Clinical trial NCT03820258
Conditions: Hepatitis C Virus Infection
Sponsor: Gilead Sciences
Start date: 2019-01-28; Completion date: 2020-02-19
Enrollment: 21 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of this study is to evaluate the steady-state pharmacokinetics (PK) and confirm the age-appropriate dose of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) fixed-dose combination (FDC) in pediatric participants with chronic hepatitis C virus (HCV) infection.

Detailed description:
Participants will receive placebo to match SOF/VEL/VOX FDC to assess ability to swallow tablets at screening up to Day 1.

Arms: arm 1: Direct-acting antiviral (DAA)-naive participants without cirrhosis in Cohort 1 (12 to \< 18 years old) will receive SOF/VEL/VOX FDC 400/100/100 mg for 8 weeks. arm 2: DAA-naive participants with cirrhosis or DAA-experienced participants with or without cirrhosis in Cohort 1 (12 to \< 18 years old) will receive SOF/VEL/VOX FDC 400/100/100 mg for 12 weeks. arm 3: DAA-naive participants without cirrhosis in Cohort 2 (6 to \< 12 years old) will receive SOF/VEL/VOX FDC for 8 weeks. arm 4: DAA-naive participants with cirrhosis or DAA-experienced participants with or without cirrhosis in Cohort 2 (6 to \< 12 years old) will receive SOF/VEL/VOX FDC for 12 weeks. arm 5: DAA-naive participants without cirrhosis in Cohort 3 (6 to \< 12 years old) will receive SOF/VEL/VOX FDC for 8 weeks. arm 6: DAA-naive participants with cirrhosis or DAA-experienced participants with or without cirrhosis in Cohort 3 (3 to \< 6 years old) will receive SOF/VEL/VOX FDC for 12 weeks.
Interventions: intervention 1: SOF/VEL/VOX
Intervention descriptions: intervention 1: Administered once daily with food.

Protocol documents:
Prot_001.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Study Director 
and Medical Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label, Multicenter, Multi-coho1i Study to 
Investigate the Phannacokinetics, Safety and Efficacy of 
SofosbuvirN elpatasvirN oxilaprevir Fixed Dose Combination in 
Adolescents and Children with Chronic HCV Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
Not Applicable 
2018-000480-87 
Not Applicable 
Hepatitis C Vims Infection 
GS-US-367-1175 
Name: 
IPIPD 
Telephone: IPIPD 
Fax: 
IPIPD 
Original: 
08 Febmaiy 2018 
Amendment 1: 27 March 2019 
CONFIDENTIALITY STATEMENT 
The info1mation contained in this document, paiiiculai·ly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
Institutional Review Boai·d or Independent Ethics Committee. The infonnation is only to be used 
by you in connection with authorized clinical studies of the investigational dmg described in the 
protocol. You will not disclose any of the info1mation to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessaiy to obtain info1m ed consent from those 
persons to whom the dmg may be administered. 


SOFNEIJVOX FDC 
Protocol GS-US-367-1175 
Gilead Sciences, Inc. 
Amendment 1 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 4 
PROTOCOL SYNOPSIS .............................................................................................................................................. 5 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 12 
1. 
INTRODUCTION .............................................................................................................................................. 16 
1.1. 
Background ............................................................................................................................................ 16 
1.2. 
SofosbuvirN elpatasvirN oxilaprevir Fixed-Dose Combination ............................................................ 17 
1. 2 .1. 
General Infonnation ............................................................................................................. 18 
1.3. 
Rationale for This Study ........................................................................................................................ 18 
1.4. 
Rationale for Dose Selection of SOFNELN OX FDC .......................................................................... 19 
1.5. 
Rationale for Study Design .................................................................................................................... 20 
1.6. 
Risk/Benefit Assessment for the Study .................................................................................................. 20 
1.7. 
Compliance ............................................................................................................................................ 21 
2. 
OBJECTIVES ..................................................................................................................................................... 22 
3. 
STUDY DESIGN ................................................................................................................................................ 23 
3.1. 
3.2. 
3.3. 
3.4. 
3.5. 
3.6. 
3.7. I 
Study Design .......................................................................................................................................... 23 
Study Treatments ................................................................................................................................... 23 
Duration of Treatment ............................................................................................................................ 24 
Virologic Response-Based Stopping Criteria ......................................................................................... 24 
Discontinuation Criteria ......................................................................................................................... 24 
End of Study ........................................................................................................................................... 25 
Reconsent ............................................................................................................................................... 25 
4. 
SUBJECT POPULATION .................................................................................................................................. 27 
4.1. 
Number of Subjects and Subject Selection ............................................................................................ 27 
4.2. 
Inclusion Criteria .................................................................................................................................... 27 
4.3. 
Exclusion Criteria ................................................................................................................................... 28 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS ........................................................................................... 30 
5 .1. 
Description and Handling of SOFNELN OX FDC ............................................................................... 30 
5.1.1. 
Foimulation .......................................................................................................................... 30 
5.1.2. 
Packaging and Labeling ....................................................................................................... 30 
5.1.3. 
Storage and Handling ........................................................................................................... 30 
5.2. 
Dosage and Administrntion of SOFNEIJVOX FDC ............................................................................ 31 
5.3. 
Prior and Concomitant Medications ....................................................................................................... 31 
5.4. 
Accountability for SOFNELN OX FDC ............................................................................................... 33 
5.4.1. 
Investigational Medicinal Product Retuin or Disposal.. ....................................................... 33 
6. 
STUDY PROCEDURES .................................................................................................................................... 34 
6.1. 
Subject Enrollment and Treatment Assignment ..................................................................................... 34 
6.1.1. 
Screening Visit ..................................................................................................................... 34 
6.1.2. 
Day 1 Assessment.s ............................................................................................................... 36 
6.2. 
Enrollment .............................................................................................................................................. 37 
CONFIDENTIAL 
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SOF/VEL/VOX FDC
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Gilead Sciences, Inc. 
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6.3.
Treatment Assessments..........................................................................................................................37
6.3.1.
Week 1 (± 3 days) ................................................................................................................37
6.3.2.
Week 2 (± 3 days) ................................................................................................................38
6.3.3.
Week 4 (± 3 days) ................................................................................................................39
6.3.4.
Week 8 (± 3 days) ................................................................................................................40
6.3.5.
End of Treatment (± 3 days) or Early Termination ..............................................................41
6.4.
Posttreatment Assessments ....................................................................................................................42
6.4.1.
4-Week Posttreatment Visit (± 5 days).................................................................................42
6.4.2.
12-Week Posttreatment Visit (± 5 days)...............................................................................43
6.4.3.
24-Week Posttreatment Visit (±5 days)................................................................................44
6.6.
Unscheduled Visit ..................................................................................................................................47
6.7.
Assessments for Premature Discontinuation from Study.......................................................................47
6.8.
Procedures and Specifications................................................................................................................47
6.8.1.
Clinical Laboratory Analytes ...............................................................................................47
6.8.2.
Medical History....................................................................................................................48
6.8.3.
Physical Examination...........................................................................................................48
6.8.4.
Tanner Pubertal Stage Assessment.......................................................................................48
6.8.5.
Height & Weight Measurement............................................................................................48
6.8.6.
Radiographic Bone Age Assessment....................................................................................49
6.8.7.
Bone Age Biomarkers ..........................................................................................................49
6.8.8.
Acceptability and Swallowability Assessment.....................................................................49
6.8.9.
Vital Signs............................................................................................................................49
6.8.10.
Body Mass Index (BMI).......................................................................................................50
6.8.11.
Estimated Glomerular Filtration Rate (GFR) .......................................................................50
6.8.13.
Pharmacokinetic (PK) Sample .............................................................................................50
6.8.14.
HBV DNA............................................................................................................................50
6.8.15.
Pregnancy Testing................................................................................................................50
6.8.16.
Quality of Life Survey (PedsQL™) .....................................................................................51
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................52
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................52
7.1.1.
Adverse Events.....................................................................................................................52
7.1.2.
Serious Adverse Events........................................................................................................52
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................53
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................53
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................53
7.2.2.
Assessment of Severity ........................................................................................................54
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................54
7.4.
Gilead Reporting Requirements.............................................................................................................56
7.5.
Toxicity Management ............................................................................................................................56
7.5.1.
Subject Stopping Rules ........................................................................................................56
7.6.
Special Situations Reports......................................................................................................................56
7.6.1.
Definitions of Special Situations..........................................................................................56
7.6.2.
Instructions for Reporting Special Situations.......................................................................57
8.
STATISTICAL CONSIDERATIONS................................................................................................................59
8.1.
Analysis Objectives and Endpoints........................................................................................................59
8.1.1.
Analysis Objectives..............................................................................................................59
8.1.2.
Primary Endpoint .................................................................................................................60
8.1.3.
Secondary Endpoint .............................................................................................................60
CCI
CCI
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8.1.4.
Other Endpoints of Interest ..................................................................................................60
8.2.
Analysis Conventions.............................................................................................................................61
8.2.1.
Analysis Sets ........................................................................................................................61
8.3.
Data Handling Conventions ...................................................................................................................61
8.4.
Demographic Data and Baseline Characteristics ...................................................................................62
8.5.
Pharmacokinetic Analysis......................................................................................................................63
8.6.
Safety Analysis.......................................................................................................................................64
8.6.1.
Extent of Exposure...............................................................................................................64
8.6.2.
Adverse Events.....................................................................................................................64
8.6.3.
Laboratory Evaluations ........................................................................................................65
8.6.4.
Other Safety Evaluations......................................................................................................65
8.7.
Efficacy Analysis ...................................................................................................................................66
8.7.1.
Analysis of the Key Efficacy Endpoint................................................................................66
8.7.2.
Secondary Analyses .............................................................................................................66
8.8.
Acceptability and Swallowability ..........................................................................................................66
8.9.
Sample Size............................................................................................................................................66
8.10.
Data Monitoring Committee ..................................................................................................................66
9.
RESPONSIBILITIES..........................................................................................................................................68
9.1.
Investigator Responsibilities ..................................................................................................................68
9.1.1.
Good Clinical Practice..........................................................................................................68
9.1.2.
Independent Ethics Committee (IEC) Review and Approval...............................................68
9.1.3.
Informed Consent.................................................................................................................68
9.1.4.
Confidentiality......................................................................................................................69
9.1.5.
Study Files and Retention of Records ..................................................................................69
9.1.6.
Electronic Case Report Forms..............................................................................................70
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................71
9.1.8.
Inspections............................................................................................................................71
9.1.9.
Protocol Compliance............................................................................................................71
9.2.
Sponsor Responsibilities ........................................................................................................................72
9.2.1.
Protocol Modifications.........................................................................................................72
9.2.2.
Study Report and Publications .............................................................................................72
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................72
9.3.1.
Payment Reporting...............................................................................................................72
9.3.2.
Access to Information for Monitoring..................................................................................73
9.3.3.
Access to Information for Auditing or Inspections ..............................................................73
9.3.4.
Study Discontinuation..........................................................................................................73
10.
REFERENCES ...................................................................................................................................................74
11.
APPENDICES ....................................................................................................................................................76
Appendix 1.
Investigator Signature Page....................................................................................................77
Appendix 2.
Study Procedures Table..........................................................................................................78
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............83
Appendix 4.
Tanner Stages* .....................................................................................................................106
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................107
LIST OF IN-TEXT TABLES
Table 5-1.
Disallowed Medications and Concomitant Medications to be used with Caution..................32


SOF/VEL/VOX FDC
Protocol GS-US-367-1175
Gilead Sciences, Inc. 
Amendment 1
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to 
Investigate the Pharmacokinetics, Safety and Efficacy of Sofosbuvir/ 
Velpatasvir/Voxilaprevir Fixed-Dose Combination in Adolescents 
and Children with Chronic HCV Infection
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
Not Applicable
2018-000480-87
Not Applicable
Study Centers Planned:
Approximately 20 sites in Europe. 
Objectives:
The primary objective of this study is as follows:

To evaluate the steady-state pharmacokinetics (PK) and confirm 
the age-appropriate dose of Sofosbuvir/Velpatasvir/Voxilaprevir 
(SOF/VEL/VOX) FDC in pediatric subjects with chronic 
hepatitis C virus (HCV) infection
The secondary objectives of this study are:

To evaluate the safety and tolerability of SOF/VEL/VOX FDC
in pediatric subjects with chronic HCV infection

To evaluate the antiviral efficacy of SOF/VEL/VOX FDC
treatment in pediatric subjects with chronic HCV infection, as 
assessed by the proportion of pediatric subjects with sustained 
virological response (SVR) 12 weeks after cessation of treatment 
(SVR12)

To evaluate the antiviral efficacy of SOF/VEL/VOX FDC
treatment in pediatric subjects with chronic HCV infection, as 
assessed by the proportion of pediatric subjects with SVR 4 and 
24 weeks after cessation of treatment (SVR4 and SVR24)

To evaluate the proportion of pediatric subjects with virologic 
failure, including on-treatment virologic failure and relapse

To evaluate the kinetics of circulating HCV ribonucleic acid 
(RNA) during treatment and after cessation of treatment 

To evaluate the emergence of viral resistance to SOF, VEL, and
VOX during treatment and after cessation of treatment


