·eatment 
wruTant the eru·ly te1mination of the study in the best interests of the pruiicipants, whether the 
study should continue as planned, or the study should continue with modifications. 
The DMC's specific activities will be defmed by a mutually agreed chruier, which will defme the 
DMC's membership, conduct and meeting schedule. 
While the DMC will be asked to advise Gilead regru·ding future conduct of the study, including 
possible eru·ly study tennination, Gilead retains fmal decision-making authority on all aspects of 
the study. 
9.9. 
Sample Size 
With approximately 50 subjects enrolled into each age group of Treatment Phase, a two-sided 
95.0% confidence interval of the SVR12 rate will extend at most 11.1% in both directions from 
the observed SVR12 rate, assuming the expected SVR12 rate is 80%. In addition, a saiUple size 
of 100 subjects will provide over 80% power to detect an 11% improvement in SVR12 rate from 
80% to 91% using two-sided one-sample binomial test at significance level of 0.05. 
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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.


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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);

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.


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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 
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.


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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 competent 
authority, IRB or IEC in accordance with local requirements. Approval must be obtained before 
changes can be implemented.
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.


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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.
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.
20280
Schwarz KB, Gonzalez-Peralta RP, Murray KF, Molleston JP, Haber BA, Jonas 
MM, et al. The combination of ribavirin and peginterferon is superior to 
peginterferon and placebo for children and adolescents with chronic hepatitis C. 
Gastroenterology 2011;140 (2):450-8 e1.


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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.
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.
23275
Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. 
Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J 
Med 2013;368 (1):34-44.
24713
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, 
Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients 
without treatment options. N Engl J Med 2013;368 (20):1867-77.
24715
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et 
al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J 
Med 2013;368 (20):1878-87.
27503
Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US 
Prescribing Information.  Foster City, CA. December 2013.  2013:
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


Sofbsbuvh· 
ProtQc:nl OS·J.JS-334·1 r 1.2 
ttlNAL 
Ollead Sclenocs, Inc 
Amcndm0nt (j 
Appendix 1. 
Investigator Slgnatut'~ Page 
I 
GILEAD SCIENCES, lNC. 
333 I.AKESIDE DRIVE 
:FOS'fER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2. Open-Label, Multicenter, Multi-cohort, Slngle-AI'm Study to Investigate the 
Safety a.nd Efficacy of Sofo•buv:ir + R.Jbav.lrln In Adolescents and Children wtth Genotype 2 
· 
or 3 Ch•·onlc flCV lnfcction 
GS~US..334 .. 1111! :Protoool Amendment 6, 26 Feba·unry 2016 
This protocol baa been approvod by Ollead Sciences, Inc. The following idgnature daaumat1ts 
this approval. 
/) 
; 
P O 
1 Vo o,....,. u~ >;,:..., ~ 
TI1e0 ~raudt-Sttrif. MD (Printed) 
Modica.) Monitor 
Date 
INVESTIGATOR STAT.Ji:MENT 
I bave read the protocol, including a~l app~diceat and I aA.gree that it contains all necessary 
d&taits for me and my stRffto conduot this study as desscribed. l will conduct this study as 
out1ined herein and will make a rea.spna.ble eftbrt to oo.oo.pltt~ the study witbill the thne 
designated. 
: 
I will p.rovid8 atl study personnel under my supcrvjsion copies of tlle protocol and accus to ali 
information provided by Gilead Sciences, Inc. I will discuss this IW\tedal wilh them to el'l.Suro 
that they are flJUy infonned ab~t the- drugs nnd the study. 
Principal Investigator Name (Pdnted) 
Signature 
Date 
Site NUJJ:J.be.r 
CONFIDENTIAL 
PageS6 


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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 7
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
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
SOF Swallowability Assessment
X
Xh
Quality of Life Survey
Xi
Review of Study 
Medication Compliance
X
X
Study Drug Dispensingb
X


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Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 7
(+ 3 days)
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X
X
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
Subject Dosing Diary
X
X
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
Palatability Assessment of Oral GranulesJ
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, body weight, and height
PPD


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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 drugs on Day 7 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 8, 
and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 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 (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).
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
Palatability of SOF oral granules will be assessed at Day 1, applicable.
PPD


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Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningc
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12g
16g
20g
24g
Early 
Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Complete Physical Examination
X
X
X
X
X
Symptom-Directed Physical Examination
X
X
X
X
X
X
Tanner Pubertal Stage Assessment
X
X
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 Counselingh
X
X
X
X
SOF Swallowability Assessment
X
Xj
Quality of Life Surveye
X
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
X
X
X
Study Drug Dispensingb
X
X
X
Xi
Xi
Xi


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Screeningc
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12g
16g
20g
24g
Early 
Termination
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
Viral Sequencing d
X
X
X
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testing
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
X
X
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
Palatability Assessment of Oral Granulesk
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, 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 at Day 1, Week 12 (only GT-2 subjects), Week 24 (only GT-3 subjects) and Early Termination 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
GT-2 subjects will complete through the Week 12 visit; GT-3 subjects will complete through the Week 24 visit. 
PPD
PPD


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h
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).
i
Study Drug Dispensing at the Week 12, Week 16, and Week 20 visit for GT-3 subjects only
j
Swallowability can occur at Day 1 if not completed during screening.
k
Palatability of SOF oral granules will be assessed at Day 1, applicable.


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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
Xd
Xd
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment 
X
X
Bone Age Assessment
X
Pregnancy Prevention Counseling e
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Testc
X
X
X
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
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.
d
At Post Treatment Week 12 and 24, only SAEs will be captured
e
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).


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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


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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
—
—


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Amendment 6.0
CONFIDENTIAL
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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.  


Sofosbuvir
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Gilead Sciences, Inc
Amendment 6.0
CONFIDENTIAL
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant  <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 to <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant  <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L


Sofosbuvir
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Gilead Sciences, Inc
Amendment 6.0
CONFIDENTIAL
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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


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Gilead Sciences, Inc
Amendment 6.0
CONFIDENTIAL
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26 February 2016
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


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Gilead Sciences, Inc
Amendment 6.0
CONFIDENTIAL
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26 February 2016
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


Sofosbuvir
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Gilead Sciences, Inc
Amendment 6.0
CONFIDENTIAL
Page 101
26 February 2016
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.  


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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years 
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


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Amendment 6.0
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26 February 2016
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(e.g., 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 
(e.g., 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 
(e.g., tamponade) OR Urgent 
intervention indicated


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


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Amendment 6.0
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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 [e.g., tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (e.g., 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 
(e.g., sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(e.g., 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 
(e.g., 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 (e.g., aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (e.g., 
IV fluids)
Life-threatening consequences 
(e.g., hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(e.g., sepsis, circulatory 
failure, hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(e.g., perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(e.g., hypotensive shock)


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


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


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


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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 [e.g., 
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 (e.g., upper 
arm/thigh)
Erythema OR Induration 
OR Edema involving 
50% surface area of the 
extremity segment (e.g., 
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 (e.g., 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 
(e.g., 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 
(e.g., 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 
(e.g., myxedema coma)
Lipoatrophy (e.g., 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 (e.g., stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing life-
threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic antiμbial 
treatment indicated AND 
Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening 
consequences (e.g., septic 
shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc


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Appendix 4.
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}


Sofosbuvir
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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 sofosbuvir demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of sofosbuvir 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:

Complete abstinence from intercourse. Abstinence is an acceptable method of contraception 
only when it is in line with 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 the last dose of RBV:
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent
tubal sterilization
vasectomy in male partner


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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 Baseline 
until 7 months after the last dose of 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.
Male subjects must agree to refrain from sperm donation for at least 7 months after the last dose 
of 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. 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.

Prot_000.pdf: 
Study Title: 
Sponsor: 
IND No.: 
EudraCT Number: 
Indication: 
Protocol ID: 
Gilead Sciences Medical 
Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Aim 
Study to Investigate the Safety and Efficacy of Sofosbuvir + 
Ribavirin in Adolescents and Children with Genotype 2 or 3 
Chronic HCV Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
106,739 
TBD 
Hepatitis C Vims Infection 
GS-US-334-1112 
Name: 
Telephone: 
Mobile: 
Fax: 
E-mail: 
Original: 
Luisa Stamm, MD, PhD 
FPD 
l PD 
PD 
t-'U 
20 December 2013 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, patticularly lmpublished data, is the prope1ty 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 Bom·d or Independent Ethics Committee. The inf01mation is 
only to be used by you in connection with authorized clinical studies of the investigational 
dmg described in the protocol. You will not disclose any of the infonnation to others without 
written authorization from Gilead Sciences, Inc., except to the extent necessaty to obtain 
inf01med consent from those persons to whom the dmg may be administered. 


