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
Phase: PHASE2
Conditions: Hepatitis C Virus Infection
Sponsor: Gilead Sciences

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The inf01mation contained in this document, pruiicularly unpublished data, is the prope1iy or 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. 

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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

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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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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

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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

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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

Sofosbuvir 
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Study Design: 
CONFIDENTIAL 
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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 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 
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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 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 
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Substudy and 
Long-Te1m 
Follow-Up Study: 
CONFIDENTIAL 
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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. 
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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.

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 
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26 Febmaty 2016 

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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
(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.

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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 
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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.

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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
GFR
glomerular filtration rate
GSI
Gilead Sciences, Inc.

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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

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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.  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.

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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
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
PPD
PPD
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 
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........................................................ ..................... 
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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.

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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. 
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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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26 Febmaty 2016 

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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. 
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 
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• 
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 
I"'U 
26 Febmaty 2016 

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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 
FINAL 
Amendment6 
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
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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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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 
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. 
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.
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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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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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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 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

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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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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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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

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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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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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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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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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Gilead Sciences, Inc
Amendment 6.0
CONFIDENTIAL
Page 111
26 February 2016
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (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

Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6.0
CONFIDENTIAL
Page 112
26 February 2016
MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia
See also Arthritis
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing greater than 
minimal interference with usual 
social & functional activities
Joint pain causing inability 
to perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic self-
care functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional activities
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0 
BMD t-score or z-score –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Pediatric 21 Years
BMD z-score 
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Myalgia
(non-injection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities
Muscle pain causing 
inability to perform usual 
social & functional activities
Disabling muscle pain causing 
inability to perform basic self-
care functions
Osteonecrosis
NA
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention 
indicated
Disabling bone pain with 
radiographic findings causing 
inability to perform basic self-
care functions

Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6.0
CONFIDENTIAL
Page 113
26 February 2016
SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Acute Systemic Allergic 
Reaction 
Localized urticaria 
(wheals) with no medical 
intervention indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR Life-
threatening bronchospasm OR 
laryngeal edema
Chills
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & 
functional activities
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7C to 38.6C
99.8F to 101.5F
38.7C to 39.3C
101.6F to 102.8F
39.4C to 40.5C
102.9F to 104.9F
40.5C 
104.9F
Pain- Indicate Body Site
See also Injection Site 
Pain, Headache, 
Arthralgia, and Myalgia
Pain causing no or 
minimal interference with 
usual social & functional 
activities
Pain causing greater than minimal 
interference with usual social & 
functional activities
Pain causing inability to 
perform usual social & 
functional activities
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization (other than ER 
visit) indicated
Unintentional Weight 
Loss
NA
5% to 9% loss in body weight from 
baseline
10% to 19% loss in body 
weight from baseline
20% loss in body weight 
from baseline OR  Aggressive 
intervention indicated [e.g., 
tube feeding or total parenteral 
nutrition]

Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6.0
CONFIDENTIAL
Page 114
26 February 2016
INJECTION SITE REACTION
Grade 1
Grade 2
Grade 3
Grade 4
Injection Site Pain (pain 
without touching)
Or Tenderness (pain when 
area is touched) 
Pain/tenderness causing no 
or minimal limitation of use 
of limb
Pain/tenderness limiting use of 
limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social 
& functional activities
Pain/tenderness causing 
inability to perform usual
social & functional activities
Pain/tenderness causing inability 
to perform basic self-care 
function OR Hospitalization 
(other than ER visit) indicated 
for management of 
pain/tenderness
Injection Site Reaction 
(Localized), 15 Years
Erythema OR Induration
of 5 5 cm to 9 9 cm (or 
2581 cm2)
Erythema OR Induration OR 
Edema 9 cm any diameter 
(or 81 cm2)
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis and 
deeper tissue)
Pediatric 15 Years
Erythema OR Induration 
OR Edema present but 
2.5 cm diameter
Erythema OR Induration 
OR Edema > 2.5 cm 
diameter but < 50% surface 
area of the extremity 
segment (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

Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6.0
CONFIDENTIAL
Page 115
26 February 2016
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
FINAL
Gilead Sciences, Inc
Amendment 6.0
CONFIDENTIAL
Page 116
26 February 2016
GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding 
(IMB)
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle
Hemorrhage with life-
threatening hypotension OR 
Operative intervention 
indicated
Urinary Tract 
obstruction (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

Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6.0
CONFIDENTIAL
Page 117
26 February 2016
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
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6.0
CONFIDENTIAL
Page 118
26 February 2016
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

Sofosbuvir
Protocol GS-US-334-1112
FINAL
Gilead Sciences, Inc
Amendment 6.0
CONFIDENTIAL
Page 119
26 February 2016
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.