SOFNEIJVOX FDC 
Protocol GS-US-367-1175 
Gilead Sciences, Inc. 
Study Design: 
CONFIDENTIAL 
Amendment 1 
• 
To evaluate the effect of SOFNEIJVOX FDC on growth and 
development of pediati·ic subjects dming and after ti·eatment 
• 
To evaluate acceptability, including palatability, and 
swallowability, of fo1mulations (as applicable) used in the study 
• 
To assess the effect ofti·eatment with SOFNEIJVOX FDC on 
quality of life as measmed by PedsQL™ Pediau-ic Quality of 
Life survey 
Open-label, multi-coho1t study evaluating the PK, safety, and 
antiviral activity of SOFNEIJVOX FDC in pediati·ic subjects with 
chronic HCV infection. 
Pediati·ic subjects with chronic HCV infection of any HCV 
genotype, including indete1minate or Inixed genotypes, will be 
enrolled. Both direct-acting antiviral (DAA)-naive and DAA-
experienced subjects will be enrolled. DAA-experienced subjects are 
defined as subjects who have been exposed to a regimen including 
any DAAs ( eg, NS3/4A protease inhibitors, NS5A inhibitor, or 
NS5B nucleotide/nucleoside inhibitor). 
Three sequential age-based coho1ts will be enrolled: 
• 
Coho1t 1: at least 20 subjects 12 to < 18 years old 
• 
Coho1t 2: at least 20 subjects 6 to < 12 years old 
• 
Coho1t 3: at least 20 subjects 3 to < 6 years old 
PK and safety data from at least 20 evaluable subjects in each coho1t 
will be reviewed to confom the appropriateness of the 
SOFNELNOX FDC dose used in each coho1t and to dete1mine the 
dose to be evaluated in the next coho1t. 
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SOFNEIJVOX FDC 
Protocol GS-US-367-1175 
Gilead Sciences, Inc. 
Number of Subjects 
Planned: 
Target Population: 
Duration of 
Treatment: 
Diagnosis and Main 
Eligibility Criteria: 
Study Procedures/ 
Frequency: 
CONFIDENTIAL 
Amendment 1 
At least 60 
DAA-naive and DAA-experienced adolescents and children who are 
3 to <18 years old with HCV infection 
8 weeks (DAA-naive subjects without cinhosis), or 
12 weeks (DAA-naive subjects with cin hosis or DAA-experienced 
subjects with or without cinhosis) 
DAA-naive and DAA-experienced subjects, who are 3 to < 18 years 
old as detennined at Day 1. 
Refer to Section 4.2 and 4.3 for detailed Inclusion and Exclusion 
Criteria. 
Screening assessments will be completed within 28 days of the 
Day 1 visit. The screening window can be extended to 42 days for 
extenuating circumstances with sponsor approval. 
DAA-naive subjects without cinhosis will complete the following 
study visits: Screening, Day 1, Weeks 1, 2, 4, and Week 8/End of 
Treatment. 
DAA-naive subjects with cin hosis or DAA-experienced subjects 
with or without cin hosis will complete the following study visits: 
Screening, Day 1, Weeks 1, 2, 4, 8, and Week 12/End of Treatment. 
All subjects will complete posttreatment visits at Weeks 4, 12, and 
24 weeks after discontinuation of study drng. 
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SOFNEIJVOX FDC 
Protocol GS-US-367-1175 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Amendment 1 
Screening assessments will include: info1med consent, medical 
histo1y , detennine eligibility, complete physical examination, vital 
signs, height and weight, adverse events (AEs ), concomitant 
medications, SOFNELN OX FDC swallowability assessment (may 
be perfo1med at Screening up to Day 1), transient elastography test 
(FibroScan® if available; may be perfo1med at Screening up to Day 
1 ), safety laborato1y tests (including hematology, chemistiy, and 
coagulation tests), hemoglobin Ale (HbAlc), alpha-I anti-tiypsin 
(AA T), thyroid stimulating honnone (TSH), serology (hepatitis A 
vims [HA V], HCV, and hepatitis B vims [HBV]), serology and/or 
antigen testing for HIV, HCV RNA, HCV genotyping, semm 
~-human chorionic gonadoti·opin (~-hCG - females of childbearing 
potential only), IL28B (may be perfonned at Screening up to Day 1), 
Fibrotest®, AST to Platelet Ratio Index (APRI), urinalysis, and urine 
diug screen. 
On-Treatment assessments include: complete or 
symptom-directed physical examinations (as applicable), parental 
height (if available), vital signs, height and weight (with calculation 
ofBMI), AEs and serious adverse events (SAEs), concomitant 
medications, pregnancy prevention counseling (all subjects 
12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject's pubertal status), medication 
compliance, ti·ansient elastography test (FibroScan® if available; 
may be perfo1med at Day 1 if not perfo1med at Screening), safety 
laborato1y tests (including hematology, chemistiy, and coagulation 
tests), TSH, bone age biomarkers, HBV DNA for subjects he- titis 
B core antibod (HBcAb) positive at Screening, HCV RNA, 
IL28B (may be perfo1med at Day 1 if not 
per onne at Screening), urinalysis, urine pregnancy tests (females 
of childbearing potential only), a quality of life survey, Tanner 
Pube1ial Stage assessment, and radiographic bone age assessment. 
SOFNELN OX FDC swallowability assessment may be perfo1med 
at Day 1 if not perfo1med at Screening. Acceptability questionnaire, 
including palatability assessment, will be completed by the subject 
and parent/legal guardian at Dayl and End of Treatinent. 
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SOFNEIJVOX FDC 
Protocol GS-US-367-1175 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Amendment 1 
On-Treatment PK assessments include the following: 
2) For all enrolled subjects, the following sparse PK samples will 
be collected, as applicable: 
• 
For subjects receiving 8 weeks of ti·eatment: a single sparse 
PK sample will be collected at any time at Weeks 1 and 8; 
Unscheduled and Early Tennination visits as applicable. 
• 
For subjects receiving 12 weeks of ti·eatment: a single sparse 
PK sample will be collected at any time at Weeks 1, 8, and 
12; Unscheduled and Early Tennination visits as applicable. 
• 
For all subjects 2 sparse PK samples will be collected at 
Week 2 and Week 4 at the following timepoints: re-dose 
and between 15 minutes to 4 hours ostdos 
Posttreatment assessments will include: vital signs, height and 
weight (with calculation of BMI), symptom-directed physical 
examination, AEs, SAEs, concomitant medications, safety 
laboratory tests (including hematology and chemistiy tests), bone 
age biomarkers, HBV D -b positive at 
Screening, HCV RNA,_ 
urine pregnancy tests 
(females of childbearing potential only), pregnancy prevention 
counseling for females of childbearing potential, a quality of life 
survey, and Tanner Pubertal Stage assessment. 
An external Data Monitoring committee (DMC) will meet at an 
interval of approximately eve1y 6 months from the first subject 
enrolled. 
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SOF/VEL/VOX FDC
Protocol GS-US-367-1175
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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Test Product, Dose, 
and Mode of 
Administration:
SOF/VEL/VOX FDC is manufactured as a tablet, consisting of: 

400 mg SOF, 100 mg VEL, and 100 mg VOX (adult tablet) for
oral administration
SOF/VEL/VOX FDC tablets will be administered once daily with 
food. Smaller tablets of lower dose and a non-tablet pediatric 
formulation for oral use will be developed.
Cohort 1: DAA-naive subjects without cirrhosis who are 12 to < 18 
years old will receive SOF/VEL/VOX FDC (400/100/100 mg) adult 
tablet for 8 weeks. DAA-naive subjects with cirrhosis and        
DAA-experienced subjects with or without cirrhosis will receive 
SOF/VEL/VOX FDC (400/100/100 mg) treatment for 12 weeks.
Subjects unable to swallow the SOF/VEL/VOX FDC      
(400/100/100 mg) adult tablet (as determined by SOF/VEL/VOX 
FDC swallowability assessment at Screening or at Day 1) will be   
re-assigned to a smaller tablet of lower dose or a non-tablet 
formulation of SOF/VEL/VOX FDC when available. The smaller 
tablet dose and non-tablet formulation will be included in a protocol 
amendment, when available.
Reference Therapy, 
Dose, and Mode of 
Administration:
None
Criteria for Evaluation:
Safety:
AEs, SAEs, laboratory tests, physical examinations, and vital sign 
measurements 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.
Pharmacokinetics:
For all subjects, the steady-state PK of SOF, and its major 
metabolite (GS-331007), VEL and VOX will be assessed. Plasma
PK parameters such as Cmax, Ctau, AUCtau, CLss/F, and Vz/F will be 
estimated, as appropriate.


SOF/VEL/VOX FDC
Protocol GS-US-367-1175
Gilead Sciences, Inc. 
Amendment 1
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Statistical Methods:
The primary endpoint for determining steady-state PK is AUCtau of 
SOF, GS-331007, VEL and VOX in each cohort. The following 
plasma PK parameters will be estimated and summarized: AUCtau, 
Cmax, Ctau, volume of distribution and clearance, as appropriate. The 
effect of age and SOF/VEL/VOX FDC dose on PK will be explored.
The main secondary safety endpoint is review of any AEs with a 
focus on AEs that lead to discontinuation of study drug. In addition,
neuropsychiatric examinations as measured by PedsQL™Pediatric 
Quality of Life survey, growth and development endpoints (eg,
height and weight percentiles, Tanner Pubertal Stage assessment, 
radiographic bone age assessment and bone age biomarkers) will be 
assessed.
The key efficacy endpoint is SVR12 in all enrolled and treated 
subjects.
Other secondary efficacy endpoints include SVR4, SVR24, antiviral 
activity (on-treatment HCV RNA), on-treatment virologic failure, 
and relapse.
Acceptability, including palatability, and swallowability assessments
are secondary endpoints of the study.
All continuous endpoints will be summarized using an 8-number 
summary (n, mean, standard deviation [SD], median, first quartile 
[Q1], third quartile [Q3], minimum, and maximum). All categorical 
endpoints will be summarized by number and percentage of subjects 
who meet the endpoint definition. Safety endpoints will be analyzed 
by the number and percentage of subjects with events or 
abnormalities for categorical values or by the 8-number summary (n, 
mean, standard deviation, median, Q1, Q3, minimum maximum) for 
continuous data. 
Assuming similar variability for SOF, GS-331007, VEL, or VOX 
AUCtau in the pediatric population compared to adults, a sample size 
of 20 pediatric subjects per cohort will provide at least 80% power to 
target a 90% confidence interval of the geometric mean ratio (GMR) 
within the bounds of 50% to 200% when comparing with the adult 
population.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


SOF/VEL/VOX FDC
Protocol GS-US-367-1175
Gilead Sciences, Inc. 
Amendment 1
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
AAT
alpha-1 anti-trypsin
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
ANOVA
analysis of variance
APRI
AST: platelet ratio index
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)
BCRP
breast cancer resistance protein
BLQ
below the lower limit of quantification
BMI
body mass index
CatA
Cathepsin A
CES1
carboxylesterase
CFR
Code of Federal Regulations
CI
confidence interval
CK
creatine kinase
CLss/F
apparent clearance at steady state
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)
CRO
contract (or clinical) research organization 
CYP2B6
Cytochrome P450 2B6
CYP2C8 
Cytochrome P450 2C8
CYP3A4
Cytochrome P450 3A4
CTX 
C-type collagen sequence
DAA
Direct-acting antiviral
dL
deciliter
DNA
deoxyribonucleic acid
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic case report form(s)
EMA
European Medicines Agency
Emax
maximum effect
ESA
erythropoiesis stimulating agent


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eSAE
electronic serious adverse event
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
fixed dose combination
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
granulocyte colony stimulating factor
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GMR
geometric mean ratio
GSI
Gilead Sciences, Inc.
GT
genotype (viral)
HAV
hepatitis A virus
Hb
hemoglobin
HbA1c
hemoglobin A1c
HBsAg
hepatitis B surface antigen
HBsAb
hepatitis B surface antibody
HBcAb
hepatitis B core antibody
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
IFN
Interferon 
IL28B
IL28B gene
IMP
investigational medicinal product
INR
International Normalized Ratio 
IU
International Units
IUD
intrauterine device
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDV
ledipasvir
LiPA
line probe assay
LLN
Lower limit of the normal range
LLOQ
Lower limit of quantification


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Amendment 1
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LLT
Lower-Level Term 
MedDRA
Medical Dictionary for Regulatory Activities
MCV
mean corpuscular volume
Mg
Milligram
mL
Milliliter
Mmol
millimole
Min
Minute
mmHg
millimeters mercury
n
number
NS (3/4A/5A/5B)
Non-structural Protein
OATP
Organic Anion-Transporting Polypeptide
PBMC
peripheral blood mononuclear cell(s)
PCR
Polymerase Chain Reaction
PEG
peginterferon alfa-2a
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
PPI
Proton pump inhibitors
PT 
Prothrombin time or Preferred Term 
PVE
Pharmacovigilance & Epidemiology 
P1NP
Procollagen type 1 N-terminal propeptide
Q1
first quartile
Q3
third quartile
RBC
Red blood cell count
RBV
ribavirin
RNA
ribonucleic acid
SADR
Serious adverse drug reaction
SAE
serious adverse event
Scr
serum creatinine (mg/dL)
SD
Standard deviation
SNP
single nucleotide polymorphism
SOC
System Organ Class or Standard of Care
SOF
Sofosbuvir
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TND
Target not detected
TSH
Thyroid stimulating hormone
CCI


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t1/2
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
VEL
Velpatasvir
Vz/F
apparent volume of distribution
VOX 
Voxilaprevir
WBC
white blood cells counts


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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. Based on recent 
modeling studies, the global prevalence of chronic hepatitis C is estimated to average 1% in 
2015, for a total of 71.1 million {The Polaris Observatory HCV Collaborators 2017}. Although 
data on the global prevalence of HCV in children are limited, there are estimated to be 5 to 
6.6 million viremic infections in children 15 years of age or younger {El-Sayed 2015, Sokal 
2017}. The prevalence varies by geographic location. The estimated prevalence of HCV 
infection in children is up to 0.4% in Europe and the United States (US); and up to 6% in 
resource-limited countries {El-Shabrawi 2013, Khaderi 2014}. 
The natural history of children with chronic HCV infection differs from that in adults since HCV
infection in children is relatively benign. Most children chronically infected with HCV are 
asymptomatic or have mild nonspecific symptoms. Clinical symptoms are present in 
approximately 20% of children in the first 4 years of life, with hepatomegaly being the most 
frequent sign (10%). Many, but not all, perinatally infected children will have intermittently or 
persistently abnormal alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
levels, particularly in the first 2 years of life. In children with vertical HCV infection who have 
undergone liver biopsy, the histological spectrum is usually mild, although severe liver disease is 
encountered {Mohan 2010}. 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 {Hu 2010}. 
Recently, in the United States (US) and European Union (EU), sofosbuvir (Sovaldi®) and 
ledipasvir/sofosbuvir (Harvoni®) were approved for use in treatment-naive or interferon 
(IFN)-experienced patients who are 12 years old and older or weighing at least 35 kg (US only). 
For patients younger than 12 years or weighing less than 35 kg the only currently available HCV 
treatment is pegylated-interferon (Peg-IFN) and weight-based ribavirin (RBV) for 24 or 48 
weeks depending on HCV genotype. The option of Peg-IFN+RBV therapy remains inadequate in 
regard to both efficacy and safety {Jonas 2012, Wirth 2012}.
Sofosbuvir (SOF) in combination with RBV is indicated in patients 12 to < 18 years old with 
genotype 2 or genotype 3 HCV infection for 12 or 24 weeks, respectively, based on the results of 
study GS-US-334-1112. In study GS-US-334-1112, this treatment was demonstrated to be safe, 
well tolerated and highly effective resulting in SVR12 rates of 100% and 97% in genotype 2 and 
genotype 3 subjects 12 to < 18 years old, respectively. No subject experienced on-treatment 
virologic failure or relapse; one genotype 3 subject was lost to follow up {Wirth 2017}. The 
study is ongoing in 3 to < 12 years old subjects. 