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TABLE OF CONTENTS
TABLE OF CONTENTS .......................................................................................................................................2
LIST OF IN-TEXT FIGURES ...............................................................................................................................4
PROTOCOL SYNOPSIS .......................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................14
1.
INTRODUCTION .......................................................................................................................................17
1.1.
Background.....................................................................................................................................17
1.2.
Sofosbuvir.......................................................................................................................................18
1.3.
Ribavirin (RBV)..............................................................................................................................19
1.4.
Rationale for the Current Study ......................................................................................................19
1.5.
Rationale for Dose Selection of SOF ..............................................................................................20
1.6.
Overall Risk/Benefit Assessment....................................................................................................20
2.
OBJECTIVES..............................................................................................................................................22
3.
STUDY DESIGN ........................................................................................................................................23
3.1.
Treatment Plan and Regimen..........................................................................................................23
3.1.1.
Part A ............................................................................................................................23
3.1.2.
Part B ............................................................................................................................23
3.2.
Visit Schedule .................................................................................................................................25
3.2.1.
Part A ............................................................................................................................25
3.2.2.
Part B ............................................................................................................................26
3.3.
Virologic Response-Based Stopping Criteria..................................................................................26
3.4.
Treatment Discontinuations Criteria...............................................................................................27
3.5.
Discontinuations .............................................................................................................................27
3.6.
Pharmacogenomic Substudy...........................................................................................................27
3.7.
Long Term Follow Up ....................................................................................................................27
4.
SUBJECT POPULATION...........................................................................................................................28
4.1.
Number of Subjects and Subject Selection .....................................................................................28
4.2.
Inclusion Criteria ............................................................................................................................28
4.3.
Exclusion Criteria ...........................................................................................................................28
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ....................................................................................30
5.1.
Randomization and Blinding...........................................................................................................30
5.2.
Sofosbuvir.......................................................................................................................................30
5.2.1.
Description and Handling..............................................................................................30
5.2.2.
Storage and Handling....................................................................................................30
5.2.3.
Dosage and Administration of SOF ..............................................................................31
5.3.
Ribavirin .........................................................................................................................................31
5.3.1.
Description and Handling of RBV................................................................................31
5.3.2.
Dosage and Administration of RBV .............................................................................32
5.4.
Co-administration of SOF and RBV...............................................................................................32
5.5.
Study Drug Compliance..................................................................................................................33
5.6.
Prior and Concomitant Medications................................................................................................33
6.
STUDY PROCEDURES .............................................................................................................................35
6.1.
Subject Enrollment..........................................................................................................................35
6.2.
Screening Assessments ...................................................................................................................35
6.2.1.
Screening Visit (Day –28 to Day 0)..............................................................................35


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6.3.
Part A: Treatment Assessments ......................................................................................................37
6.3.1.
Day 1 Visit ....................................................................................................................37
6.3.2.
Day 3.............................................................................................................................38
6.3.3.
Day 7 – Intensive PK ....................................................................................................38
6.4.
Part B: Treatment Assessments.......................................................................................................40
6.4.1.
Day 1 Visit ....................................................................................................................40
6.4.2.
Weeks 1 and 2 (3 days)..............................................................................................41
6.4.3.
Weeks 4 and 8 (3 days)..............................................................................................42
6.4.4.
Week 12 (3 days) .......................................................................................................42
6.4.5.
Week 16 and 20 (3 days) – GT-3 Subjects only.........................................................43
6.4.6.
Week 24(3 days) – GT-3 Subjects only .....................................................................44
6.4.7.
Unscheduled Visit/Early Termination Visit ..................................................................45
6.5.
Post-Treatment Assessments...........................................................................................................46
6.5.1.
4-Week Post-Treatment Visit (5 days).......................................................................46
6.5.2.
12-Week Post-Treatment Visit (5 days).....................................................................46
6.5.3.
24-Week Post-Treatment Visit (5 days).....................................................................47
6.6.
Procedures and Specifications.........................................................................................................48
6.6.1.
Clinical Laboratory Analytes ........................................................................................48
6.6.2.
Medical History.............................................................................................................48
6.6.3.
Complete Physical Examination ...................................................................................48
6.6.4.
Tanner Pubertal Stage Assessment................................................................................49
6.6.5.
Vital Signs.....................................................................................................................49
6.6.6.
Body Mass Index (BMI) ...............................................................................................49
6.6.7.
Viral Sequencing (Archive) ..........................................................................................49
6.6.8.
Pregnancy Testing.........................................................................................................49
6.6.9.
Quality of Life Survey (PedsQL™)................................................................................49
7.
TOXICITY MANAGEMENT.....................................................................................................................50
7.1.
Modification of Dose/Schedule Due to Toxicity ............................................................................50
7.1.1.
RBV Dose Adjustments ................................................................................................50
7.2.
Subject Stopping Rules for SOF .....................................................................................................50
8.
ADVERSE EVENTS MANAGEMENT.....................................................................................................51
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events..........................51
8.1.1.
Adverse Events..............................................................................................................51
8.1.2.
Serious Adverse Events.................................................................................................51
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events..............................................................52
8.2.
Assessment of Adverse Events and Serious Adverse Events..........................................................52
8.2.1.
Assessment of Causality for Study Drugs and Procedures............................................52
8.2.2.
Assessment of Severity .................................................................................................53
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events ...............................................................................................................................53
8.4.
Gilead Reporting Requirements......................................................................................................55
8.5.
Special Situations Reports ..............................................................................................................55
8.5.1.
Definitions of Special Situations...................................................................................55
8.5.2.
Instructions for Reporting Special Situations................................................................56
9.
STATISTICAL CONSIDERATIONS.........................................................................................................58
9.1.
Analysis Objectives and Endpoints.................................................................................................58
9.1.1.
Analysis Objectives.......................................................................................................58
9.1.2.
Primary Endpoint ..........................................................................................................59
9.1.3.
Secondary Endpoints.....................................................................................................59


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9.2.
Analysis Conventions .....................................................................................................................59
9.2.1.
Analysis Sets.................................................................................................................59
9.2.2.
Data Handling Conventions ..........................................................................................60
9.2.3.
Interim Analysis............................................................................................................61
9.3.
Demographic Data and Baseline Characteristics ............................................................................61
9.4.
Pharmacokinetic Analysis...............................................................................................................62
9.5.
Efficacy Analysis............................................................................................................................62
9.5.1.
Primary Analysis...........................................................................................................62
9.5.2.
Secondary Analysis.......................................................................................................62
9.5.3.
Subgroup Analysis ........................................................................................................63
9.6.
Safety Analysis ...............................................................................................................................63
9.6.1.
Extent of Exposure........................................................................................................63
9.6.2.
Adverse Events..............................................................................................................63
9.6.3.
Laboratory Evaluations .................................................................................................64
9.6.4.
Other Safety Evaluations...............................................................................................64
9.7.
Data Monitoring Committee ...........................................................................................................65
9.8.
Sample Size.....................................................................................................................................65
10.
RESPONSIBILITIES ..................................................................................................................................66
10.1.
Investigator Responsibilities ...........................................................................................................66
10.1.1.
Good Clinical Practice ..................................................................................................66
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) Approval..............................................................................................................66
10.1.3.
Informed Consent/Assent..............................................................................................67
10.1.4.
Confidentiality ..............................................................................................................67
10.1.5.
Study Files and Retention of Records...........................................................................67
10.1.6.
Case Report Forms........................................................................................................69
10.1.7.
Drug Accountability......................................................................................................69
10.1.8.
Inspections ....................................................................................................................69
10.1.9.
Protocol Compliance.....................................................................................................69
10.2.
Sponsor Responsibilities.................................................................................................................70
10.2.1.
Protocol Modifications..................................................................................................70
10.2.2.
Study Report and Publications ......................................................................................70
10.3.
Joint Investigator/Sponsor Responsibilities ....................................................................................70
10.3.1.
Access to Information for Monitoring...........................................................................70
10.3.2.
Access to Information for Auditing or Inspections .......................................................71
10.3.3.
Study Discontinuation...................................................................................................71
11.
REFERENCES ............................................................................................................................................72
12.
APPENDICES .............................................................................................................................................74
Appendix 1.
Investigator Signature Page...........................................................................................75
Appendix 2.
Study Procedures Table.................................................................................................76
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities .............................................................................................81
Appendix 4.
Tanner Stages..............................................................................................................104
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements ................................................................105
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema................................................................................................................25


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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, Single-Arm 
Study to Investigate the Safety and Efficacy of Sofosbuvir + 
Ribavirin in Adolescents and Children with Genotype 2 or 3
Chronic HCV Infection
IND Number:
EudraCT Number:
106,739
TBD
Study Centers:
Approximately 50 sites in the United States, Europe, Russia, 
Australia, and New Zealand
Number of Subjects:
Approximately 100 subjects
Target Population:
Adolescents and children (aged 3 to < 18) with chronic hepatitis C 
virus (HCV) infection
Treatment Duration:
Part A – 7 days
Part B – 12 or 24 weeks
Objectives:
The primary objective of Part A of this study is:

To evaluate the steady state pharmacokinetics (PK) and 
confirm the dose of sofosbuvir (SOF) in HCV-infected 
pediatric subjects
The secondary objective of Part A of this study is:

To evaluate the safety and tolerability of 7 days of dosing of 
SOF in HCV-infected pediatric subjects
The primary objectives of Part B of this study are:

To evaluate the safety and tolerability of SOF + ribavirin 
(RBV) for 12 or 24 weeks in HCV-infected pediatric subjects
with genotype 2 or 3, respectively

To determine the antiviral efficacy of SOF+RBV treatment in 
genotype 2 and genotype 3 HCV-infected subjects separately, 
as assessed by the proportion of subjects with SVR 12 weeks 
after completion of treatment (SVR12)