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Ledipasvir/sofosbuvir (LDV/SOF) is indicated in patients 12 to < 18 years old with genotype 1, 
4, 5 or 6 HCV infection, for 12 or 24 weeks depending on the HCV genotype and cirrhosis 
status, based on the results of study GS-US-337-1116. In addition, in some countries, 
ledipasvir/sofosbuvir plus ribavirin for 24 weeks is indicated in patients with genotype 3. In 
study GS-US-337-1116, treatment with LDV/SOF for 12 weeks was safe, well tolerated and 
highly effective in subjects 12 to < 18 years old with genotype 1 chronic hepatitis C infection
resulting in SVR12 rates of 98%. No subject experienced on-treatment virologic failure or 
relapse; two subjects were lost to follow-up {Balistreri 2017}. The study is ongoing in 3 to 
< 12 year-old subjects infected with genotypes 1, 3, 4, 5, or 6.
The availability of the first oral direct-acting antiviral (DAA) therapies for HCV infected 
pediatric patients represents a major therapeutic advance, by eliminating the need for weekly 
Peg-IFN injections and incidence of systemic side effects associated with its use. However, the 
treatment combination of SOF with RBV may remain less attractive to patients due to the 
significant toxicities associated with RBV, including hematologic, constitutional and teratogenic 
side effects. In addition, treatment duration of 12 or 24 weeks with either SOF or LDV/SOF 
depending on the HCV genotype and the cirrhosis status may represent a limiting factor for some 
pediatric patients. Therefore, treatment options that do not include RBV, with shorter fixed 
duration, and are effective across all HCV genotypes would be beneficial in the pediatric setting 
by decreasing the frequency of monitoring, blood tests, and increasing patient adherence. 
Moreover, the availability of a pangenotypic regimen is anticipated to be especially beneficial in 
areas where HCV genotype diversity is high and genotyping may not be readily available or 
routinely performed.
It is anticipated that as more pediatric patients are treated for HCV with DAA-based therapies, 
patients who fail those treatments will increase. Currently, there are no approved treatment 
options for pediatric patients who fail treatment with DAAs. Therefore, there is an unmet 
medical need for a pediatric salvage therapy with highly potent DAAs that are active against
resistant associated variants.
1.2.
Sofosbuvir/Velpatasvir/Voxilaprevir Fixed-Dose Combination
Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) fixed dose combination (FDC) is a 
coformulation of SOF 400 mg, VEL 100 mg, and VOX 100 mg into a single tablet for the 
treatment of chronic HCV infection. This fixed dose combination combines three unique 
mechanisms of action into a single tablet:

Sofosbuvir, a nucleotide analog HCV NS5B polymerase inhibitor, which is currently 
approved in the US, and other regions for the treatment of HCV infection as a component of 
an antiviral treatment regimen.

Velpatasvir, an HCV NS5A inhibitor that has potent in vitro anti-HCV activity across all
genotypes, which is currently approved in the US, EU, and other regions for the treatment of 
HCV infection in combination with SOF.


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
Voxilaprevir, a macrocyclic HCV NS3/4A protease inhibitor (PI) with potent in vitro
antiviral activity against genotypes 1 to 6 HCV, and an improved resistance profile compared
to previously developed PIs which is currently approved in the US and other regions for the 
treatment of HCV infection in combination with SOF and VEL.
1.2.1.
General Information
Please refer to the SOF/VEL/VOX FDC Investigator Brochure (IB) for additional information on 
SOF/VEL/VOX FDC.
Information in the IB includes:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism
Interactions with other medicinal products and other forms of interaction 

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.3.
Rationale for This Study
This clinical study is designed to evaluate the PK, safety and efficacy of treatment with 
SOF/VEL/VOX FDC in adolescents and children with chronic HCV infection who are either 
DAA-naive or DAA-experienced with or without cirrhosis. 
Recently in the US and EU, treatment with SOF+RBV and LDV/SOF for 12 or 24 weeks was 
approved for use in treatment naive or IFN-experienced pediatric patients who are ≥12 years old 
or who weigh at least 35 kg (US only). For all other pediatric patients treatment with Peg-IFN 
and weight-based RBV is considered the standard of care (SOC). Therefore, for patients younger 
than 12 years old, there is a need for new treatments that combine potent and sustained efficacy 
with improved tolerability and safety. In addition for all pediatric patients of any age, oral, RBV-
free, highly effective and well-tolerated shorter courses of therapy would require less frequent 
medical monitoring and blood tests. This represents an advantage enhancing convenience and 
patient adherence. 
Furthermore, it can be anticipated that as more pediatric patients are treated for their HCV 
infection with DAA-based therapies, the unmet medical need for effective retreatment options
for patients who fail these treatments will increase. Currently, there are no approved treatment 
options for pediatric patients who fail DAA treatments. Therefore, there is a need for 
development of a salvage therapy with a combination of highly potent DAAs that have enhanced 
activity against common NS5A and NS5B resistant associated variants. 


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Data from the Phase 3 study POLARIS-2 (GS-US-367-1172) in adult DAA-naive subjects 
demonstrated that SOF/VEL/VOX FDC for 8 weeks was safe, generally well tolerated and 
highly efficacious, with SVR12 rates of 96% in subjects without cirrhosis and 91% in subjects 
with cirrhosis. Data from the Phase 3 studies POLARIS-1 (GS-US-367-1171) and POLARIS-4
(GS-US-367-1170) in adult DAA-experienced subjects demonstrated that SOF/VEL/VOX FDC 
for 12 weeks was safe, generally well tolerated and resulted in SVR > 95%, representing an 
effective retreatment option for subjects who have previously failed treatment with multiple 
DAAs. Furthermore, in these studies, the SVR12 rate in cirrhotic DAA-experienced subjects 
treated for 12 weeks was 99%.
In summary, GS-US-367-1175, will evaluate the efficacy of an 8 week treatment of
SOF/VEL/VOX FDC in DAA-naive pediatric subjects who do not have cirrhosis and a 12 week
treatment in DAA-naive pediatric subjects who have cirrhosis or DAA-experienced pediatric 
subjects with or without cirrhosis. 
1.4.
Rationale for Dose Selection of SOF/VEL/VOX FDC
SOF/VEL (400/100 mg) once daily is the approved marketed dose and, as such, was selected for 
co-formulation with VOX into a fixed dose combination tablet. The VOX 100 mg dose was 
selected based on the anti-HCV activity of VOX established in the Phase 1b proof-of-concept 
study GS-US-338-1121 and Phase 2 studies in subjects with HCV infection (GS-US-367-1169 
and GS-US-367-1168). These studies indicated that the voxilaprevir exposures achieved 
following administration of VOX 100 mg + SOF/VEL (400/100 mg) with food are associated 
with > 90% of the maximum antiviral response across all HCV genotypes.
The combination of SOF 400 mg, VEL 100 mg, and VOX 100 mg has been administered in
Phase 2 and Phase 3 studies to over 1900 subjects. SOF/VEL/VOX FDC (400/100/100 mg) 
tablet was evaluated in the registrational Phase 3 POLARIS program and these doses represent 
the marketed dose of SOF/VEL/VOX FDC tablet for the treatment of HCV-infection in adults.
Sofosbuvir is a substrate for efflux drug transporters P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP). SOF is extensively metabolized to the pharmacologically active 
nucleoside analog phosphate. The activation pathway involves hydrolysis by intestinal and 
hepatically expressed carboxylesterase (CES1) and Cathepsin A (CatA) enzymes {Yang 2009, 
Zhu 2009}. SOF is also converted to GS-331007, an inactive circulating metabolite, which is 
eliminated renally by active tubular secretion and glomerular filtration. 
Velpatasvir is also a substrate for P-gp and BCRP. VEL has low systemic clearance in 
nonclinical species and low metabolic turnover by Cytochrome P450 2B6 (CYP2B6), 
Cytochrome P450 2C8 (CYP2C8) and Cytochrome P450 3A4 (CYP3A4). It is eliminated 
through biliary excretion as unchanged parent drug and metabolites (76.6% of the administered 
dose is recovered as VEL in feces). 
Voxilaprevir is a substrate for P-gp, BCRP, and Organic Anion-Transporting Polypeptide 
(OATP) 1B1/3. VOX has low in vitro turnover, primarily by CYP3A4. It is eliminated through 
biliary excretion as unchanged parent drug and metabolites (40% of the administered dose is 
recovered as VOX in feces).


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Selection of doses of SOF/VEL/VOX FDC for adolescents and younger age groups will target 
systemic exposures similar to those observed in adults at the proposed marketed dose. Body 
weight/surface area, the potential ontogenic changes in transporters and metabolic enzymes that 
govern the disposition of SOF, VEL and VOX and the results obtained in older age groups will 
be taken into consideration. For younger age groups, allometric scaling and observed exposures 
in the previous age groups will be used to inform dose selection. Available data suggest 
comparable hepatic expression of CYP2B6 and CES1 in adolescents and adults with modestly 
decreased expression in children, and comparable levels of CYP2C8, CYP3A4 and OATP1B1/3 
to adults from a young age (~3-6 years of age) {Brouwer 2015, Johnson 2006, Prasad 2016}, 
however, little is known about the developmental regulation of OATP, Pgp, CES, and CatA. 
The adult clinical doses of SOF/VEL/VOX FDC (400/100/100 mg) will be evaluated in 
adolescents (12 to <18 years old). Safety and PK data in the adolescent group (Cohort 1), in 
addition to considerations of body weight/body surface area, will inform dose selection for the 
younger age groups.
Age-appropriate formulations of SOF/VEL/VOX FDC (a smaller tablet of lower dose and a non-
tablet formulation currently under development) that offer an important option in the treatment 
of HCV infection in the pediatric population are planned for evaluation in children below 12 
years of age or children who are unable to swallow the adult dose tablet formulation. The smaller 
tablet and non-tablet formulation of SOF/VEL/VOX FDC will be included in a protocol 
amendment, when available.
1.5.
Rationale for Study Design 
This open-label, multi-cohort study is designed to collect safety, efficacy, and PK data to 
determine the appropriate dose for each age group. The treatment durations of 8 weeks for 
DAA-naive subjects without cirrhosis and 12 weeks for DAA-naive subjects with cirrhosis and 
DAA-experienced subjects with or without cirrhosis, are based on the Phase 3 POLARIS 
program. The choice of no comparator or active control group is in line with international 
guidelines that support single-arm pediatric studies when safety and efficacy have been 
demonstrated in adults. The minimum number of subjects planned to be enrolled in each age 
group is considered acceptable to collect PK data to determine the appropriate dose for each age 
group.
1.6.
Risk/Benefit Assessment for the Study
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 {Bortolotti 
2008}. 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.


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Recently in the US and EU, treatment with SOF+RBV and LDV/SOF for 12 or 24 weeks were 
approved for use in treatment naive or IFN-experienced patients who are 12 years old and older 
or weighing at least 35 kg (US only). For all other pediatric patients treatment with Peg-IFN and 
weight-based RBV is still considered the SOC. Therefore, for patients younger than 12 years 
there is a need for new treatments that combine potent and sustained efficacy with improved 
tolerability and safety. In addition, for all pediatric patients of any age there continues to be a 
need for new pangenotypic HCV treatments free of RBV and of shorter duration, requiring less 
frequent medical monitoring and a lower amount of blood tests to ensure greater convenience 
and patient adherence. Moreover, there are no approved treatment options for pediatric patients 
who fail treatment with DAAs. Therefore, there is also a need for development of a salvage 
therapy with combination of highly potent DAAs.
If high rates of SVR can be obtained with short, pangenotypic, well-tolerated regimen, the 
anticipated improvements in safety and tolerability would offer a favorable risk-benefit 
determination for individuals with chronic HCV infection.
1.7.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


SOFNEIJVOX FDC 
Protocol GS-US-367-1175 
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2_ 
OBJECTIVES 
The prima1y objective of this study is: 
Amendment 1 
• 
To evaluate the steady-state phannacokinetics (PK) and confnm age-appropriate dose of 
SOFNELN OX FDC in pediatric subjects with chronic HCV infection 
The secondaiy objectives of this study are: 
• 
To evaluate the safety and tolerability of SOF N ELN OX FDC in pediatric subjects with 
chronic HCV infection 
• 
To evaluate the antiviral efficacy of SOFNELNOX FDC treatment in pediatric subjects 
with chronic HCV infection, as assessed by the proportion of pediatric subjects with 
sustained virological response (SVR) 12 weeks after cessation of treatment (SVR12) 
• 
To evaluate the antiviral efficacy SOFN ELNOX FDC treatment in pediatric subjects with 
chronic HCV infection, as assessed by the propo1tion of pediatric subjects with SVR 4 and 
24 weeks after cessation of treatment (SVR4 and SVR24) 
• 
To evaluate the propo1tion of pediatric subjects with virologic failure, including on-treatment 
virologic failure and relapse 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment 
• 
To evaluate the emergence of viral resistance to SOF, VEL, and VOX during treatment and 
after cessation of treatment 
• 
To evaluate the effect of SOFNELNOX FDC on growth and development of pediatric 
subjects during and after treatment 
• 
To evaluate acceptability, including palatability, and swallowability of fo1mulations (as 
applicable) used in the study 
• 
To assess the effect of treatment with SOFNELNOX FDC on quality of life as measured by 
PedsQL™ Pediatric Quality of Life survey 
I 
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SOFNEIJVOX FDC 
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3_ 
STUDY DESIGN 
3.1. 
Study Design 
Amendment 1 
This is an open-label, multi-coho1i study evaluating the PK, safety, and antiviral activity of 
SOFNELNOX FDC in pediatric subjects with chronic HCV infection. 
Pediatric subjects with chronic HCV infection of any HCV genotype, including indeterminate or 
inixed genotypes, will be enrolled. Both DAA-na'ive and DAA-experienced subjects will be 
eligible. DAA-experienced subjects are defined as subjects who have been exposed to treatment 
with DAAs including NS3/4A protease inhibitors, NS5A inhibitor or NS5B 
nucleotide/nucleoside inhibitor. 
3.2. 
Study Treatments 
Three sequential age-based coho1is will be enrolled: 
• 
Coho1i 1: at least 20 subjects 12 to < 18 years old 
• 
Coh01i 2: at least 20 subjects 6 to < 12 years old 
• 
Coho1i 3: at least 20 subjects 3 to < 6 years old 
For all subjects, sparse PK samples will also 
iiiliiiiiiieks 1, 2, 4, 8, and 12) dependent on treatment duration 
The study will start with Coho1i 1. DAA-naive subjects without cnThosis will receive 
SOFNELNOX FDC (400/100/100 mg) adult tablet for 8 weeks. DAA-naive subjects with 
cnThosis and DAA-experienced subjects with or without cinhosis will receive treatment for 
12 weeks. 
Subjects unable to swallow the SOFNELNOX FDC (400/100/100 mg) adult tablet (as 
determined by SOFNELNOX FDC swallowability assessment at Screening or at Day 1) will be 
re-assigned to a smaller tablet oflower dose and/or a non-tablet fonnulation of SOFNELNOX 
FDC when available. 
PK and safety data from at least 20 evaluable subjects in each coho1i will be reviewed to confom 
the appropriateness of the SOFNELNOX FDC dose used in each cohort and to dete1mine the 
dose to be evaluated in the next cohort. 
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3.3.
Duration of Treatment
DAA-naive subjects without cirrhosis will receive treatment for 8 weeks and will then return for 
follow-up visits at 4, 12, and 24 weeks after discontinuation of study drug. 
DAA-naive subjects with cirrhosis and DAA-experienced subjects with or without cirrhosis will 
receive treatment for 12 weeks and will then return for follow-up visits at 4, 12, and 24 weeks 
after discontinuation of study drug.
3.4.
Virologic Response-Based Stopping Criteria
The following on-treatment virologic response-based treatment stopping criteria will be utilized:

Confirmed HCV RNA ≥LLOQ after 2 consecutive HCV RNA <LLOQ

Confirmed >1 log10 increase on-treatment nadir
Confirmation should be performed as soon as possible and must occur no later than 2 weeks after
an initial observation indicating virologic failure during the on-treatment phase.
3.5.
Discontinuation Criteria
The medical monitor should be consulted prior to subject discontinuation when medically
feasible. Study medication must be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator

Unacceptable toxicity (as defined in Section 7.5 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 3.4

Significant protocol violation including non-compliance with study assessments

Subject or parent/legal guardian request to discontinue for any reason; it is important to 
determine whether the withdrawal of consent is primarily due to an AE, lack of efficacy, or 
other reason

Discontinuation of the study at the request of Gilead, regulatory agency, or an Independent 
Ethics Committee (IEC)


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Protocol GS-US-367-1175 
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Amendment 1 
Subjects who meet any of the following criteria must stop ti·eatment with SOFNELNOX FDC: 
• 
Elevation of ALT and/or AST above the upper limit of no1mal and > 5x Day 1 or nadir, 
confinned by immediate repeat testing 
• 
Elevation of ALT >3x Day 1 and total bilirnbin >2x ULN, confomed by immediate repeat 
testing 
• 
Any Grade 3 or greater rash associated with constitutional symptoms (see Appendix 3) 
• 
Any Grade 4 adverse event assessed as related to administi·ation of SOF N ELNOX FDC 
(see Appendix 3) 
3.6. 
End of Study 
The end of study is defined as when the last subject has completed their final visit in the study. 
Discontinuation from study diug dosing and discontinuation from the overall study, including the 
postti·eatment period, will be collected as two separate events. 
The end of study will occm at the postti·eatment Week 24 visit. 
3.7. 
Reconsent 
When a subject reaches the age of consent in their country/region, they will be invited to consent 
with an age-appropriate consent to continue participating in the clinical u-ial. 
-
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
At least 60 subjects will be enrolled in this study.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Subject or parent/ legal guardian able to provide written informed consent prior to any 
screening evaluations. Willing to comply with study requirements in accordance with 
IEC/local requirements and the Investigator’s discretion. Subject will provide assent, if 
possible.
2) 3 to < 18 years of age as determined at Day 1
3) Chronic HCV infection (≥ 6 months) as documented by prior medical history or liver biopsy 
4) HCV RNA ≥ 1000 IU/mL at Screening 
5) Subjects must have a determination of prior treatment status:
a) DAA-naive is defined as either:
i)
Treatment naive with no prior exposure to any IFN, RBV, or approved or 
experimental HCV-specific DAA
ii) Treatment experienced with an IFN-based regimen and no prior exposure to an 
approved or experimental HCV-specific DAA
b) DAA-experienced is defined as prior exposure to a regimen including any DAA 
(eg, NS3/4A protease inhibitor, NS5A inhibitor, or NS5B nucleotide/nucleoside 
inhibitor)
6) A negative serum pregnancy test is required at Screening and a negative urine test is required 
at Day 1 for female subjects of childbearing potential (as defined in Appendix 5). 
7) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 5. 
8) Lactating females must agree to discontinue nursing before the study drug is administered


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9) Subject must be able to comply with the dosing instructions for study drug administration 
and be able to complete the study schedule of assessments.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Current or prior history of clinical hepatic decompensation (eg, clinical ascites, 
encephalopathy, and/or variceal hemorrhage)
2) Any of the following laboratory parameters at Screening:
a) INR >1.2 x ULN
b) Platelets < 50,000/mm3
c) Albumin < 3.5 g/dL
d) ALT> 10 x ULN
e) AST > 10 x ULN
f)
Direct bilirubin > 1.5 x ULN
g) Estimated glomerular filtration rate < 90 mL/min/1.73m2, as calculated by the Schwartz 
formula
3) Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)
4) Evidence of hepatocellular carcinoma or other malignancy (with exception of certain 
resolved skin cancers)
5) Co-infection with human immunodeficiency virus (HIV), acute hepatitis A virus (HAV) or 
hepatitis B virus (HBV) (hepatitis B surface antigen [HBsAg] positive at Screening)
6) Current or prior history of any of the following:
a) Clinically significant illness (other than HCV) or any other major medical disorder that 
may have interfered with subject treatment, assessment, or compliance with the protocol; 
subjects currently under evaluation for a potentially clinically significant illness (other 
than HCV) are also excluded
b) Significant cardiac disease
c) Gastrointestinal malabsorption syndrome that may interfere with absorption of orally 
administered medications
d) History of solid organ or bone marrow transplantation


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e) 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 6 months prior to enrollment or has not required medication in the last 12 months 
may be included
7) 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 
8) Use of any prohibited concomitant medications as described in Section 5.3. 
9) Investigational agents taken within the past 28 days (except with the approval of the sponsor)
10) Known hypersensitivity to the study drug, the metabolites, or formulation excipients


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Description and Handling of SOF/VEL/VOX FDC
5.1.1.
Formulation
SOF/VEL/VOX FDC (400/100/100 mg) tablets, with dimensions of approximately 10 20mm, 
are available as beige, capsule-shaped film-coated tablets debossed with “GSI” on one side and a
“square” containing the number “3” on the other side. In addition to the active ingredients, 
SOF/VEL/VOX FDC (400/100/100 mg) tablets also contain copovidone, microcrystalline 
cellulose, lactose monohydrate, silicon dioxide, croscarmellose sodium, and magnesium stearate. 
The active tablet film coating material contains polyvinyl alcohol, titanium dioxide, 
macrogol/polyethylene glycol, talc, iron oxide yellow, iron oxide red, and ferrosoferric oxide.
Placebo tablets to assess swallowability of SOF/VEL/VOX FDC (400/100/100 mg) tablets, are 
of similar size and shape. The placebo tablets are available as beige, capsule-shaped film-coated 
tablets debossed with “GSI” on one side and a “square” containing the number “3” on the other 
side. The tablets contain copovidone, microcrystalline cellulose, lactose monohydrate, 
croscarmellose sodium, and magnesium stearate. The placebo tablet film coating material 
contains polyvinyl alcohol, titanium dioxide, macrogol/polyethylene glycol, talc, iron oxide 
yellow, iron oxide red, and ferrosoferric oxide.
5.1.2.
Packaging and Labeling
SOF/VEL/VOX FDC (400/100/100 mg) tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 28 tablets, silica gel desiccant, and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant screw cap fitted 
with an induction-sealed, aluminum-faced liner.
Placebo tablets to assess swallowability of SOF/VEL/VOX FDC (400/100/100 mg) tablets, are 
packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 28 tablets, 
silica gel desiccant, and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child-resistant screw cap fitted with an induction-sealed, aluminum-faced 
liner.
SOF/VEL/VOX FDC (400/100/100 mg) tablet bottles and placebo tablets to be distributed to 
study centers in the participating countries shall be labeled to meet all applicable requirements of 
the United States Food and Drug Administration (FDA), and EU Guideline to Good 
Manufacturing Practice-Annex 13 (Investigational Medicinal Products) and/or local regulations 
as applicable.
Sufficient quantities of SOF/VEL/VOX FDC (400/100/100 mg) tablets will be shipped to the 
investigator or qualified designee from Gilead Sciences Clinical Supply Management (or its 
designee).
5.1.3.
Storage and Handling
SOF/VEL/VOX FDC (400/100/100 mg) bottles should be stored below 30°C (86°F).  


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Placebo to match SOF/VEL/VOX FDC (400/100/100 mg) tablets for Swallowability Assessment 
should be stored at controlled room temperature until required for administration. Controlled 
room temperature is defined as 25°C (77°F); excursions are permitted between 15C and 30C 
(59°F to 86°F).
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/VEL/VOX FDC
(400/100/100 mg).
5.2.
Dosage and Administration of SOF/VEL/VOX FDC
Cohort 1 (12 to < 18 years): SOF/VEL/VOX FDC (400/100/100 mg) tablets will be administered 
once daily with food. Enrollment of subjects unable to swallow the placebo to match the 
SOF/VEL/VOX FDC (400/100/100 mg) tablet will be deferred until small tablet of lower dose
and/or non-tablet formulations are available.
DAA-naive subjects without cirrhosis will receive SOF/VEL/VOX FDC (400/100/100 mg)
treatment for 8 weeks. DAA-naive subjects with cirrhosis or all DAA-experienced subjects with 
or without cirrhosis will receive treatment for 12 weeks.
Subjects should be instructed that if vomiting occurs within 4 hours of dosing an additional tablet 
of SOF/VEL/VOX FDC (400/100/100 mg) should be taken. If vomiting occurs more than 
4 hours after dosing, no further dose is needed.
If a dose is missed and it is within 18 hours of the regularly scheduled time, subjects should be 
instructed to take the tablet as soon as possible and then follow with the next dose at the usual
scheduled time.
If a dose is missed after 18 hours of the regularly scheduled time, then it is a missed dose. 
Subjects should be instructed to take the next dose at the usual next scheduled time. Subjects 
should be instructed not to take a double dose.
5.3.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to Screening, through 30 days after the last 
dose of study drug need to be recorded in the source documents and electronic case report 
form(s) (eCRFs).
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Day 1 visit through the end of treatment:

Hematologic stimulating agents (eg, erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)


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
Chronic use of systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (eg, infliximab)

Investigational agents or devices for any indication
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters, ie, OATP and P-gp) with study drug(s) may result in PK interactions resulting 
in increases or decreases in exposure of study drug(s). In addition, study drug(s) may have an 
impact on pharmacokinetics of other concomitant medicinal products that are substrates of P-gp, 
BCRP, OATP1B1, OAT1B3, or OATP2B1 as described in the Investigator’s Brochure. The use 
of amiodarone is prohibited from 60 days prior to Day 1 through the end of treatment. Other 
examples of representative medications which are prohibited or are to be used with caution from 
21 days prior to Day 1 through the end of treatment are listed below; this list is not exhaustive. 
For all co-medications, consult label for pediatric-specific recommendations.
Table 5-1.
Disallowed Medications and Concomitant Medications to be used with 
Caution
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton-Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Anticonvulsantsb
Carbamazepine, Phenobarbital, 
Phenytoin, Oxcarbazepine
Antimycobacterialsb
Rifabutin, Rifapentine, Rifampin
Cardiac Medications
Amiodaronec, Dabigatran 
Etexilated
Digoxind,  Vitamin K antagonistse
Herbal/Natural 
Supplementsbf
St. John’s Wort, Echinacea, Milk thistle 
(ie, silymarin), Chinese herb sho-saiko-to (or Xiao-
Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsf
Rosuvastatin, Atorvastatinf, 
Pravastatinf
Other
Modafinilb, Sulfasalazined, Methotrexate d, 
Ethinylestradiol-containing products g, 
Cyclosporineh
a
Proton pump inhibitors (PPIs) comparable to omeprazole 20 mg once-daily may be taken. H2 receptor antagonists must not 
exceed the equivalent of 40 mg famotidine taken twice daily. Antacids that directly neutralize stomach acid (eg, Tums, Maalox) 
are permitted, but may not be taken within 4 hours (before or after) study drug administration.
b
May result in a decrease in the concentrations of study drugs.
c
The use of amiodarone is prohibited from 60 days prior to Day 1 through the end of treatment
d
May result in an increase in the concentration of study drugs and/or concomitant medications
e
Close monitoring of International Normalized Ratio (INR) is recommended as liver function may improve during treatment 
with study drug
f
Use with study drugs may result in an increase in the concentration of the HMG-CoA Reductase Inhibitors. Monitor for
signs and symptoms of muscle weakness or myopathy, including rhabdomyolysis. Pravastatin and atorvastatin should initiate 
dosing at the lowest dose, and a gradual dose increase may be tailored to clinical response. Pravastatin may be administered with 
SOF/VEL/VOX FDC at a dose that does not exceed pravastatin 40 mg, and atorvastatin may be administered with 
SOF/VEL/VOX FDC at a dose that does not exceed 20 mg.
g
May increase the risk of ALT elevations
h
May increase the exposure of VOX