Sofosbuvir 
Protocol GS-US-334-1112 
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Study Design: 
CONFIDENTIAL 
The seconda!y objectives ofPrui B of this study ru·e: 
Final 
Original 
• 
To detennine the antiviral efficacy of SOF+RBV u·eatment in 
genotype 2 and genotype 3 HCV -infected subjects sepru·ately, 
as assessed by the prop01iion of subjects with SVR 4 and 
24 weeks after completion ofu·eatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA dming 
u·eatment and after completion of u·eatment 
• 
To evaluate the emergence of viral resistance to SOF dming 
u·eatment and after completion of u·eatment 
The explorat01y objective of this study is: 
• 
PO 
Open-label, multi-coh01i, two-part study evaluating the PK, safety, 
and antiviral activity ofSOF in chronic HCV-infected pediau·ic 
subjects. 
The study will be divided into 2 patis as follows: 
Part A: Part A (PK lead-in) will evaluate and/or confitm age 
appropriate SOF doses by analyzing PK, safety, and antiviral 
activity of SOF through 7 days of dosing for each of three coh01is. 
Children aged 3 to 6, children aged 6 to < 12 yeru·s and adolescents 
aged 12 to < 18 yeru·s with genotype (GT) 2 or 3 HCV infection 
and evidence ofHCV RNA > 1000 IU/mL at study ently will be 
evaluated. 
Three coh01is of up to 10 subjects each will be sequentially 
emolled: 
• 
Cohort 1: 12 to < 18 yeru·s old weighing ~ 45kg 
• 
Coh01i 2: 6 to < 12 yeru·s old 
• 
Coh01i 3: 3 to < 6 yeru·s old 
The study will start with Coh01i 1. Subjects will receive SOF 
( 400-mg adult tablet or 4 x 1 00-mg tablets if detennined necessruy 
based on SOF swallowability assessment) for 7 days with intensive 
PK conducted on Day 7. 
Subjects in each coh01i (Coh01is 1, 2 and 3) will immediately 
emoll in Prui B as they complete Day 7 of Prui A. They will begin 
dosing with SOF + RBV with no intenuption of study dmg 
adminisu·ation. 
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Following completion of study treatment in Cohort 1 (Part A) and 
pending PK and safety results from Cohort 1 (Part A), Cohort 2
will initiate and receive study treatment (age-appropriate 
formulation). Following completion of study treatment in Cohort 2
(Part A) and pending PK and safety results from Cohort 2 (Part A), 
Cohort 3 will receive study treatment (age-appropriate 
formulation). 
Part B: Part B will be initiated by dose cohort after confirmation 
of age-appropriate SOF dosage levels. Subjects who participated in 
Part A will immediately rollover into Part B (Day 1), with no 
interruption of study drug administration:
Children aged 3 to < 12 years and adolescents aged 12 to 
< 18 years with GT-2 or GT-3 infection and evidence of HCV 
RNA > 1000 IU/mL at study entry (those who were dosed in 
Part A will have met this criteria prior to enrollment) will be 
evaluated. 
Subjects enrolled in Part B will receive the following regimen.

GT-2 subjects: SOF + RBV for 12 weeks

GT-3 subjects: SOF + RBV for 24 weeks
The study will enroll both treatment-naïve and 
treatment-experienced pediatric subjects, with up to 20 subjects 
allowed to be treatment experienced. Approximately 100 total 
subjects, including subjects from Part A, will be enrolled in Part B 
as follows

Group 1: Approximately 50 adolescent subjects (12 to 
< 18 years of age)

Group 2: Approximately 50 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)


Sofosbuvir 
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Substudy and 
Long-Te1m 
Follow-Up Study: 
Final 
Original 
The study schedule contains the following visits: Screening, Day 1, 
Weeks 1, 2, 4, 8, 12 (and Weeks 16, 20, and 24 for GT-3) 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. 
Pharmacogenomics (PG) Substudy 
PO 
Long-Term Follow-up 
Subjects who attain SVR24 or those who do not attain SVR24 and 
do not initiate experimental or approved anti-HCV therapy will be 
followed eve1y 6 months for assessments of growth, quality of life, 
and long-te1m viral suppression (if applicable) in a separate 
protocol. This follow-up will continue for 5 years. 
Diagnosis and Main Chronic HCV-infected, treatment-naive and up to 20 subjects may 
Eligibility Criteria: 
be treatment experienced, male and female subjects aged 3 to < 18. 
CONFIDENTIAL 
Inclusion Criteria: 
• 
Documented chronic GT 2 or 3 HCV infection 
• 
HCV RNA~ 1000 IU/mL at Screening 
• 
Part A only: subjects in coh01i 1 (age 12 to <18 years of age) 
must weigh ~ 45kg 
• 
Agree to use 2 fonns of highly effective contraception, as 
referenced in Appendix 5, for the duration of the study and for 
6 months (for female subjects) or 7 months (for male subjects) 
after the last dose of study medication if age, cultural, and 
sexual activity status appropriate ( eg: if sexually active; does 
not pe1iain to pre-pube1ial subjects). Females of childbearing 
potential (as defined in Appendix 5) must have a negative 
pregnancy test at Screening and Day 1. 
Exclusion Criteria: 
• 
Hematologic or biochemical parameters at screening outside 
the protocol-specified requirements 
• 
HIV, acute hepatitis A vims (HA V) or chronic HBV infection 
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
Decompensated liver disease

Hepatocellular carcinoma or other malignancy (with exception 
of certain resolved skin cancers)

Chronic liver disease of a non-HCV etiology 
(eg, hemochromatosis, Wilson’s disease, alpha-1 antitrypsin 
deficiency)

Chronic use of systemic immunosuppressive agents or
immunomodulatory agents

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.
See Sections 4.2 and 4.3 of the protocol for full eligibility criteria.
Study Procedures/
Frequency:
Part A: 
Screening assessments will be completed within 28 days of the 
Day 1 visit. 
Screening assessments will include: physical examination, vital 
signs (including height and weight), Tanner Pubertal Stage 
assessment, concomitant medications, safety laboratory tests, 
coagulation tests, HCV RNA, serology (HIV, HAV, HCV, HBV), 
alpha-1 anti-trypsin, serum β-human chorionic gonadotropin hCG 
(females of childbearing potential only), thyroid stimulating 
hormone, HbA1c, IL28B genotyping, alpha fetoprotein, urinalysis, 
and urine drug screen.
Study Visits will occur at Screening, Day 1, Day 3, and Day 7
On-Treatment assessments include adverse events (AEs), 
concomitant medications, physical examination, vital signs, height, 
weight, safety laboratory tests, HCV RNA, viral sequencing 
sampling, urine pregnancy tests (females of child bearing potential 
only), and urinalysis. Coagulation will be performed at Day 1 only.
SOF swallowability assessment will be performed on Day 1 for a 
subject’s ability to swallow the 400 mg SOF tablet (only subjects 
administered SOF in tablet form).
Subjects (up to 10 subjects) enrolled in Part A will participate in an 
intensive PK evaluation on Day 7. Following completion of the 
Day 7 intensive PK visit, subjects will then return for scheduled 
study visits outlined in Part B and begin dosing with SOF + RBV
with no interruption of study drug administration.


Sofosbuvir 
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CONFIDENTIAL 
Part B: 
Final 
Original 
Screening assessments will be completed within 28 days of the 
Day 1 visit. For subjects continuing from Patt A, screening for 
Patt B will not be required. 
Screening assessments will include physical examination, vital 
signs, concomitant medications, safety laborat01y tests, HCV 
RNA, serology (HIV, HA V, HCV, HBV), alpha-1 anti-1lypsin 
sennn ~-human chorionic gonadou·opin hCG (females of 
childbem·ing potential only), thyroid stimulating h01mone, IL28B 
genotyping, urinalysis, and urine dmg screen. 
• 
GT-2 Subjects: Study visits for GT-2 subjects will occur at 
screening, Day 1, and the end of Weeks 1, 2, 4, 8, and 12. 
• 
GT-3 Subjects: Study visits for GT-3 subjects will occur at 
screening, Day 1, and the end of Weeks 1, 2, 4, 8, 12, 16, 20, 
and 24. 
All Pali B subjects will then retu.m for follow-up visits at 4, 12 and 
24 weeks after discontinuation of therapy. 
On-u·ea1:Inent assessments will include adverse events, concomitant 
medications, physical examination, vital signs (including height 
and weight), safety laborat01y tests, coagulation tests, HCV RNA, 
PK samples, and urine pregnancy tests (females of childbearing 
potential only). Rates of growth (height and weight percentiles) 
and Tanner Pube1tal Stage assessment will be assessed at Day 1, 
end ofu·ea1:Inent, post-u·ea1:Inent Week 12 and at the end of the 
24-week follow-up phase; parental heights will be recorded at 
Day 1. When available, results from liver biopsies perf01med 
within 2 years prior to screening will be collected at Day 1. SOF 
swallowability assessment will be perf01med on Day 1 for a 
subject's ability to swallow the 400 mg SOF tablet (all subjects 
administered SOF in tablet f01m). 
Post-u·eatment assessments will include adverse events, 
concomitant medications, vital signs, safety laborat01y tests, HCV 
RNA, and urine pregnancy tests (females of childbearing potential 
only). Samples for viral RNA sequencing/phenotyping will be 
collected at Day 1 and eve1y visit thereafter. 
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Test Product, Dose, 
and Mode of 
Administration:
Age group 12 to < 18 years: 
Part A: (Cohort 1) SOF 400-mg tablets will be administered once 
daily. Subjects determined unable to swallow the 400-mg tablet 
(by SOF swallowability assessment at Day 1 or at any time during 
the study) will be re-assigned to 4 x 100-mg tablets daily.  Subjects 
who weigh <45 kg are excluded from this age group in Part A.
Part B: SOF 400-mg tablets will be administered once daily for 
subjects who weigh ≥ 45 kg. Subjects determined unable to 
swallow the 400-mg tablet (by SOF assessment at Day 1 or at any 
time during the study) will be re-assigned to 4 x 100-mg tablets 
daily. For subjects in this age group who weigh < 45 kg, PK data 
from part A will be used to determine the appropriate dose of SOF 
to be administered.   
Subjects who participated in Part A will continue the assigned dose 
in Part B.
Age group 3 to < 12 years: 
(Part A and Part B) SOF age-appropriate formulation will be 
administered once daily with a dose and formulation to be 
determined. 
RBV Weight-Based Dosing (All age groups):
The RBV dose is:

15 mg/kg divided BID for subjects with weight below 50 kg

400 mg BID for subjects weighing  ≥ 50 to less than 65 kg

400 mg q AM and 600 mg q PM (i.e., 1,000 mg Total Daily 
Dose) for subjects weighing ≥ 65 kg to less than 75 kg

600 mg BID for subjects with weights greater than 75 kg.
The morning dose of RBV will be taken with an age-appropriate 
dose of SOF with food. The evening dose of RBV will be taken 
with food.
Reference Therapy:
None
Evaluation Criteria:
Safety:
AEs, laboratory tests, and Tanner Pubertal Stage assessments will 
be collected throughout the study. 
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV 
RNA performed using COBAS® AmpliPrep/COBAS® TaqMan®
HCV Test.


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PK:
For subjects in Part A, steady-state PK of SOF and its major 
metabolites GS-566500 and GS-331007 will be assessed at Day 7.
For Cohorts 1 and 2, plasma samples will be collected for PK 
analyses following dosing of study drugs on Day 7 at the following 
time points: 0 (predose), 0.5, 1, 2, 3, 4, 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), 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 subjects in Part B, a single PK blood sample will be collected 
at all visits while on treatment for all subjects. The PK of SOF, 
GS-566500 and GS-331007 and/or ribavirin will be assessed.
The effect of age and SOF dose on PK (SOF and GS-331007) will
be explored. 
Statistical Methods:
For Part A, plasma PK parameters Cmax, Tmax, Clast, Tlast, 
CtauAUCtau, and T1/2 will be estimated.The PK parameters will be 
summarized by cohort. The effect of age and SOF dose on PK 
(SOF and GS-331007) will be explored.
For Part B, the primary efficacy endpoint is SVR12 in all enrolled 
and treated subjects. Secondary endpoints are SVR4, SVR24, 
breakthrough and relapse. Efficacy endpoints will be summarized 
by age group and genotype.  Point estimate and its 95% confidence 
interval will be provided. 
Subgroup analysis on SVR24 and SVR12 will be performed by 
treatment experience (treatment-naive vs. experienced) and by 
treatment experience and genotype. 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). 
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.
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 treatment group.


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With approximately 50 subjects enrolled into each age group of 
Part B, a two-sided 95.0% confidence interval of the SVR12 rate 
will extend at most 11.1% in both directions from the observed 
SVR12 rate, assuming the expected SVR24 rate is 80%.
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
β-hCG
β-human chorionic gonadotropin
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)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BW
body weight
CLcr
creatinine clearance
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)
CMH
Cochran-Mantel-Haenszel
COPD
Chronic obstructive pulmonary disease
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
Emax
maximal effect
EU
European Union
EVR
Early virologic response
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
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
IV
Intravenous
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDH
Lactase dehydrogenase
LLN
lower limit of the normal range
LLOD
Lower limit of detection
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


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
QD
once daily (use only in tables)
QTcF
QT interval corrected using Fridericia’ formula
RBC
Red blood cell count 
RBV
Ribavirin
RDRP
RNA-dependent RNA polymerase
RNA
ribonucleic acid
RVR
rapid virologic response 
SADR
Serious adverse drug reaction
SAE
serious adverse event
SD
Standard deviation
SOC
Standard of Care
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TND
Target not detected
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 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 standard of care 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.
Novel anti-hepatitis C treatments under study are directed against a variety of molecular 
targets, which include the virally encoded RNA-dependent RNA polymerase (RDRP, NS5B) 
and proteases (NS2 and NS3). Some of the most consistently effective antivirals have been 
nucleoside/tide analogs. These compounds share characteristics with the natural nucleoside 
substrates found in the cell, and once phosphorylated to the nucleoside-triphosphate, cause 
termination of the newly encoded viral genome.
SOF is a novel nucleotide analogue that inhibits HCV RNA replication in vitro and has 
demonstrated efficient inhibition of viral replication in in vitro and in vivo studies.. 
Furthermore, even in subjects who did experience off-treatment viral breakthrough, 
population sequencing revealed no treatment-emergent S282T mutations. No adverse effects 
on the nervous, cardiovascular, or respiratory systems have been observed, and no specific 
target organs of toxicity have been identified in long-term toxicology studies. Available 
clinical data indicate SOF has a favorable safety profile and is well tolerated.
Based on its observed safety and efficacy in adult patients with HCV, SOF has the potential 
to be a safe, tolerable, and effective treatment for HCV infection in the pediatric population.
1.2.
Sofosbuvir
Sovaldi™(Sofosbuvir) is a potent nucleotide analogue that inhibits HCV RNA replication in 
vitro and has demonstrated high rates of sustained viral response (SVR) when given with 
RBV +/- PEG to subjects with chronic GT- 1, 2, 3 or 4 HCV infection {27503}, {23275}, 
{24713}, {24715}.  Sovaldi™  has been approved in the United States by the Food and Drug 
Administration  (FDA) for the treatment of HCV infection GT- 1, 2, 3 and 4 including 
treatment naïve and experienced patients and HIV/HCV co-infected patients.
For further information on the clinical pharmacology, virology, safety and efficacy of SOF, 
please refer to the current version of the Investigator’s Brochure and US prescribing 
information.  


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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.
1.4.
Rationale for the Current Study
This clinical study is designed to evaluate the efficacy and safety of treatment with 
SOF+RBV for adolescents and children with GT-2 and GT-3 chronic HCV infection. 
Currently PEG and weight-based RBV are considered the standard of care for the treatment 
of HCV infection in children. However, this PEG and RBV regimen is long in duration, 
relatively toxic, and not well tolerated. Thus, there continues to be a need for new treatments 
for HCV that combine potent and sustained efficacy with improved tolerability and safety. 
Therapy that provides shorter duration and improved efficacy with an all-oral regimen would 
be a significant advancement over current options in pediatric patients.
The main aim for the treatment of pediatric patients with HCV is to eliminate the need to use 
IFN-based regimens. In this way, pediatric patients are able to avoid the necessity of weekly 
injections, which can be traumatic and burdensome, and also to significantly reduce the 
serious adverse events seen on administration of IFN-based regimens. 
SOF is a promising candidate to combine with RBV based on its acceptable safety profile 
and its antiviral activity.  Clinical trials from adult studies have demonstrated the antiviral 
efficacy, potency, and safety of SOF in subjects with HCV infection. SOF in combination 
with RBV would provide an all-oral, IFN-free regimen with a shorter treatment duration 
(12 - 24 weeks of SOF treatment versus standard-of-care 24 to 48 weeks of treatment) and 
would offer another important option in the treatment of HCV infection in the pediatric 
population.
While emerging Phase 3 data demonstrate high SVR12 rates in subjects with GT- 2 HCV 
infection, these studies suggest that patients with GT- 3 infection may benefit from a longer 
treatment duration with SOF+RBV. Optimal duration of SOF+RBV, for genotype 3 subjects,
was established in FISSION and VALENCE.  Increasing treatment duration from 12 to 
24 weeks increased SVR12 from 61 to 93% in non-cirrhotics and from 34 to 92% in 
cirrhotics.


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1.5.
Rationale for Dose Selection of SOF
SOF 400 mg, once daily, when dosed in combination with RBV with or without PEG has 
demonstrated broad genotypic efficacy and favorable safety profile in over 
3300 HCV-infected subjects across multiple patient populations in Phase 2 and 3 trials. This 
dose is the marketed dose of SOF for the treatment of HCV-infection.
Selection of doses of SOF for adolescents and younger age groups will target systemic 
exposures similar to those observed in adults at the marketed dose, taking into account body 
weight/body surface area, the potential ontogenic changes in hepatically expressed 
carboxylesterase 1 (CES1) and Cathepsin A (CatA) enzymes, and the results obtained in 
older age groups.  Available data suggest comparable hepatic expression of CES1 in 
adolescents and adults, with modestly decreased expression in children.  As such, the adult 
clinical dose, 400mg, will be evaluated in adolescents {20288}.  Safety and PK data in the 
adolescent group (Cohort 1) in Part A, will inform dose selection for the younger age groups 
in addition to body weight/body surface area. 
Age-appropriate formulations of SOF that offer an important option in the treatment of HCV 
infection in the pediatric population are planned for evaluation in children below 6 years of 
age or children who are unable to swallow a solid-dose 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 standard of care 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. 
SOF has demonstrated efficient inhibition of viral replication in in vitro and in vivo studies. 
Available clinical data indicate SOF has a favorable safety profile and is well tolerated. SOF 
in combination with RBV is likely to provide significant therapeutic benefit in the treatment 
of HCV infection in pediatric patients compared to currently available therapies in the 
following areas:

Expected improved efficacy in a pediatric population compared to the current standard of 
care

Expected improvement in safety and tolerability in relation to either adverse reactions or 
potential medication errors in the pediatric population compared to the current standard 
of care


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
Improved dosing scheme or method of administration (oral compared to subcutaneously 
administration and reduced treatment duration) leading to improved safety, efficacy,
tolerability, and compliance

Expected availability of a clinically relevant age-appropriate formulation

Different mechanism of action with potential advantage for the pediatric population in 
terms of improved efficacy and safety

Expected improvement in quality of life (eg, minimized duration of therapy and
avoidance of IFN-related adverse events that affect patient quality of life such as flulike
syndrome and depression)
Additionally, the study sponsor will perform an ongoing review of safety data during the 
conduct of the study.