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Medications for disease conditions excluded from the protocol (eg, transplantation) are not listed 
under this Concomitant Medication section, but are disallowed in the study.
Should subjects have a need to initiate treatment with any disallowed concomitant medication, 
the medical monitor must be consulted prior to initiation of the new medication. In instances 
where disallowed medication is initiated prior to discussion with the sponsor, the investigator 
must notify Gilead as soon as he/she is aware of the use of the medication.
5.4.
Accountability for SOF/VEL/VOX FDC
The investigator is responsible for ensuring adequate accountability of all used and unused
investigational medicinal product (IMP) bottles. This includes acknowledgement of receipt of 
each shipment of IMP (quantity and condition). All used and unused IMP bottles dispensed to 
subjects must be returned to the site.
SOF/VEL/VOX FDC accountability records will be provided to each study site to:

Record the date received and quantity of IMP kits

Record the date, subject number, subject initials, the IMP kit number dispensed

Record the date, quantity of used and unused IMP kits returned, along with the initials of the 
person recording the information.
5.4.1.
Investigational Medicinal Product Return or Disposal
Refer to Section 9.1.7 for information on return and disposal of study drugs.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
Entry into screening does not guarantee enrollment into the study.  In order to manage the total 
trial enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any 
site or trial-wide at any time.
6.1.1.
Screening Visit
Subjects will be screened within 28 days prior to enrollment to determine eligibility for 
participation in the study. The screening window can be extended to 42 days with sponsor
approval for subjects with extenuating circumstances. In cohort 2 and Cohort 3, for subjects 
weighing ≤25 kg the screening visit samples will be collected in two different days (please see 
Appendix 2 Table 1). If the subject’s weight is > 25 kg, the screening visit blood draw can be 
completed in one day. The following will be performed and documented at Screening:

Obtain written informed consent/assent

Determine eligibility 

Obtain medical history

Perform complete physical examination 

Vital signs 

Body weight and height

Assessments of AEs and concomitant medications

SOF/VEL/VOX FDC swallowability assessment (may be performed at Screening up to 
Day 1) 

Transient elastography test (FibroScan® if available; may be performed at Screening up to 
Day 1)


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
Obtain blood samples for: 
Hematology
Chemistry
Coagulation tests
HCV RNA
HCV Genotyping 
Serum -hCG pregnancy test for females of childbearing potential only
IL28B genotyping (may be performed at Screening up to Day 1) 
HIV testing, HAV antibody, HCV antibody, HBsAg, HBV surface antibody (HBsAb), 
HBV core antibody (HBcAb) 
HbA1c
TSH
Alpha-1 anti-trypsin (ATT)
Fibrotest®
APRI 

Obtain urine samples for:
Urinalysis
Urine Drug Screen
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 28 days after Screening for enrollment into the study.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all SAEs, as well as any AEs related to protocol-mandated procedures 
on the adverse events eCRF. All other untoward medical occurrences observed during the 
screening period, including exacerbation or changes in medical history are to be captured on the 
medical history eCRF. See Section 7 Adverse Events and Toxicity Management for additional 
details.


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6.1.2.
Day 1 Assessments
Subjects returning to the clinic for enrollment at Day 1 should be instructed to fast (no food or 
drink, except water), starting from midnight (00:00) or earlier, as appropriate, on the evening 
prior to the Day 1 visit to ensure an approximate 8-hour fast prior to the blood sample collection 
the next morning.  
After confirmation of eligibility has been evaluated, the following tests and procedures must be 
completed prior to enrollment and dosing/dispensing on Day 1:

Parental height, if known

Complete physical examination 

Tanner Pubertal Stage assessment

Vital signs 

Body weight and height (with calculation of BMI)

A single X-ray of the left wrist, hand, and fingers for radiographic bone age assessment

Assessment of AEs and concomitant medications

Transient elastography test (FibroScan® if available and if not completed at Screening) 

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the investigator based on subject’s pubertal status) 

Quality of life survey: Subject is to review questionnaire and write/mark answers directly 
onto the questionnaire.  Parent/guardian completes the parent/guardian questionnaire.

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
IL28B genotyping (may be performed at Screening, up to Day 1) 
CCI


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Bone age biomarkers: CTX and PlNP 
-
HBV DNA testing for subjects HBcAb positive at Screening 
I 
• 
Obtain urine samples for: 
-
Urinalysis 
-
Urine pregnancy test for females of childbearing potential only 
6.1.2.1. 
Drng Administration 
Amendment 1 
• 
Perfo1m SOFNELNOX FDC swallowability assessment (if not previously perfo1med at 
Screening). 
• 
Dispense study drng as directed by the Interactive Web Response System (IWRS) 
• 
Instruct the subject on the packaging, storage, and adminish'ation of the study diug 
• 
Observe the subject taking the first dose of study diug with food and record the time of first 
dose. 
• 
Subject or parent/legal guardian (if needed) will complete the relevant acceptability 
questionnaires. 
6.2. 
Enrollment 
An IWRS will be employed to manage subject emollment and ti·eatment assignment. The study 
will not be randomized; subjects will be emolled in the appropriate age-based coho1t. 
6.3. 
6.3.1. 
Treatment Assessments 
Week 1 (::1: 3 days) 
The following procedures/assessments are to be completed at this visit: 
• 
Perfo1m symptom-directed physical examination 
• 
Vital signs 
• 
Body weight and height 
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• 
Assessment of AEs and concomitant medications 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemist:Iy 
-
HBV DNA testing for subjects HBcAb positive at Screening 
-HCVRNA 
-
Single sparse PK sample collected anytime 
6.3.2. 
Week 2 (::1: 3 days) 
The following procedures/assessments are to be completed at this visit: 
• 
Perfo1m symptom-directed physical examination 
• 
Vital signs 
• 
Body weight and height 
• 
Assessment of AEs and concomitant medications 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemist:Iy 
-HCVRNA 
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HBV DNA testing for subjects HBcAb positive at Screening 
Amendment 1 
-
Two s arse PK sam les collected re-dose and between 15 minutes and 4 hours 
6.3.3. 
Week 4 (::1: 3 days) 
The following procedures/assessments are to be completed at this visit: 
• 
Perfo1m symptom-directed physical examination 
• 
Vital signs 
• 
Body weight and height 
• 
Assessment of AEs and concomitant medications 
• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
paiiicipants (all subjects ~ 12 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 
-HCVRNA 
-
HBV DNA testing for subjects HBcAb positive at Screening 
-
Two s ai·se PK sam les collected re-dose and between 15 minutes and 4 hours 
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• 
Obtain urine sample for: 
-
Urine pregnancy test for females of childbearing potential only 
Amendment 1 
• 
Review medication compliance with subject and/or parent/guardian (subject should return all 
study dmg at these visits) 
• 
Dispense study chug as directed by the IWRS 
6.3.4. 
Week 8 (::1: 3 days) 
The Week 8 Visit will only be completed for subjects that are DAA-naive with cinhosis or 
DAA-experienced with or without cinhosis completing 12 weeks of treatment. The following 
procedures/assessments are to be completed at this visit: 
• 
Perfo1m symptom-directed physical examination 
• 
Vital signs 
• 
Body weight and height 
• 
Assessment of AEs and concomitant medications 
• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
paiiicipants (all subjects ~ 12 years of age and subjects < 12 yeai·s of age at the discretion of 
the investigator based on subject's pube1ial status) 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-HCVRNA 
I 
-
HBV DNA testing for subjects HBcAb positive at Screening 
-
Single spai·se PK sample collected anytime 
I 
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
Obtain urine sample for:
Urine pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS
6.3.5.
End of Treatment (± 3 days) or Early Termination 
For subjects that are DAA-naive without cirrhosis, the End of Treatment visit will occur at Week 
8.  For subjects that are DAA-naive with cirrhosis or DAA-experienced with or without cirrhosis 
the End of Treatment Visit will occur at Week 12.  
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Early Termination visit only to 
ensure an approximate 8-hour fast prior to the blood sample collection the next morning.  The 
following procedures/assessments are to be completed at this visit:

Complete physical examination

Tanner Pubertal Stage assessment 

A single X-ray of the left wrist, hand, and fingers for radiographic bone age assessment

Vital signs 

Body weight and height 

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the investigator based on subject’s pubertal status)

Subject and parent/legal guardian will complete the relevant acceptability questionnaires.

Quality of life survey: Subject is to review questionnaire and write/mark answers directly 
onto the questionnaire.  Parent/guardian completes the parent/guardian questionnaire.

Obtain blood samples for:
Hematology
Chemistry


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Coagulation tests 
-HCVRNA 
I 
-TSH 
-
Single sparse PK sample collected anytime 
-
HBV DNA testing for subjects HBcAb positive at Screening 
Amendment 1 
-
Bone age biomarkers: CTX and PlNP (will only be collected at Early Termination) 
I 
• 
Obtain urine sample for: 
-
Urine pregnancy test for females of childbearing potential only 
• 
Review medication compliance with subject and/or parent/guardian. 
Subjects should return all bottles of study drng at the End of Treatment (Week 8 for DAA-naive 
subjects without cinhosis or Week 12 for DAA-naive subjects with cinhosis and 
DAA-experienced subjects with or without cinhosis) or Early Tennination Visit 
6.4. 
6.4.1. 
Posttreatment Assessments 
4-Week Posttreatment Visit (::1:: 5 days) 
The following procedures/assessments are to be completed at this visit: 
• 
Vital signs 
• 
Body weight and height 
• 
Perfo1m symptom-directed physical examination 
• 
Assessment of AEs and concomitant medications 
• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
paiiicipants (all subjects ~ 12 years of age and subjects < 12 yeai·s of age at the discretion of 
the investigator based on subject's pube1ial status) 
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SOFNEIJVOX FDC 
Protocol GS-US-367-1175 
Gilead Sciences, Inc. 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-HCVRNA 
I 
-
HBV DNA testing for subjects HBcAb positive at Screening 
I 
• 
Obtain urine sample for: 
-
Urine pregnancy test for females of childbearing potential only 
6.4.2. 
12-Week Posttreatment Visit {:I: 5 days) 
The following procedures/assessments are to be completed at this visit: 
• 
Vital signs 
• 
Body weight and height 
• 
Perfo1m symptom-directed physical examination 
• 
Assessment of SAEs 
Amendment 1 
• 
Quality of life survey: Subject is to review questionnaire and write/mark answers directly 
onto the questionnaire. Parent/guardian completes the parent/guardian questionnaire. 
• 
Tanner Pube1ial Stage assessment (do not complete if Tanner Pube1ial Stage is 5 at 
Screening) 
• 
Obtain blood samples for: 
-HCVRNA 
I 
-
HBV DNA testing for subjects HBcAb positive at Screening 
I 
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6.4.3. 
24-Week Posttreatment Visit (::1::5 days) 
Amendment 1 
Subjects should be instructed to fast (no food or drink, except water), staiiing from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the 24-Week Postti·eatment visit to 
ensure an approximate 8-hour fast prior to the blood sample collection the next morning. 
The following procedures/assessments are to be completed at this visit: 
• 
Vital signs 
• 
Body weight and height measurements 
• 
Perfo1m symptom-directed physical examination 
• 
Assessment of SAEs 
• 
Quality of life survey: Subject is to review questionnaire and write/mark answers directly 
onto the questionnaire. Parent/guardian completes the parent/guai·dian questionnaire. 
• 
Tanner Pube1ial Stage assessment 
• 
Obtain blood samples for: 
-HCVRNA 
-
HBV DNA testing for subjects HBcAb positive at Screening 
-
Bone age biomarkers: CTX and PlNP 
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I 
I 
I 
I 
I 
I 
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6.6.
Unscheduled Visit 
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The
assessments are at the investigator’s discretion as clinically indicated, but the investigator should
at a minimum collect AE and concomitant medication information. At all unscheduled visits 
initiated for the purpose of confirming virologic failure, a sample for a viral RNA 
sequencing/phenotyping must be collected. Unscheduled visits can be initiated to collect the 
sparse PK sample if not collected during the treatment visits. 
6.7.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures (see Section 3.5, Criteria for Discontinuation of Study Treatment). If 
this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.
6.8.
Procedures and Specifications
6.8.1.
Clinical Laboratory Analytes
Hematology: Hematocrit, hemoglobin (Hb), platelet count, red blood cell count (RBC), white 
blood cell count (WBC) with differential (absolute and percentage) including lymphocytes, 
monocytes, neutrophils, eosinophils, basophils, reticulocyte count and mean corpuscular volume 
(MCV).
Coagulation: INR, Prothrombin time (PT), Activated partial thromboplastin time (APTT) 
Chemistry: Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), 
albumin, alkaline phosphatase, creatinine, total and direct bilirubin, glucose, lipase, potassium, 
sodium, gamma-glutamyl transferase (GGT) and creatine kinase (CK).
Urinalysis: Appearance, blood, color, glucose, leukocyte esterase, pH, protein, urobilinogen. 
Reflex to microscopic urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HAV, HCV, HBV (HBsAg, HBsAb, HBcAb). HBV DNA 
testing will be performed in subjects HBcAb positive at Screening. Serology and/or antigen 
testing for HIV (including reflex testing as necessary).
HCV RNA will be measured using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, 
v2.0 for Use with the High Pure System.
HCV 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.


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IL28B genotype will be determined by polymerase chain reaction (PCR) amplification of the 
single nucleotide polymorphism (SNP), rs12979860, with sequence specific forward and reverse 
primers and allele specific fluorescently labeled TaqMan® minor groove binder (MGB) probes. 
Gilead reserves the rights to use alternate assays for IL28B determination should the above assay 
become unavailable.
Pregnancy Tests: Serum -hCG, Urine -hCG (if positive, requires immediate confirmation with 
Serum -hCG)
Additional Tests: Urine drug screen (for amphetamines, cocaine, methadone, opiates), 
hemoglobin A1c (HbA1c), TSH (reflex Free T4), AAT, bone biomarker (CTX and P1NP), 
Fibrotest®, and APRI.
6.8.2.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history will be collected on all subjects during 
Screening.
6.8.3.
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. 
The focus of a symptom directed physical examination will be determined by the investigator 
based on subject complaint.  For example, if a subject complains of a cough, a lung exam should 
be performed.  If consistent with pneumonia (rales/crackles on exam) then an AE would be 
documented.
6.8.4.
Tanner Pubertal Stage Assessment
The Tanner Stage scale is available in Appendix 4. All subjects will receive a baseline Tanner 
Pubertal Stage assessment. If the assessment determines that the subject is at a Tanner 5 at 
Day 1, no further Tanner Pubertal Stage Assessments are to be completed. 
6.8.5.
Height & Weight Measurement
Height and weight measurement will be collected at each study visit. The difference in body 
weight and height measurements between Day 1 and End of Treatment (Week 8 for DAA-naive 
subjects without cirrhosis or Week 12 for DAA-naive with cirrhosis and DAA-experienced 
subjects with or without cirrhosis), posttreatment Week 12, and posttreatment Week 24 will be 
calculated. Parental heights will be recorded at Day 1 as available.


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6.8.6.
Radiographic Bone Age Assessment
A single X-ray of the left wrist, hand, and fingers will be performed at Day 1 and End of 
Treatment (Week 8 for DAA-naive subjects without cirrhosis or Week 12 for DAA-naive
subjects with cirrhosis and DAA-experienced subjects with or without cirrhosis). A local 
radiologist will determine radiographic bone age from X-ray.
6.8.7.
Bone Age Biomarkers
Fasting blood samples for bone age biomarkers (CTX and P1NP), will be collected at Day 1, 
Early Termination (if applicable) and posttreatment Week 24. 
6.8.8.
Acceptability and Swallowability Assessment
A SOF/VEL/VOX FDC swallowability assessment will be performed at Screening up to Day 1. 
Subjects who have indicated that they can take pills will be observed taking a placebo to match 
the SOF/VEL/VOX FDC (400/100/100 mg) adult tablet. This will confirm the swallowability of 
the (400/100/100 mg) adult tablet formulation size. Subjects unable to swallow the
SOF/VEL/VOX FDC (400/100/100 mg) adult tablet will be re-assigned to a smaller tablet of 
lower dose and/or to a non-tablet formulation of SOF/VEL/VOX FDC is available.
A questionnaire will be administered to subjects to assess acceptability, including palatability, of 
the formulation they received on Day 1 and End of Treatment (Week 8 for DAA-naive subjects
without cirrhosis or Week 12 for DAA-naive subjects with cirrhosis and DAA-experienced 
subjects with or without cirrhosis) or Early Termination. If the subject is unable to complete the 
questionnaires, the parent/legal guardian will assist to complete the questionnaire. The subject’s 
parent/legal guardian will also complete a questionnaire at End of Treatment (Week 8 for 
DAA-naive subjects without cirrhosis or Week 12 for DAA-naive subjects with cirrhosis and 
DAA-experienced subjects with or without cirrhosis) or Early Termination for their assessment 
of acceptability of the formulation the subject received. 
6.8.9.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for ≥5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.


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6.8.10. 
Body Mass Index (BMI) 
BMI is calculated by the following equation. 
BMI = weight (pounds) x 703 
(height in inches )2 
or 
weight in kilograms 
(height in meters )2 
6.8.11. 
Estimated Glomerular Filtration Rate (GFR) 
Amendment 1 
Estimated Glomemlar Filtrntion Rate (GFR) using Schwaiiz Fonnula (mL/min/1.73m2) = 
k x L/Scr [(k is a propo1iionality constant, for adolescent females~ 12 yeai·s old is 0.55; and for 
adolescent males~ 12 yeai·s old is 0.70); Lis height in centimeters (cm); and Ser is serum 
creatinine (mg/dL)] 
-
6.8.13. 
Pharmacokinetic (PK) Sample 
Sparse PK samples will be c 
ependent on treatment duration 
. Collected samples will be use 
metabolite GS-331007, VEL, and VOX. 
6.8.14. 
HBVDNA 
HBV DNA will only be tested in subjects HBcAb positive at Screening. HBV DNA testing will 
occur at Day 1, Weeks 1, 2, 4, 8, and End of Treatment (Week 8 for DAA-naive subjects without 
cinhosis or Week 12 for DAA-naive subjects with cinhosis and DAA-experienced subjects with 
or without cinhosis), or Eai·ly Tennination and all posttreatment visits. 
6.8.15. 
Pregnancy Testing 
All females of childbearing potential will have a senun pregnancy test at Screening. Urine 
pregnancy testing will occur at Day 1 and eve1y 4 weeks during the dosing period and for a 
minimum of30 days following the last dose of SOFNELNOX FDC. If required by local 
regulations, additional pregnancy tests beyond 30 days may be added. In the event of a positive 
urine pregnancy result, subjects will be instructed to stop study diugs immediately (if applicable) 
and return to the clinic as soon as possible for a serum pregnancy test. 
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6.8.16.
Quality of Life Survey (PedsQL™)
The PedsQL™Pediatric Quality of Life Inventory V4.0 Short Form (SF15) will be completed by 
the subject and the parent/guardian at Day 1, End of Treatment (Week 8 for DAA-naive subjects
without cirrhosis or Week 12 for DAA- naive subjects with cirrhosis and DAA-experienced 
subjects with or without cirrhosis), Early Termination (if applicable), 12-Week Posttreatment,
and 24-Week Posttreatment 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). Surveys will be administered for the corresponding age group of the subject at the 
time of survey administration.  


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre or posttreatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
Screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
eCRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs associated
with laboratory abnormalities, the event should be graded on the basis of the clinical severity in
the context of the underlying conditions; this may or may not be in agreement with the grading
of the laboratory abnormality.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead 
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the eCRF: all SAEs and adverse events related to protocol mandated 
procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30 days after last administration of study IMP and report to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required posttreatment follow-up period, must be reported to the 
eCRF database and Gilead Pharmacovigilance and Epidemiology (PVE) as instructed. This also 
includes any SAEs resulting from protocol associated procedures performed after informed 
consent is signed.


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Any SAEs and deaths that occur after the posttr·eatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be repo1ted. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period; 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and repo1t 
the event to Gilead PVE. 
• 
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
Elecu-onic Serious Adverse Event ( eSAE) Repo1t ing Process 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit the SAE 
infonnation to Gilead PVE 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 infonnation electr·onically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event repo1ting 
fo1m and submit within 24 hours to: 
Gilead Sciences, 
Phaim acovigilance and 
Epidemiology: 
Fax: 
E-mail: 
PPD 
PPU 
• 
As soon as it is possible to do so, any SAE repo1ted via paper must be u-anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repo1ted via a paper fonn because the eCRF database has been locked, no 
fuither action is necessaiy. 
• 
For fatal or life-threatening events, copies of hospital case repo1ts, autopsy repo1ts, 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 tr·aceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensure the timely completion of accurate safety 
repo1ts. 
• 
Any medications necessaiy for tr·eatment of the SAE must be recorded onto the concomitant 
medication section of the subject's eCRF and the event description section of the SAE fonn. 
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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the 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. 
To minimize the possibility of exposing study subjects to unusual risk, the safety information
from this study will also be reviewed periodically by an independent DMC. The DMC will make 
recommendations regarding the study according to the DMC charter.
7.5.
Toxicity Management 
7.5.1.
Subject Stopping Rules
See Section 3.5 for Subject Stopping Rules. 
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, occupational exposure with an AE, 
pregnancy reports regardless of an associated AE, and AE in an infant following exposure from 
breastfeeding.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.


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


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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 PVE, fax number 
 or email 
 
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead PVE within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.
PPD
PPD


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is:

To evaluate the steady-state PK and confirm age-appropriate dose of SOF/VEL/VOX FDC in 
pediatric subjects with chronic HCV infection
The secondary objectives of this study are:

To evaluate the safety and tolerability of SOF/VEL/VOX FDC in pediatric subjects with 
chronic HCV infection

To evaluate the antiviral efficacy of SOF/VEL/VOX FDC treatment in pediatric subjects 
with chronic HCV infection, as assessed by the proportion of pediatric subjects with 
sustained virological response (SVR) 12 weeks after cessation of treatment (SVR12)

To evaluate the antiviral efficacy of SOF/VEL/VOX FDC treatment in pediatric subjects 
with chronic HCV infection, as assessed by the proportion of pediatric subjects with SVR 4 
and 24 weeks after cessation of treatment (SVR4 and SVR24)

To evaluate the proportion of pediatric subjects with virologic failure, including on-treatment 
virologic failure and relapse

To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment 

To evaluate the emergence of viral resistance to SOF, VEL, and VOX during treatment and 
after cessation of treatment

To evaluate the effect of SOF/VEL/VOX FDC on growth and development of pediatric 
subjects during and after treatment

To evaluate acceptability, including palatability, and swallowability, of formulations (as 
applicable) used in the study

To assess the effect of treatment with SOF/VEL/VOX FDC on quality of life as measured by 
PedsQL™ Pediatric Quality of Life survey


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8.1.2. 
Primary Endpoint 
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The appropriateness of the SOFNELNOX FDC dose will be assessed by evaluating its steady-
state PK. The primaiy PK endpoint is AUCtauof SOF, its major metabolite (GS-331007), VEL 
and VOX. 
8.1.3. 
Secondary Endpoint 
The secondaiy endpoints are: 
• 
Any AE leading to pennanent discontinuation of study dmg 
• 
The proportion of subjects with sustained virological response (SVR) 12 weeks after 
cessation of treatment (SVR12) is the key efficacy endpoint 
• 
The propo1tion of subjects with HCV RNA < LLOQ at 4 or 24 weeks after cessation of 
treatment (SVR4 and SVR24) 
• 
The proportion of subjects with virologic failure, including on-treatment virologic failure and 
relapse 
• 
The propo1tion of subjects with HCV RNA < LLOQ on treatment 
• 
Emergence of viral resistance to SOF, VEL, and VOX during treatment and treatment is 
discontinued 
• 
HCV RNA change from Day 1 
• 
Growth and development measurements including height and weight percentiles, Tanner 
Stage, radiographic bone age and two bone tum-over biochemical mai·kers (CTX and Pl NP) 
• 
Acceptability, including palatability, and swallowability assessments 
• 
Neuropsychiatric assessments as measured by PedsQL™ Pediatric Quality of Life survey 
8.1.4. 
Other Endpoints of Interest 
Other endpoint of interest may include ALT n01malization. 
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8.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using SAS® software (SAS Institute, Cary, North Carolina, USA).
The study drug in this study is SOF/VEL/VOX FDC. Last dose of study drug will be used in the 
definition of treatment emergent AEs and laboratory abnormalities as well as the efficacy 
endpoints of SVR at various posttreatment time points.
8.2.1.
Analysis Sets
8.2.1.1.
Pharmacokinetics
The primary analysis set for PK analysis set will include all enrolled subjects who took at least 
one dose of study drug and for whom at least one non-missing concentration data SOF, its 
primary metabolite(s), VEL or VOX, are available. 
8.2.1.2.
Safety
The primary analysis set for safety analyses will include all subjects who took at least 1 dose of 
the study drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose of the 
study drug through the last dose date of the study drug plus 30 days.
8.2.1.3.
Efficacy
The primary analysis set for efficacy analyses will be the Full Analysis Set (FAS), which 
includes all enrolled subjects who received at least 1 dose of the study drug.
8.3.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. Other than the 
endpoints discussed below, values for missing data will not be imputed.
For the analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have 
the missing data imputed. Missing on-treatment HCV RNA will have the missing data imputed 
up to the time of the last dose.
If a data point is missing and is preceded and followed in time by values that are “< LLOQ target 
not detected (TND),” then the missing data point will be set to “< LLOQ TND.” If a data point is 
missing and preceded and followed by values that are “< LLOQ detected,” or preceded by 
“< LLOQ detected” and followed by “< LLOQ TND,” or preceded by “< LLOQ TND” and 
followed by “< LLOQ detected,” then the missing value will be set to “< LLOQ detected.” In 
these situations the data point will be termed a bracketed success; otherwise, the data point will 
be termed a bracketed failure (ie, ≥LLOQ detected). If a data point is missing and is not 
bracketed, the missing data point will also be termed a failure (ie, ≥LLOQ detected) except for 


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SVR24, which will be imputed according to the SVR12 status. Success for SVR12 who have no 
further HCV RNA measurements collected will be counted as a success for SVR24 due to the 
high correlation between these 2 endpoints.
Where appropriate, safety data for subjects who did not complete the study will be included in 
summary statistics. For example,

If a subject took at least 1 dose of study drug, the subject will be included in a summary of 
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 the summary statistics for that time point. If the 
subject is missing a predose value, then the subject will be excluded from the calculation of
the summary statistics for the predose value and the change from predose values.
Values for missing safety laboratory data will not be imputed; however, a missing Day 1 result 
will be replaced with a screening result, if available. If no pretreatment laboratory value is 
available, the Day 1 value will be assumed to be normal (ie, no grade [Grade 0]) for the summary 
of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing Day 1 result will be 
replaced with a screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for the 
calculation of summary statistics for the actual HCV RNA values and the change from baseline
values by study visit. The reported values will be provided in the HCV RNA listing. 
For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed to 
the logarithmic (base 10) scale (log10 IU/mL).
For PK plasma concentrations and analysis of PK parameters natural logarithmic transformation
will be used. Plasma concentration values that are below the lower limit of quantitation (BLQ)
will be presented as “BLQ” in the concentration data listing. 
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by age cohort (as described in Section 3.2) and treatment duration (8 weeks vs 12 
weeks).
Demographic data will include sex, self-identified race/ethnicity and age. 
Baseline characteristics data will include body mass index, HCV RNA level (log10 IU/mL), 
genotype of HCV infection, IL28B genotype, and additional endpoints as necessary.