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2. 
OBJECTIVES 
The prima1y objective of Part A of this study is: 
Final 
Original 
• 
To evaluate the steady state phrumacokinetics (PK) and confmn the dose of SOF in 
HCV -infected pediatric subjects 
The secondruy objective of Part A of this study is: 
• 
To evaluate the safety and tolerability of 7 days of dosing of SOF in HCV -infected 
pediatric subjects 
The primary objectives of Prui B of this study are: 
• 
To evaluate the safety and tolerability of SOF + ribavirin (RBV) for 12 or 24 weeks in 
HCV infected pediatric subjects with GT- 2 or 3, respectively 
To dete1mine the antiviral efficacy of SOF+RBV treatment in GT- 2 and GT- 3 
HCV-infected subjects separately, as assessed by the prop01iion of subjects with SVR 
12 weeks after completion oftreatment (SVR12) 
The secondruy objectives of Prui B of this study ru·e: 
• 
To dete1mine the antiviral efficacy of SOF+RBV treatment in genotype 2 and genotype 3 
HCV-infected subjects sepru·ately, as assessed by the prop01iion 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 SOF during treatment and after 
completion of treatment 
The explorat01y objective ofthis study is: 
• 
PD 
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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 SOF in chronic HCV-infected pediatric subjects.
3.1.1.
Part A
Part A (PK lead-in) will evaluate and/or confirm age appropriate SOF doses by analyzing 
PK, safety, and antiviral activity of SOF through 7 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 
genotype (GT) 2 or 3 HCV infection and evidence of HCV RNA > 1000 IU/mL at study 
entry will be evaluated. Three cohorts of up to 10 subjects each will be sequentially enrolled: 

Cohort 1:  12 to < 18 years old weighing ≤45kg

Cohort 2:  6 to < 12 years old 

Cohort 3:  3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive SOF (400-mg adult tablet or 
4 x 100-mg tablets if determined necessary based on SOF swallowability assessment) for 
7 days with intensive PK conducted on Day 7. A SOF swallowability assessment will be 
administered on Day 1 in which subjects will be observed taking the first 400-mg SOF tablet 
to confirm the swallowability of the 400-mg tablet size in adolescents aged 12 to < 18 years. 
If, at Day 1 or any time during the study, a subject is unable to continue with the 400-mg 
tablet size he/she will be re-assigned to 4 x 100mg SOF tablets.  
Following completion of study treatment in Cohort 1 (Part A) and pending PK and safety 
results from Cohort 1 (Part A), Cohort 2 will initiate and receive study treatment (age 
appropriate formulation). Following completion of study treatment in Cohort 2 (Part A)  and 
pending PK and safety results from Cohort 2 (Part A), Cohort 3 will receive study treatment 
(age-appropriate formulation). 
Subjects in each cohort (Cohorts 1, 2 and 3) will immediately enroll in Part B as they 
complete Day 7 of Part A.  On completion of Day 7 of Part A; subjects (aged 3 to < 18 years) 
will immediately enroll in Part B. They will begin dosing with SOF + RBV with no 
interruption of study drug administration.
3.1.2.
Part B
Part B will be initiated by cohort after confirmation of age-appropriate SOF dosage levels. 
Subjects who participated in Part A will immediately rollover into Part B (Day 1), with no 
interruption of study drug administration:


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Children aged 3 to < 12 years (Group 2) and adolescents aged 12 to < 18 years (Group 1) 
with GT-2 or GT-3 infection and evidence of HCV RNA > 1000 IU/mL at study entry (those 
who were dosed in Part A will have met this criteria prior to enrollment) will be evaluated.
Subjects enrolled in Part B will receive the following regimen.

GT-2 subjects: SOF + RBV for 12 weeks

GT-3 subjects: SOF + RBV for 24 weeks
The study will enroll both treatment-naïve and treatment–experienced pediatric subjects, with 
up to 20 subjects allowed to be treatment experienced. Approximately 100 total subjects, 
including subjects from Part A, will be enrolled in Part B as follows:

Group 1: Approximately 50 adolescent subjects (12 to < 18 years of age)

Group 2:Approximately 50 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 standard-of-care (SOC) therapy with their healthcare provider.


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Figure 3-1.
Study Schema
3.2.
Visit Schedule
3.2.1.
Part A
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 7.
Subjects (up to 10 subjects) enrolled in Part A will participate in an intensive PK evaluation 
on Day 7. 
Following completion of the Day 7 intensive PK visit, subjects will then return for scheduled 
study visits outlined in Part B and begin dosing with SOF + RBV with no interruption of 
study drug administration.


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3.2.2.
Part B
Screening assessments will be completed within 28 days of the Day 1 visit. For subjects 
continuing from Part A, screening for Part B will not be required.

GT-2 Subjects: Study visits for GT-2 subjects will occur at screening, Day 1, and the 
end of weeks 1, 2, 4, 8, and 12. 

GT-3 Subjects: Study visits for GT-3 subjects will occur at screening, Day 1, and the 
end of weeks 1, 2, 4, 8, 12, 16, 20, and 24. 
All Part B 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.


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3.4. 
Treatment Discontinuations Criteria 
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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 defmed in Section 7 of the protocol, 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 imp01tant to detennine 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, regulat01y agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC). 
3.5. 
Discontinuations 
Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an Early Tennination visit as described in the Section 6.4.7. 
Subjects who pennanently discontinue all study dmgs for any reason including safety and/or 
tolerability concems prior to completion of the assigned dosing period will be followed 
according to the post-u·eatment study assessments described in Section 6.5. 
3.6. 
Pharmacogenomic Substudy 
PD 
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 eve1y 6 months for 
assessments of growth, quality of life, and long-te1m viral suppression (if applicable) in a 
separate protocol. This follow-up will continue for 5 years. SUBJECT POPULATION 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 100 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
2. 3 years to < 18 years of age (consent of parent or legal guardian required)
3. Part A only: subjects in Cohort 1 (age 12 to <18 years of age) must weigh 45 kg
4. Documented chronic HCV infection, GT-2 or GT-3
5. HCV RNA ≥1000 IU/mL at Screening
6. Adequate hematologic function (absolute neutrophil count 1,500/mm3; 
hemoglobin 10.0 g/dL)
7. Negative serum -HCG pregnancy test (for females of childbearing potential only, as 
defined in Appendix 5)
8. 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)


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3. 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)
4. Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)
5. -fetoprotein 50 ng/mL
6. Serum creatinine > 1.5 mg/dL
7. Evidence of hepatocellular carcinoma (HCC)
8. Co-infection with HIV, acute HAV, or HBV
9. Significant cardiovascular, pulmonary or neurological disease
10. Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption 
of orally administered medications
11. History of solid organ or bone marrow transplantation
12. Chronic daily non-steroidal anti-inflammatory drug therapy
13. Systemic corticosteroid use for 5 days (pulmonary/nasal administration is permitted)
14. Investigational agents (except with the expressed approval of the Sponsor)
15. 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
16. Known hypersensitivity to the study drugs, the metabolites or formulation excipients
17. 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
18. Use of any prohibited concomitant medications as described in Section 5.6 within 
28 days of the Day 1 visit


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
Not applicable.
5.2.
Sofosbuvir
5.2.1.
Description and Handling
5.2.1.1.
Formulation:
SOF tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets debossed with “GSI” on 
one side and “7977” on the other side. In addition to the active ingredient, SOF tablets 
contain the following inactive ingredients: mannitol, microcrystalline cellulose, 
croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, 
titanium dioxide, macrogol, talc, and yellow iron oxide.
SOF tablets, 100 mg, are yellow, round, film-coated, plain-faced tablets. In addition to the 
active ingredient, SOF tablets contain the following inactive ingredients: mannitol, 
microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium 
stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, and yellow iron oxide.
Ages appropriate formulations for children aged 3 to < 12 years are to be determined.
5.2.1.2.
Packaging and Labeling
SOF 400 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 30 tablets and a silica gel desiccant canister or sachet and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant screw cap 
with an induction-sealed, aluminum-faced liner.
SOF 100 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 28 tablets and a polyester packing material. Each bottle is enclosed with a 
white, continuous thread, child-resistant screw cap with an induction-sealed, aluminum faced 
liner.
SOF bottles to be distributed to centers in the US, EU and the rest of the countries will meet 
all applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 of 
Good Manufacturing Practices: Manufacture of investigational medicinal products 
(July 2010) and/or other local regulations as applicable.
5.2.2.
Storage and Handling
SOF tablets should be stored at controlled room temperature until required for 
administration. Controlled room temperature is defined as 25 C (77 F); excursions are 
permitted between 15 C and 30 C (59 F to 86 F).


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All drug products should be stored in a securely locked area, accessible only to authorized 
site personnel. To ensure the stability of the study drug and to ensure proper product 
identification, the drug product should not be stored in a container other than the container in 
which they are supplied. Consideration should be given to handling, preparation, and 
disposal through measures that minimize drug contact with the body. Appropriate 
precautions should be followed to avoid direct eye contact or exposure through inhalation 
when handling SOF.
Sufficient quantities of SOF tablets to complete the entire study will be shipped to the 
investigator or qualified designee from Gilead Sciences Materials & Logistics (or its 
designee).
5.2.3.
Dosage and Administration of SOF
Age group 12 to < 18 years: 
Part A: SOF 400-mg tablets will be administered once daily. Subjects determined unable to 
swallow the 400-mg tablet, by SOF swallowability assessment at Day 1 or any time during 
the study, will be re-assigned to 4 x 100-mg tablets daily.
Part B: SOF 400-mg tablets will be administered once daily for subjects who weigh ≥45 kg. 
Subjects determined unable to swallow the 400-mg tablet (by SOF assessment at Day 1 or at 
any time during the study) will be re-assigned to 4 x 100-mg tablets daily. For subjects in this 
age group who weigh < 45 kg, PK data from part A will be used to determine the appropriate 
dose of SOF to be administered. 
Subjects who participated in Part A will continue the assigned dose in Part B.
Age group 3 to < 12 years: 
SOF age-appropriate formulation will be administered once daily with a dose and 
formulation to be determined.
5.3.
Ribavirin 
5.3.1.
Description and Handling of RBV
5.3.1.1.
Formulation 
RBV tablets, 200 mg, are blue, capsule-shaped, film-coated tablets debossed with “3RP” on 
one side and “200” on the other side. In addition to the active ingredient, RBV tablets contain 
the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, 
croscarmellose sodium, povidone, magnesium stearate, polyvinyl alcohol), titanium dioxide, 
macrogol, talc and FD&C blue #2.
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.