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8.5.
Pharmacokinetic Analysis
Pharmacokinetic parameters (eg, AUCtau, Cmax, Ctau, volume of distribution and clearance) will 
be listed and summarized for, SOF, its primary metabolite(s), VEL and VOX using descriptive 
statistics (eg, sample size, arithmetic mean, geometric mean, % coefficient of variation, standard 
deviation, median, minimum, and maximum). 
To evaluate if the exposures of SOF, GS-331007, VEL and VOX achieved in pediatric subjects 
of this study are similar to the exposures observed in adult subjects, SOF, GS-331007, VEL and 
VOX exposure data from this study will be compared to the integrated adult data. The primary
endpoint of this analysis will be evaluated by carrying out an analysis of variance (ANOVA) for
log-transformed SOF, GS-331007, VEL and VOX AUCtau. The 90% confidence intervals will be 
constructed for the ratio of geometric means of each PK parameters. The equivalence boundary 
is set as 50% to 200%. The equivalence boundary is based on exposure-response (efficacy and 
safety) relationships observed in the integrated adult data.
Dose ranging studies for SOF established that a dose of 200 mg results in suboptimal exposure 
compared to the 400 mg dose, and no clinically significant exposure-safety relationships were 
observed across a broad range of GS-331007 exposure. The Phase 1b dose ranging studies,
GS-US-281-0102 and GS-US-338-1121, established the anti-HCV activity of VEL and VOX, 
respectively. At exposures observed in Phase 3 studies, maximum effect (Emax) models predict 
near maximal antiviral activity for all analytes: 90%, ≥99.5%, ≥90%, of Emax for SOF, VEL, and 
VOX, respectively.
In the Phase 3 population treated with SOF/VEL/VOX FDC (400/100/100 mg), virologic 
response rates were high across all treatment groups, HCV genotypes and exposure ranges for 
SOF, GS-331007, VEL and VOX, including for subjects with cirrhosis, with no consistent trends 
in exposure-efficacy relationships. Similarly, exposure-safety analyses in Phase 3 clinical studies 
showed a lack of relationship over a wide range of SOF/VEL/VOX FDC exposures. The 
observed safety and efficacy profile and the lack of exposure-response relationships across a 
wide range of SOF/VEL/VOX FDC exposures, the bounds of 50-200% support identification of 
a clinically relevant difference in SOF, GS-331007, VEL or VOX exposure in the pediatric 
population.
In all pediatric age groups, the targeted exposures for SOF, GS-331007, VEL and VOX are the 
adult equivalent for which safety and efficacy has been established. Assuming similar variability 
for SOF, GS-331007, VEL or VOX AUCtau in the pediatric population compared to adults, the 
predicted 90% confidence interval (CIs) of the geometric mean ratio (GMR) will be contained 
within the bounds of 50% to 200%.
Individual patient management will be performed by maintaining exposures comparable to
adults. In the event more than one subject in each cohort exhibits SOF, GS-331007, VEL or
VOX exposures (AUCtau) less than the 2.5th percentile of adult values, a dose assessment may be
require for the cohort as appropriate.
The effect of age and SOF/VEL/VOX FDC dose on PK (SOF, GS-331007, VEL and VOX) will 
be assessed.


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8.6.
Safety Analysis
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital
signs measurements at various time points during the study, and by the documentation of AEs.
All safety data collected on or after the first dose of the study drug administration up to 30 days
after the last dose of the study drug will be summarized by age cohort and treatment duration (8 
weeks vs 12 weeks) according to the study drug taken. 
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug
administration data page of the eCRF. Exposure data will be summarized by age cohort and
treatment duration (8 weeks vs 12 weeks).
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent
adverse event will be defined as any adverse event with an onset date on or after the study drug
start date and no later than 30 days after permanent discontinuation of the study drug or any
adverse event leading to premature discontinuation of the study drug.
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC, 
and PT) will be provided by age cohort and treatment duration (8 weeks vs 12 weeks):

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

All SAEs

All treatment-related SAEs

All AEs leading to premature discontinuation of the study drug
All AEs collected during the study will be presented in the data listings. 


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8.6.3.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized (n, mean, SD, median,
Q1, Q3, minimum, and maximum) by study visit along with the corresponding change from
baseline. 
Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme 
defined 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 cohort and treatment duration (8 
weeks vs 12 weeks). 
Values for missing safety laboratory data will not be imputed; however, a missing Day 1 result 
will be replaced with a screening result, if available. If no pretreatment laboratory value is 
available, the baseline value will be assumed to be normal (ie, no grade [Grade 0]) for the 
summary of graded laboratory abnormalities.
All laboratory abnormalities will be included in the listings of laboratory data. 
8.6.4.
Other Safety Evaluations
8.6.4.1.
Tanner Pubertal Stage Assessment
Tanner Stages (Appendix 4) will be summarized by baseline Tanner Stage using frequency and 
percentage by gender for each age cohort and treatment duration (8 weeks vs 12 weeks). 
8.6.4.2.
Vital Signs (including Body Weight and Height)
Vital signs including body weight and height and change from baseline will be summarized at 
each visit.
8.6.4.3.
Radiographic Bone Age Assessment
Radiographic bone age will be summarized by age cohort and treatment duration (8 weeks vs 12 
weeks).
8.6.4.4.
Bone Age Biomarkers Assessment
Bone turn-over biochemical marker will be summarized by age cohort and treatment duration (8 
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8.6.4.5.
Neuropsychiatric Assessments measured by PedsQL ™ Pediatric Quality of Life 
survey
The data from PedsQL ™ Pediatric Quality of Life survey will be summarized by visit and age 
cohort and treatment duration (8 weeks vs 12 weeks).
8.7.
Efficacy Analysis
8.7.1.
Analysis of the Key Efficacy Endpoint
The key efficacy endpoint is SVR12 on the FAS. The proportion of subjects with sustained 
virological response (SVR) 12 weeks after cessation of treatment (SVR12) will be summarized 
by age cohort and treatment duration (8 weeks vs 12 weeks).
8.7.2.
Secondary Analyses
The proportion of subjects with HCV RNA below the LLOQ over time (including SVR4 and
SVR24) will be presented by age cohort and treatment duration (8 weeks vs 12 weeks) in tabular 
and graphical form. Descriptive summaries and listings will be provided for additional efficacy 
evaluations of the proportion of subjects who experience virologic failure, serum HCV RNA 
actual values and change from baseline, and other endpoint of interest may include ALT 
normalization.
8.8.
Acceptability and Swallowability 
Acceptability and swallowability of the study drug will be summarized using descriptive 
statistics. Swallowability will be assessed by the subject’s ability or inability to swallow the solid 
dosage tablet formulations. Acceptability, including palatability, will be assessed quantitatively 
in the questionnaire administered to subjects and their parent/legal guardian on Day 1 and/or End 
of Treatment (Week 8 for DAA-naive subjects without cirrhosis or Week 12 for DAA-naive 
subjects with cirrhosis and DAA-experienced subjects with or without cirrhosis).
8.9.
Sample Size
Assuming similar variability for SOF, GS-331007, VEL, or VOX AUCtau in the pediatric 
population compared to adults, a sample size of 20 pediatric subjects per cohort will provide at 
least 80% power to target a 90% confidence interval of the geometric mean ratio (GMR) within 
the bounds of 50% to 200% when comparing with the adult population.
8.10.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety data at intervals of approximately 6 months from the 
first subject enrolled. The DMC will recommend to Gilead whether the nature, frequency, and 
severity of adverse effects associated with study treatment warrant the early termination of the 
study in the best interests of the participants, whether the study should continue as planned, or 
the study should continue with modifications. The DMC may also provide recommendations as 
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The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 Code of Federal Regulations (CFR) 312, subpart D, “Responsibilities of Sponsors 
and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Independent Ethics Committee (IEC) Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IEC. The investigator will not begin any study subject activities until 
approval from the IEC has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IEC any modifications made to the protocol or any accompanying material to be provided to 
the subject after initial IEC approval, with the exception of those necessary to reduce immediate 
risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IEC-approved consent form for documenting written 
informed consent. Each informed consent (or assent as applicable) will be appropriately signed 


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The investigator must assure that subjects' anonymity will be strictly maintained and that their 
identities are protected from unauthorized pa1ties. Only subject initials, date ofbiith, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
fo1m or biological sample submitted to the sponsor, IEC, or laborato1y. Laborato1y specimens 
must be labeled in such a way as to protect subject identity while allowing the results to be 
recorded to the proper subject. Refer to specific laborato1y instrnctions or in accordance with 
local regulations. NOTE: The investigator must keep a screening log showing codes, names, and 
addresses for all subjects screened and for all subjects enrolled in the trial. Subject data will be 
processed in accordance with all applicable regulations. 
The investigator agrees that all info1mation received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRF, the IMP, and any other study infonnation, remain the 
sole and exclusive prope1ty of Gilead during the conduct of the study and thereafter. This 
info1mation is not to be disclosed to any thii·d paity ( except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator fmther agxees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or othe1wise into the 
public domain. 
9.1.5. 
Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully doclllllented and the study data to be subsequently verified. These doclllllents should 
be classified into at least the following two categories: (1) investigator's study file, and 
(2) subject clinical source doclllllents. 
The investigator's study file will contain the protocoVamendments, CRF and que1y fo1ms, IEC 
and governmental approval with conespondence, info1med consent, drng records, staff 
cmTicullllll vitae and authorization fonns, and other appropriate documents and conespondence. 
The required source data should include sequential notes containing at least the following 
info1mation for each subject: 
• 
Subject identification (name, date of bi1th, gender); 
• 
Doclllllentation that subject meets eligibility criteria, ie, histo1y, physical examination, and 
confmnation of diagnosis (to suppo1t inclusion and exclusion criteria); 
• 
Doclllllentation of the reason(s) a consented subject is not enrolled 
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
Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Electronic Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received. Subsequent to data entry, a study monitor will perform source data 
verification within the EDC system. Original entries as well as any changes to data fields will be 
stored in the audit trail of the system. Prior to database lock (or any interim time points as 


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described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (eg, data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead , the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IEC or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to IEC in 
accordance with local requirements and receive documented IEC approval before modifications 
can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
The results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years.
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, eg, attendance at Investigator's Meetings.  If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.


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


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10.
REFERENCES
Balistreri WF, Murray KF, Rosenthal P, Bansal S, Lin CH, Kersey K, et al. The Safety and 
Effectiveness of Ledipasvir-Sofosbuvir in Aolescents 12-17 Years Old With 
Hepatitis C Virus Genotype 1 Infection. Hepatology 2017;66 (2):371-8.
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.
Brouwer KL, Aleksunes LM, Brandys B, Giacoia GP, Knipp G, Lukacova V, et al. Human 
Ontogeny of Drug Transporters: Review and Recommendations of the Pediatric 
Transporter Working Group. Clin Pharmacol Ther 2015;98 (3):266-87.
El-Sayed MH, Razavi H. Global Estimate of HCV Infection in the Pediatric and Adolescent 
Population [Abstract P1263]. European Association for the Study of the Liver 
(EASL); 2015 22-26 April; Vienna, Austria p. S831.
El-Shabrawi MH, Kamal NM. Burden of pediatric hepatitis C. World J Gastroenterol 2013;19 
(44):7880-8.
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.
Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the clearance of eleven drugs and 
associated variability in neonates, infants and children. Clin Pharmacokinet 
2006;45 (9):931-56.
Jonas MM, Balistreri W, Gonzalez-Peralta RP, Haber B, Lobritto S, Mohan P, et al. Pegylated 
Interferon for Chronic Hepatitis C in Children Affects Growth and Body 
Composition: Results From The Pediatric Study of Hepatitis C (Peds-C) Trial. 
Hepatology 2012;56 (2):523-31.
Khaderi S, Shepherd R, Goss JA, Leung DH. Hepatitis C in the pediatric population: 
transmission, natural history, treatment and liver transplantation. World J 
Gastroenterol 2014;20 (32):11281-6.
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of disease 
in childhood 1969;44 (235):291-303.
Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Archives of 
disease in childhood 1970;45 (239):13-23.
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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Amendment 1
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Prasad B, Gaedigk A, Vrana M, Gaedigk R, Leeder JS, Salphati L, et al. Ontogeny of Hepatic 
Drug Transporters as Quantified by LC-MS/MS Proteomics. Clin Pharmacol Ther 
2016;100 (4):362-70.
Sokal EM. Direct-Acting Antivirals for Paediatric HCV: We Got There. Nature reviews. 
Gastroenterology & hepatology 2017;14 (8):452-3.
The Polaris Observatory HCV Collaborators. Global prevalence and genotype distribution of 
hepatitis C virus infection in 2015: a modelling study. Lancet Gastroenterol 
Hepatol 2017;2:161–76.
Wirth S. Current treatment options and response rates in children with chronic hepatitis C. World 
J Gastroenterol 2012;18 (2):99-104.
Wirth S, Rosenthal P, Gonzalez-Peralta RP, Jonas MM, Balistreri WF, Lin CH, et al. Sofosbuvir 
and Ribavirin in Adolescents 12-17 Years Old With Hepatitis C Virus Genotype 2 
or 3 Infection. Hepatology 2017;66 (4):1102-10.
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.
Zhu HJ, Appel DI, Jiang Y, Markowitz JS. Age- and sex-related expression and activity of 
carboxylesterase 1 and 2 in mouse and human liver. Drug Metab Dispos 2009;37 
(9):1819-25.