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5.3.1.2.
Packaging and Labeling
The RBV tablets are packaged in white, HDPE bottles. Each bottle contains 168 tablets and 
rayon coil packing material and is enclosed with a white, continuous thread, child-resistant 
screw cap with an induction-sealed, aluminum-faced liner. 
The RBV oral solution is packaged in 4-oz amber glass bottles (100 mL/bottle) with 
child-resistant closures.
RBV bottles to be distributed to centers in the US, EU and the rest of the countries will meet 
all applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 of 
Good Manufacturing Practices: Manufacture of investigational medicinal products 
(July 2010) and/or other local regulations as applicable.
5.3.1.3.
Storage and Handling
RBV tablets should be stored at 25 C (77 F); excursions are permitted between 15 and 
30 C (59 and 86 F).
RBV oral solution should be stored between 2-8°C (36-46°F) or at 25°C (77°F); excursions 
permitted to 15-30°C (59-86°F).
5.3.2.
Dosage and Administration of RBV
RBV dose will be administered by weight as follows:

Below 50 kg: RBV 15 mg/kg divided BID 

50 kg to < 65 kg : RBV 400 mg BID 

65 kg to < 75 kg: RBV 400 mg in the morning and 600 mg in the evening

Greater than or equal to 75 kg: 600 mg BID 
The morning dose of RBV will be taken with SOF and food. The evening dose of RBV will 
be taken with food.
RBV tablets will be supplied by Gilead Sciences for all subjects.
5.4.
Co-administration of SOF and RBV
In Part B 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 with food as follows:

SOF

Weight-based RBV (as per Section 5.3.2).


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For evening doses, subjects will be instructed to take study drug with food as follows:

Weight-based RBV (as per Section 5.3.2).
If a subject forgets to take the medication at the correct time, it may be taken later in the day; 
however, no more than 400 mg dose of SOF 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. 
5.5.
Study Drug Compliance
Subjects will be instructed to return any unused SOF and RBV in the original container on 
Day 7 (Part A) and/or at study treatment visits every 4 weeks (Part B).  
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 of Screening, up to and including the date of 
the visit four weeks after discontinuation of study treatment, need to be recorded in the 
source documents and eCRFs. All concomitant medications should be recorded in the source 
documents.
The following medications are prohibited from 28 days prior to the Day 1 visit through the 
end of treatment:

Erythropoiesis-stimulating agents (ESAs); including but not limited to Procrit®, Aranesp®
and Epogen®

Granulocyte colony stimulating factor (GCSF)

Chronic systemic immunosuppressants including 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®

Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters i.e. P-gp) with study drug(s) may result in pharmacokinetic interactions 
resulting in decreases in exposure of study drug(s). Representative medications which are 
excluded from 21 days prior to Day 1 through the end of treatment are listed below:


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Drug
Agents Disallowed
Concomitant use with study drug may 
potentially result in changes of study 
drug concentration as listed below
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Decrease in concentration of study drug
Antimycobacterials
Rifampin, rifabutine, rifapentine
Decrease in concentration of study drug
Herbal/Natural 
Supplements
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-
to (or Xiao-Shai-Hu-Tang)
Decrease in concentration of study drug
Medications for disease conditions excluded from the protocol (e.g., HIV-1 infection, active 
cancer, transplantation) are not listed under this Concomitant Medication section and are 
disallowed in the study.


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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 
genotype testing or for extenuating circumstances.
Subjects who participated in Part A will not require an additional screening visit prior to 
starting Part B.
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 (i.e., height and weight of parents, if known)
— Liver biopsy results within 2 years of Screening (if available)

Complete physical examination 


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
(Part A only) Perform Tanner Pubertal Stage assessment for subjects ≥ 6 years of age at 
the time of the visit, until Tanner Stage 5 has been reached. Date of first menses will be 
documented

Vital signs (temperature, blood pressure, pulse, respiratory rate), body weight and height

Obtain blood samples for tests as listed in Section 6.6.1:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Determination of HCV viral genotype 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

Review of all inclusion and exclusion criteria
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to 
the clinic for the Day 1 visit assessments.


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6.3.
Part A: Treatment Assessments 
6.3.1.
Day 1 Visit
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

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)

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
6.3.1.1.
Drug Administration

Dispense study drugs as directed by the IWRS

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 all study drugs

Perform SOF swallowability assessment (for subjects administered SOF in tablet form 
only)

Observe the subject taking the first dose of study drugs (with food) and record the time of 
first dose


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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 parent/guardian

Obtain blood samples for:
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing (archive)
6.3.3.
Day 7 – Intensive PK 
The Day 7 Intensive PK visit should occur on the protocol-specified visit date based on the 
Day 1 visit. For the purposes of scheduling, the Day 7 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 7 Intensive PK visit (i.e., no food or drink 
except water at least 8 hours prior to the Day 7 Intensive PK visit). Subjects and/or 
parents/guardians should be instructed that the Day 7 dose of SOF must not be taken until the 
evaluations listed below are completed. 
If the subject has already dosed prior to the Day 7 clinic visit or is not in a fasted state, the 
Day 7 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 8, 9, or 10) for the 
intensive PK visit. Appropriate study drug re-dispensation must be performed in this case.
If dosing non-compliance is identified on or prior to the Day 7 visit, the Day 7 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 7 intensive PK 
visit no sooner than 3 days following compliant dosing and no later than Day 11 (i.e., return 
on Day 10 or Day 11).  If dosing non-compliance is due to an AE, consultation with the 
Gilead Medical Monitor is required regarding the potential of rescheduling the Day 7
intensive PK visit.


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In both scenarios described above, the subject and/or parents/guardians should be reminded 
not to take the SOF prior to arriving at the clinic on the day of the re-scheduled intensive PK 
visit. All Day 7 intensive PK assessments listed below should be completed when the subject 
returns.
The following evaluations are to be completed at the Day 7 Intensive PK visit:

Perform a symptom-directed physical examination as needed

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Perform study drug accountability 

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 
— 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 
SOF per dosing requirements.


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Post-dose blood samples will be collected as follows: 
Final 
Original 
• 
For Coh01is 1 and 2: 0.5, 1, 2, 3, 4, 8, and 12 hours post-dose (with predose also 
serving as t= 24). 
• 
For Cohort 3 only: 2, 4, 8, and 12 hours post-dose (with predose also serving as 
t = 24). 
Subjects will be restr·icted from food intake until after collection of the 4-hour post 
dose blood sample, except for subjects in Coh01i 3. Please also refer to the PK 
manual for details about standardized meals and PK sample processing instructions. 
After completing the Day 7 intensive PK visit subjects will then continue to the Day 1 visit in 
Pali B described in Section 6.4.1 
6.4. 
Part B: Treatment Assessments 
6.4.1. 
Day 1 Visit 
After confnmation of eligibility has been evaluated, the following tests and procedures must 
be completed prior to emollment and dosing/dispensing on Day 1: 
• 
Perf01m complete physical examination 
• 
Vital signs, including body weight and height 
• 
Review of AEs and concomitant medications 
• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
pmiicipants (Subjects 12 to < 18 years of age only)Obtain blood samples for: 
-
Hematology 
-
Chemistry 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (m·chive) 
PD 
CONFIDENTIAL 
Page40 
20 December 2013 


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
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.
6.4.1.1.
Drug Administration

Dispense study drugs as directed by the IWRS

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 all study drugs

Observe the subject taking the first dose of study drugs (with food) and record the time of 
first dose

Perform SOF swallowability assessment (for subjects administered SOF in tablet form 
only)
6.4.2.
Weeks 1 and 2 (3 days)
The following procedures/assessments are to be completed at these visits:

Vital signs, including body weight and height

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 


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6.4.3.
Weeks 4 and 8 (3 days)

Vital signs, including body weight and height

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 drugs at these visits)

Dispense study drugs as directed by the IWRS
6.4.4.
Week 12 (3 days)

Perform complete physical examination

Tanner Staging Assessment

Vital signs, including body weight and height

Assess Rates of Growth (percentiles)

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)


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
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. (GT-2 Subjects 
only)

Review medication compliance with subject and/or parent/guardian.

Dispense study drugs as directed by the IWRS (GT-3 Subjects Only)

GT-2 Subjects should return all bottles and kits at the Week 12 Visit
6.4.5.
Week 16 and 20 (3 days) – GT-3 Subjects only

Vital signs, including body weight and height

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 


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
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 drugs at these visits)

Dispense study drugs as directed by the IWRS
6.4.6.
Week 24(3 days) – GT-3 Subjects only

Perform complete physical examination

Tanner Staging Assessment

Vital signs, including body weight and height

Assess Rates of Growth (percentiles)

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)

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


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
Review medication compliance with subject and/or parent/guardian.

GT-3 Subjects should return all bottles and kits at the Week 24 Visit
6.4.7.
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.
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

Assess Rates of Growth (percentiles)

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)

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.


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
Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles and kits at the Early Termination Visit
All subjects should complete Post-Treatment assessments after early termination, as 
described in Section 6.5.
6.5.
Post-Treatment Assessments
6.5.1.
4-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height

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 (Subjects 12 to < 18 years of age 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 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

Perform symptom-directed physical examination


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
Perform Tanner Pubertal Stage assessment for subjects ≥ 6 years of age at the time of the 
visit, until Tanner Stage 5 has been reached. Date of first menses will be documented.

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 (Subjects 12 to < 18 years of age only)

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

Perform symptom-directed physical examination

Tanner Pubertal Stage Assessment & Rates of growth

Obtain blood samples for 
— HCV RNA
— Viral sequencing (archive)

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.

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)


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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.
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 genotype and subtype will be determined using the Siemens VERSANT®
HCV Genotype INNO-LiPA 2.0 Assay. Gilead reserves the right to use alternate assays for 
HCV RNA and HCV genotype should the above assays become unavailable.
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 right 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: 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.
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. 


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6.6.4.
Tanner Pubertal Stage Assessment
The Tanner Stage scale is available in Appendix 4
6.6.5.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, 
respiratory rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm 
supported so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an 
appropriately sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or 
to the nearest whole number on an automatic device.
6.6.6.
Body Mass Index (BMI)
BMI is calculated by the following equation.
BMI = weight (pounds) 703           or            weight in kilograms
   (height in inches)2                                (height in meters)2
6.6.7.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each visit for viral sequence analysis. Unused 
samples may be archived.
6.6.8.
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. If required 
by local regulations, additional pregnancy tests beyond 6 months may be added. In the event 
of a positive urine pregnancy result, subjects will be instructed to stop study drugs 
immediately and return to the clinic as soon as possible for a serum pregnancy test.
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.
6.6.9.
Quality of Life Survey (PedsQL™)
The survey will be completed in Part B of the study at Day 1, End of Treatment (Week 12 for 
GT-2 subjects, Week 24 for GT-3 subjects, or at Early Termination, if applicable), 12-Week 
Post-Treatment, and 24-Week Post-Treatment visits.


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7.
TOXICITY MANAGEMENT
7.1.
Modification of Dose/Schedule Due to Toxicity
7.1.1.
RBV Dose Adjustments
No formal RBV dose reduction guidelines exist for pediatric patients. Prior to RBV dose 
adjustments, the Gilead Medical Monitor should be consulted.
7.2.
Subject Stopping Rules for SOF
The Gilead Medical Monitor should be consulted prior to dose discontinuation of SOF unless 
the investigator believes that immediate action is warranted to ensure the continued safety of 
the subject.
Administration of SOF may be discontinued due to a clinical or laboratory event. There is no 
option for SOF dose reduction. If SOF is stopped for toxicity, it should not be restarted, RBV 
should be stopped and the subject should complete an Early Termination Visit.
Subjects who meet any of the following laboratory criteria should stop treatment with SOF
and RBV:

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 

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event or lab abnormality assessed as related to treatment with SOF


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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)

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.)


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
In-patient hospitalization or prolongation of existing hospitalization

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 (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 8.1.1 and 8.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
8.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event
information and assessments.
8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to 
IMP therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the 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 (eg., 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 
All SAEs, regardless of causal relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required 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 from screening onwards.
All AEs, regardless of causal relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP 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 post-treatment follow 
up period.
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 this time 
and the event is deemed relevant to the use of IMP, he/she should promptly document and 
report the event directly to Gilead DSPH. Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com or Fax: +1 (650) 522-5477.  All AEs and SAEs will be
recorded in the CRF/eCRF database within the timelines outlined in the CRF/eCRF 
completion guideline.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by 
emailing or faxing the report form within 24 hours of the investigator’s knowledge of the 
event to the attention of the designated CRO Pharmacovigilance Representative.


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Electronic Serious Adverse Event (eSAE) Repmiing Process 
Final 
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• 
All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines 
outlined in the CRF/eCRF completion guideline. 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit the SAE 
infonnation to Gilead DSPH within 24 homs of the investigator's knowledge of the 
event. Detailed instructions can be fmmd in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE infonnation electr·onically, ie, the 
eCRF database is not ftmctioning, record the SAE on the paper serious adverse event 
repmiing fmm and submit within 24 homs as described above. 
• 
As soon as it is possible to do so, any SAE repmied via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repmied via a paper fonn because the eCRF database has been 
locked, no ftnther action is necessruy. 
Conta.ct infonnation is as follows: 
Gilead Sciences, 
Dmg Safety and 
Public Health: 
CRO 
Phrumacovigilance 
Representative: 
Gilead Sciences, 
Medical Monitor: 
Fax: 
E-mail: 
Fax: 
E-mail: 
Nrune: 
Phone: 
Mobile: 
Fax: 
E-mail: 
+ 1 650 522-5477 
Safety _FC@gilead.com 
TBD 
Luisa Stamm, MD, PhD 
PO 
PPD 
PPD 
t-'t-'U 
• 
For fatal or life-threatening events, copies of hospital case repmis, autopsy repmis, and 
other documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occm without personal subject identification, 
maintaining the tr·aceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensme the timely completion of accmate 
safety repmis. 
Any medications necessruy for tr·eatlnent 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 
repmi fo1m. 
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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. 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, and 
pregnancy reports regardless of an associated AE.  Also includes reports of adverse reactions 
in infants following exposure from breastfeeding, and reports of adverse reactions associated 
with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following maternal or paternal exposure 
to the medicinal product. 
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 (ie, signs the informed consent) and throughout the 
study, including the post-treatment follow-up period, to the CRO Pharmacovigilance 
Representative using the pregnancy report form within 24 hours of becoming aware of the 
pregnancy.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate 
a pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as 
an SAE. The underlying medical reason for this procedure should be recorded as the AE
term.
A spontaneous abortion is always considered to be an SAE and will be reported as described 
in Sections 8.1.1 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 CRO Pharmacovigilance Representative 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 drugs 
must also be reported and relevant information should be submitted to the CRO 
Pharmacovigilance Representative 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 the CRO Pharmacovigilance Representative within 24 hours of the investigator 


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becoming aware of the situation. These reports must consist of situations that involve study 
IMP, but do not apply to concomitant medications. Except for situations that result in AEs, 
special situations involving concomitant medications will not be reported. Any inappropriate 
use of contraindicated medications 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 prima1y objective ofPa1t A of this study is: 
Final 
Original 
• 
To evaluate the steady state phrumacokinetics (PK) and confmn the dose of SOF in 
HCV -infected pediatric subjects 
The secondruy objective ofPmt A of this study is: 
• 
To evaluate the safety and tolerability of 7 days of dosing of SOF in HCV -infected 
pediatric subjects 
The primm·y objectives of Pmt B of this study m·e: 
• 
To evaluate the safety and tolerability of SOF + RBV for 12 or 24 weeks in 
HCV-infected pediatric subjects with genotype 2 or 3, respectively 
• 
To dete1mine the antiviral efficacy of SOF+RBV treatment in genotype 2 and genotype 3 
HCV-infected subjects sepm·ately, as assessed by the proportion of subjects with SVR 
12 weeks after completion oftreatment (SVR12) 
The secondmy objectives of Pmt B of this study are: 
• 
To dete1mine the antiviral efficacy of SOF+RBV treatment in genotype 2 and genotype 3 
HCV-infected subjects sepm·ately, 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 SOF during treatment and after 
completion of treatment 
The explorat01y objective of this study is: 
• 
PD 
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9.1.2.
Primary Endpoint
In Part A, AUCtau of GS-331007 is considered as the primary PK parameter for determining 
the appropriate SOF dose.
For Part B, the primary efficacy endpoint is SVR12. Safety endpoint is any AE leading to 
permanent discontinuation of study drug(s).
9.1.3.
Secondary Endpoints
In Part A, the secondary PK endpoints include AUCtau, Cmax, AUClast, Tmax, Clast, Tlast, Ctau
and t1/2for GS-331007 and SOF as appropriate. AEs leading to permanent discontinuation of 
study drug(s) will be evaluated as a secondary safety endpoint.
For Part B, secondary efficacy endpoints include SVR4, SVR24, end-of-treatment response, 
breakthrough and relapse. Additional efficacy evaluations may include HCV RNA change 
from Day 1; ALT normalization; viral kinetic parameters; and changes in patient reported 
outcomes based on the Quality of Life survey to assess the effect of treatment on quality of 
life.
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 part A 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 SOF, and metabolites.  
Sparce 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 SOF or GS-331007 are 
available. The PK analysis set will be used for analysis of general PK and single sample 
plasma concentrations.


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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. 


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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.
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 Part A and Part B 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 genotype, prior treatment experience, and additional endpoints as 
necessary.


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9.4.
Pharmacokinetic Analysis
PK analysis will be performed for Part A using the intensive PK analysis set. The 
concentration data of SOF and metabolites (GS-566500 and GS-331007) 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 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 the exposures of GS-331007 achieved in pediatric subjects of this study are 
similar to the exposures observed in historical control subjects, GS-331007 exposure data 
from this study will be compared to the integrated historical control data by carrying out an 
analysis of variance (ANOVA) for log-transformed AUCtau of GS-331007 as the primary 
endpoint while Cmax of GS-331007 will be evaluated as secondary endpoints. 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%. Individual patient management 
will be performed by maintaining exposures comparable to adults.  AUCtau less than the 
2.5th percentile of adult values may require dose adjustment as appropriate.
The effect of age and SOF dose on PK (SOF and GS-331007) will be assessed.
9.5.
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 age group and genotype for Part B.
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.
9.5.1.
Primary Analysis
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
treatment) in the FAS population. The primary analysis will be performed after all enrolled
subjects have been followed through 12 weeks post-treatment or discontinued from study.
9.5.2.
Secondary Analysis
The proportion of subjects with HCV RNA below LLOQ over time (including SVR 
endpoints) will be presented by age group and genotype in Part B in tabular and graphical 
form. 


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Descriptive summaries and listings will be provided for additional efficacy evaluations 
including senun HCV RNA actual values and change from baseline, prop01iion of subjects 
with virologic failmes, and other endpoints of interest including ALT nonnalization. 
PD 
9.5.3. 
Subgroup Analysis 
Subgroup analysis on SVR24 and SVR12 will be perfonned by u·eatment experience 
(u·eahnent-naive vs. experienced), and by u·eatment experience and genotype. 
Details on efficacy analyses will be described in the statistical analysis plan. 
9.6. 
Safety Analysis 
Safety analysis will be perf01med for Pmi A and Pati B respectively. 
Safety will be evaluated by assessment of clinical laborat01y tests, physical exaininations, 
vital signs measmements, and by the documentation of AEs. 
All safety data collected while on or after the first dose of study dmg adminisu·ation up to 
30 days after the last dose of study dmg will be summarized by coh01i according to the study 
dmg received. 
Safety endpoints will be analyzed by the number and percent of subjects with events or 
abn01malities for categorical values or 8-number summmy (n, mean, standai·d deviation, 
median, Ql, Q3, minimum, maximum) for continuous data .. 
9.6.1. 
Extent of Exposure 
A subject's extent of exposme to study dmg will be generated from the study dmg 
adminisu·ation page of the CRF. Exposme data will be summm·ized. 
9.6.2. 
Adverse Events 
Clinical and laborat01y AEs will be coded using the Medical Dictionmy for Regulat01y 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Tetm (HLGT), 
High-Level Tetm (HLT), Prefened Tetm (PT), and Lower-Level Tetm (LLT) will be 
attached to the clinical database. 
Events will be summarized on the basis of the date of onset for the event. A 
u·eatment-emergent adverse event will be defined as any new or worsening adverse event that 
begins on or after the date of fust dose of study dmg up to the date of last dose of study dmg 
plus 30 days. 
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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,

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.
9.6.3.
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 by age group and overall.
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.
9.6.4.
Other Safety Evaluations
9.6.4.1.
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.


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9.7.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of 
the study and perform interim reviews of safety and PK data 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.
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.
9.8.
Sample Size
With approximately 50 subjects enrolled into each age group of Part B, a two-sided 95.0% 
confidence interval of the SVR12 rate will extend at most 11.1% in both directions from the 
observed SVR12 rate, assuming the expected SVR12 rate is 80%.


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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 Harmonisation (ICH) guidelines, or with the laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the study subject. 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 subinvestigators 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 subinvestigator. The investigator and subinvestigator 
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.


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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.


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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);

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 10 years for purposes of this study.


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10.1.6.
Case Report Forms
For each subject enrolled, a CRF (or eCRF) must be completed and signed by the principal 
investigator or subinvestigator (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 prerandomization screening period if a CRF was initiated). If a subject 
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.


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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 or IEC in accordance with local requirements. Approval must be obtained before 
changes can be implemented.
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.


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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.
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
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.
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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 
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15572
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
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Revised: March 2010.
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Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus 
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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.
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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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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.


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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.
23275
Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. 
Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J 
Med 2013;368 (1):34-44.
24713
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, 
Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without 
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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, Single-Arm Study to Investigate tbe 
Safety and Efficacy of Sofosbuvir + Ribavirin in Adolescents and Children with 
Genotype 2 or 3 Chronic HCV Infection 
GS-US-334-1112, Original, 20 December 2013 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Luisa Stamm, MD, Ph.D (Printed) 
Medical Monitor 
Date 
PD 
Sig'---------------' 
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 infonned about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
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Appendix 2.
Study Procedures Table
Appendix Table 1.
Part A: Screening and On-Treatment Study Visits
Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 7
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Complete Physical Examination
X
X
Symptom-directed Physical Examination
X
X
Tanner Pubertal Stage Assessment
X
Vital Signsa
X
X
X
X
AEs and Concomitant Medications
X
X
X
X
Pregnancy Prevention Counselingf
X
SOF Swallowability Assessment
X
Review of Study 
Medication Compliance
X
Study Drug Dispensingb
X
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X


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Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 7
(+ 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 height, weight, blood pressure, pulse, respiratory rate and temperature
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 drugs on Day 7 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 8, 
and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 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 (subjects 12 to < 18 years of age only).


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Protocol GS-US-334-1112
Final
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Appendix Table 2.
Part B: Screening and On-Treatment Study Visits
Screening
Day 1c
Visit identified by on-treatment study week
1
2
4
8
12
16g
20g
24g
Early 
Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Complete Physical Examination
X
X
X
X
X
Symptom-Directed Physical Examination
X
X
X
X
X
X
Tanner Pubertal Stage Assessment & 
Rates of growthh
X
X
X
X
Vital Signsa
X
X
X
X
X
X
X
X
X
X
X
AEs and Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention Counselingi
X
X
X
X
SOF Swallowability Assessment
X
Quality of Life Surveye
X
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
X
X
X
Study Drug Dispensingb
X
X
X
X
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
Viral Sequencing d
X
X
X
X
X
X
X
X
X
X


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Protocol GS-US-334-1112
Final
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Screening
Day 1c
Visit identified by on-treatment study week
1
2
4
8
12
16g
20g
24g
Early 
Termination
Serum or Urine Pregnancy Testing
X
X
X
X
X
X
X
X
X
Single PK
X
X
X
X
X
X
X
X
X
Urinalysis, Urine Drug Test
X
HCV Genotyping, IL28B
X
HCV antibody, HIV 1/2 antibody, HBs 
antigen, HAV antibody
X
HbA1c
X
TSH
X
X
X
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
a
Vital signs include height, weight, blood pressure, pulse, respiratory rate and temperature
b
The IWRS will provide direction on the specifics of each subject’s study drug dispensing.
c
Day 1 assessments must be performed prior to dosing
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 at Day 1, 12, and 24/ET 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.
f
g
GT-2 subjects will complete through the Week 12 visit; GT-3 subjects will complete through the Week 24 visit. 
h
Performed at Day 1 and End of Treatment 
I
Including partner pregnancy prevention for male participants (subjects 12 to < 18 years of age only).
PPD
PPD


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Protocol GS-US-334-1112
Final
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Original
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Appendix Table 3.
Part B: 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
Xd
Xd
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment & Rates of 
Growth
X
X
Pregnancy Prevention Counseling e
X
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Testc
X
X
X
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
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.
d
All SAEs, including deaths, regardless of cause or relationship, must be reported after patient signs the informed consent through the end of the study
e
Including partner pregnancy prevention for male participants (subjects 12 to < 18 years of age only).


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Protocol GS-US-334-1112
Final
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Original
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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18June2012
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


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Protocol GS-US-334-1112
Final
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
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
Infant, 2 – 7 Days
1250 to 1500/mm3
1.25 to 1.50 GI/L
1000 to 1250/mm3
1.00 to < 1.25 GI/L
750 to 1000/mm3
0.75 to < 1.00 GI/L
750/mm3
< 0.75 GI/L
Infant, 1 Day
4000 to 5000/mm3
4.00 to 5.00 GI/L
3000 to 4000/mm3
3.00 to < 4.00 GI/L
1500 to 3000/mm3
1.50 to < 3.00 GI/L
1500/mm3
< 1.50 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


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Final
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Original
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0% 


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
146  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


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Protocol GS-US-334-1112
Final
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Original
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4  mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


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Protocol GS-US-334-1112
Final
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Original
CONFIDENTIAL
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63  to LLN mmol/L
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.14 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 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L


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Protocol GS-US-334-1112
Final
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Original
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol/L to LLN
57 to 87 μmol/L
27 to 57 μmol/L
27 μmol/L
Creatinine 
1.50 to 2.00 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol/L
177 to 265 μmol/L
265 to 530 μmol/L
530 μmol/L
Bicarbonate
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
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L
LDL
(Fasting)
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
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


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Original
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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


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Protocol GS-US-334-1112
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Original
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20 December 2013
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.


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 90
20 December 2013
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated


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Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
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20 December 2013
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
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20 December 2013
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)


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
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20 December 2013
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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 94
20 December 2013
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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
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20 December 2013
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids)
Life-threatening consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(eg, hypotensive shock)


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 96
20 December 2013
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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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
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20 December 2013
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate 
for the setting 
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting 
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or 
other neurologic function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic self-
care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual 
social & functional activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social & 
functional activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
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20 December 2013
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase 
from Previous Level of 
Control to Any of These 
Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (eg, 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 5–20 
minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated 
with a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic self-
care functions


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
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20 December 2013
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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 100
20 December 2013
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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Protocol GS-US-334-1112
Final
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Original
CONFIDENTIAL
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20 December 2013
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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
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20 December 2013
ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, back 
of neck, breasts, 
abdomen)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current meds to regain glucose 
control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences 
(eg, ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, myxedema coma)
Lipoatrophy (eg, fat loss 
from the face, extremities, 
buttocks)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Original
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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


Sofosbuvir
Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 104
20 December 2013
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. 


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 105
20 December 2013
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1. Background
RBV 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 sofosbuvir demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of sofosbuvir 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 randomization. They must also agree 
to one of the following from 3 weeks prior to Day 1 until 6 months after last dose of RBV:

Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) is not permitted.
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 the last dose of RBV:
— intrauterine device (IUD) with a failure rate of < 1% per year
— female barrier method: cervical cap or diaphragm with spermicidal agent
— tubal sterilization
— vasectomy in male partner


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Protocol GS-US-334-1112
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
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— 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 
Baseline until 7 months after the last dose of 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.
Male subjects must agree to refrain from sperm donation for at least 7 months after the last 
dose of 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. 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.