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Amendment 1
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 4.
Tanner Stages*
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


SOFNEIJVOX FDC 
Protocol GS-US-367-1175 
Gilead Sciences, Inc. 
Amendment I 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to Investigate the Pharmacokinetics, 
Safety and Efficacy of SofosbuvirNelpatasvirNoxilaprevir Fixed Dose Combination in 
Adolescents and Children with Chronic HCV Infection 
GS-US-367-1175, Amendment 1, 27 March 2019 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PPD 
PPD 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
infonnation provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 77 
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Amendment 1
CONFIDENTIAL
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Appendix 2.
Study Procedures Table
Appendix Table 1.
Screening and On-Treatment Study Visits 
Screening
Day 1a
On-Treatment
Study Week (±3 Days)
Early 
Terminationa
Week 1
Week 2t,v
Week 4 
Week 8b
End of 
Treatmentc
Clinical Assessments
Informed Consent/Assent
X
Determine Eligibility
X
X
Medical History
X
Parental Height, if known
X
Complete Physical Examination
X
X
X
X
Symptom-Directed Physical Examination
X
X
X
X
Tanner Pubertal Stage Assessment
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
Body Weight and Height
X
X
X
X
X
X
X
X
Radiographic Bone Age Assessment
X
X
X
AEs and Concomitant Medications
Xe
X
X
X
X
X
X
X
FibroScan® (if available)
Xf
Xf
Pregnancy Prevention Counselingg
X
X
X
X
X
SOF/VEL/VOX Swallowability 
Assessment
Xh
Xh
SOF/VEL/VOX Acceptability 
Questionnairei
X
X
X
Quality of Life Surveyj
X
X
X
CCI 


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Amendment 1
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Screening
Day 1a
On-Treatment
Study Week (±3 Days)
Early 
Terminationa
Week 1
Week 2t,v
Week 4 
Week 8b
End of 
Treatmentc
Review of Study Medication Compliance
X
X
X
X
Study Drug Dispensing
X
X
X
Return of Study Drug Bottles 
X
X
X
X
Review Dosing Diary 
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
X
X
X
X
Coagulation 
X
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
HBV DNAl
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testingn
X
X
X
X
X
X
X
Single sparse PK sample collected at 
anytime 
X
X
X
X
Two sparse PK Samples collected pre-dose 
and between 15 minutes and up to 4 hours 
postdose
Xp
Xp
Urinalysis
X
X
X
X
Urine Drug Screen 
X
IL28B Genotyping
Xf
Xf
Bone Age Biomarkers
X
Xw
CCI
CCI
CCI
CCI
CC
CC
CC
CC
CC
CCI 
I 
I 
I 
I 


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Amendment 1
CONFIDENTIAL
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Screening
Day 1a
On-Treatment
Study Week (±3 Days)
Early 
Terminationa
Week 1
Week 2t,v
Week 4 
Week 8b
End of 
Treatmentc
HCV Genotyping
X
HIV testing, HAV Antibody, HCV 
Antibody, HBsAg, HBsAb, HBcAb
X
HbA1c Fibrotest®, APRI
X
TSH
X
X
X
Alpha-1 anti-trypsin
X
Approximate amount of
blood drawn (mL) _ Cohort 1
22.1
12.3
9.3
11 3
11.3
9.3
13.2
16.8
Approximate amount of
blood drawn (mL) _ Cohort 2
22.1u
12.3
9.3
18t
11.3
9.3
13.2
16.8
Approximate amount of
blood drawn (mL) _ Cohort 3
22.1u
12.3
8.3
8v
9.3
8.3
12.2
12.2
a
Subjects should be instructed to fast (no food or drink, except water), starting from midnight (00:00) or earlier, as appropriate, on the evening prior to Day 1 and Early 
Termination (if applicable) to ensure an approximate 8-hour fast prior to the blood sample collection the next morning.  
b
The Week 8 Visit will only be completed for subject DAA-naïve with cirrhosis or DAA-experienced with or without cirrhosis, who are on 12 weeks of treatment.
c
For subjects that are DAA-naive without cirrhosis, who are on 8 weeks of treatment, the End of Treatment visit will occur at Week 8.
For subjects that are DAA-naive with cirrhosis or DAA-experienced with or without cirrhosis, who are on 12 weeks of treatment, the End of Treatment Visit will occur at 
Week 12.
d
Vital signs include blood pressure, pulse, respiratory rate, and temperature.
e
From the time of obtaining informed consent through the first administration of investigational medicinal product, record all serious adverse events (SAEs), as well as any 
adverse events related to protocol-mandated procedures. 
f
FibroScan® and IL28B genotyping may be performed at Day 1 if not completed at Screening.  
g
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years old and subjects < 12 years old at the discretion of the Investigator based on subject’s 
pubertal status). 
h
Swallowability may occur at Day 1 if not completed during Screening.
i
A questionnaire will be administered to subjects to assess acceptability, including palatability, on Day 1, EOT (Week 8 or Week 12), or Early Termination (as applicable).  If 
the subject is unable to complete the questionnaires, the parent/legal guardian will assist to complete the questionnaire. The subjects’ parent/legal guardian will also complete a 
questionnaire on EOT (Week 8 or Week 12) or Early Termination (as applicable).
j
Quality of life survey will be completed by all subjects and their parent/legal guardian. Subject and parent/legal guardian is to review questionnaire and write/mark answers
directly onto the questionnaire.
CCI
CCI
CCI 
-


SOFNEIJVOX FDC 
Protocol GS-US-367-1175 
Gilead Sciences, Inc. 
Amendment 1 
u 
In coho1t 2 and coho1t 3, for subject weighing$ 25 kg, the screening visit will be pe1fon11ed in two different days. Samples for chem.istiy, hematology, coagulation, TSH, 
HIV/HA V/HCV testing will be pe1fo1med on one day (12 ml of blood will be collected) and all other samples including for HCV RNA, HCV genotype and IL28B will be 
collected on a different day within the screening window (10.1 ml of blood will be collected). If the subject's weight is > 25 kg, the screening visit blood draw can be completed in 
oneda 
' 
CONFIDENTIAL 
Page 81 
27 March 2019 


SOFNEIJVOX FDC 
Protocol GS-US-367-1175 
Gilead Sciences, Inc. 
Amendment 1 
Appendix 2. 
Study Procedures Tables 
Appendix Table 2. 
Posttreatment Visits 
Clinical Assessments 
Symptom-dit·ected Physical Exam 
Tanner Pubertal Stage assessment 
Vital Signs 
Body weight and Height 
AEs 
Concomitant Medications 
Pregnancy Prevention Counseling< 
Quality of Life Survey 
Laboratory Assessments 
Hematology, Chemistry 
HCVRNA 
Urine Pregnancy Test 
o e 
B'o 
· ers 
Approxitnate amount of 
blood drawn (mL) _ All Cohorts 
4 'Weeks Posttreatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
7.3 
Posttreatment 
Study Week (±5 Days) 
12 Weeks Posttreatment 
X 
X 
X 
X 
Xb 
X 
X 
5 
24 Weeks Posttreatment" 
X 
X 
X 
X 
Xb 
X 
X 
X 
8.6 
a 
Subjects should be instmcted to fast (no food or drink, except water), sta1ting from midnight (00:00) or earlier, as appropriate, on the evening prior to posttreatment Week 24 
to ensure an approxintate 8-hom· fast prior to the blood sample collection the next moming. 
b 
Only SAEs will be capttu·ed at posttreatment Week 12 and 24 
c 
Including partner pregnancy prevention for male pa1ticipants (all subjects~ 12 years old and subjects < 12 years old at the discretion of the Investigator based on subject's 
pube1tal statlls) 
d 
HBV DNA testing for sub'ects HBcAb ositive at Screenino 
CONFIDENTIAL 
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Amendment 1
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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L


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Amendment 1
CONFIDENTIAL
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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
—
—
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 


SOF/VEL/VOX FDC
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Amendment 1
CONFIDENTIAL
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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
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


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Amendment 1
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Page 87
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


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Amendment 1
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia               
Adult and Pediatric           
≥ 1 year   
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L


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Amendment 1
CONFIDENTIAL
Page 89
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/L to <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


SOF/VEL/VOX FDC
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Amendment 1
CONFIDENTIAL
Page 90
27 March 2019
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


SOF/VEL/VOX FDC
Protocol GS-US-367-1175
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Amendment 1
CONFIDENTIAL
Page 91
27 March 2019
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (eg, the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


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Amendment 1
CONFIDENTIAL
Page 92
27 March 2019
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated


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


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Amendment 1
CONFIDENTIAL
Page 94
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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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Protocol GS-US-367-1175
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Amendment 1
CONFIDENTIAL
Page 95
27 March 2019
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Thinning detectable by 
study participant or  
caregiver (for disabled 
adults)
Thinning or patchy hair loss 
detectable by health care 
provider
Complete hair loss
NA
Cutaneous Reaction – Rash
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or morbilliform 
rash with vesicles or limited 
number of bullae OR 
Superficial ulcerations of 
mucous membrane limited to 
one site
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson syndrome 
OR Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or generalized
NA
NA
Pruritis (itching – no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or 
minimal interference with 
usual social & functional 
activities
Itching causing greater than 
minimal interference with 
usual social & functional 
activities
Itching causing inability to 
perform usual social & 
functional activities 
NA


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Amendment 1
CONFIDENTIAL
Page 96
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening consequences 
OR Aggressive intervention 
indicated [eg, tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (eg, diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening consequences 
(eg, sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake


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


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


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Amendment 1
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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)


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


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


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


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


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Amendment 1
CONFIDENTIAL
Page 104
27 March 2019
ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, back 
of neck, breasts, 
abdomen)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current meds to regain glucose 
control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences 
(eg, ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability to 
perform usual social &
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, myxedema coma)
Lipoatrophy (eg, fat loss 
from the face, extremities, 
buttocks)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


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


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Protocol GS-US-367-1175
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Amendment 1
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Appendix 4.
Tanner Stages*
1. Pubic hair (male and female)
Tanner I
no pubic hair at all (prepubertal Dominic state)
Tanner II
small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females)
Tanner III
hair becomes more coarse and curly, and begins to extend laterally
Tanner IV
adult-like hair quality, extending across pubis but sparing medial thighs
Tanner V
hair extends to medial surface of the thighs
2. Genitals (male) (One standard deviation around mean age)
Tanner I
Testes, scrotum, and penis about same size and proportion as in early childhood
Tanner II
Enlargement of scrotum and testes; skin of scrotum reddens and changes in texture; little or no enlargement of penis (10.5-12.5)
Tanner III
Enlargement of penis, first mainly in length; further growth of testes and scrotum (11.5-14)
Tanner IV
Increased size of penis with growth in breadth and development of glans; further enlargement of testes and scrotum and increased darkening 
of scrotal skin (13.5-15)
Tanner V 
Genitalia adult in size and shape
3. Breasts (female)
Tanner I
no glandular tissue: areola follows the skin contours of the chest
Tanner II
breast bud forms, with small area of surrounding glandular tissue; areola begins to widen 
Tanner III
breast begins to become more elevated, and extends beyond the borders of the areola, which continues to widen but remains in contour with 
surrounding breast 
Tanner IV
increased breast size and elevation; areola and papilla form a secondary mound projecting from the contour of the surrounding breast
Tanner V 
breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla. 
*
Chart referenced from Marshall WA, Tanner JM, variations in the pattern of pubertal changes in boys and girls {Marshall 1969, Marshall 1970}


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Amendment 1
CONFIDENTIAL
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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming postmenopausal, unless 
permanently sterile or with medically documented ovarian failure.  
Women of any age with amenorrhea of > 12 months may be considered postmenopausal if their 
follicle stimulating hormone (FSH) level is in the postmenopausal range and they are not using 
hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Study Drug Effects on Pregnancy and Hormonal Contraception
Data on the effects of SOF/VEL/VOX FDC on pregnant women is not available.
From nonclinical studies, there is no evidence that SOF, VEL, or VOX is genotoxic.  Relevant 
nonclinical reproductive studies have demonstrated no adverse effect on fertility or embryo-fetal 
development for SOF, VEL, and VOX as individual agents.
Data from clinical pharmacokinetic interaction studies of SOF/VEL/VOX FDC have 
demonstrated that there is no reduction in the clinical efficacy of hormonal contraception.
3) Contraception Requirements for Female Subjects
The inclusion of female subjects of childbearing potential requires using at least an acceptable 
effective contraceptive measure. They must have a negative serum pregnancy test at Screening 
and a negative pregnancy test on the Day 1 visit prior to enrollment. Pregnancy tests will be 
performed every 4 weeks during the dosing period and at the posttreatment Week 4 visit. They 
must also agree to one of the following from Screening until 30 days of the last dose of 
SOF/VEL/VOX FDC.

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.


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Amendment 1
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Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS) 
Tubal sterilization
Vasectomy in the male partner 
Barrier methods (one female barrier and one male barrier must be used in combination)
■
Female barriers: Diaphragm with spermicide or Cervical cap with spermicide
■
Male barriers: Male condom (with or without spermicide)
Hormonal methods
■
Oral contraceptives (progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel or etonorgestrel
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the last dose of SOF/VEL/VOX FDC.
4) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use 
condoms until 30 days after the last dose of SOF/VEL/VOX FDC treatment when engaging in 
intercourse of reproductive potential. If their female partner is of childbearing potential (as 
defined above), their female partner must use 1 of the methods of birth control listed above from 
the date of Screening until 30 days after the last dose of SOF/VEL/VOX FDC.
Male subjects must agree to refrain from sperm donation until 30 days after the last dose of 
SOF/VEL/VOX FDC.
5) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, and post-ovulation methods), withdrawal (coitus interruptus), spermicides only, 
and lactational amenorrhea method (LAM).  Female condom and male condom should not be 
used together.


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Amendment 1
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6) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator.  Instructions for reporting pregnancy, partner pregnancy, and pregnancy 
outcome are outlined in Section 7.6.2.1.

SAP_000.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to 
Investigate the Pharmacokinetics, Safety and Efficacy of 
Sofosbuvir/Velpatasvir/Voxilaprevir Fixed Dose Combination in 
Adolescents and Children with Chronic HCV Infection
Name of Test Drug:
Sofosbuvir/Velpatasvir/Voxilaprevir Fixed Dose Combination
Study Number:
GS-US-367-1175
Protocol Version (Date):
Original:
08 February 2018
Amendment 1: 27 March 2019
Administrative 
Amendment 2: 11 October 2019
Analysis Type:
Final Analysis
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
10 April 2020
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 


Sofosbuvir/Velpatasvir/Voxilaprevir
GS-US-367-1175 
Statistical Analysis Plan - Final Analysis
Version 1.0
CONFIDENTIAL
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10 April 2020
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................3
LIST OF ABBREVIATIONS........................................................................................................................................4
PHARMACOKINETIC ABBREVIATIONS AND DEFINITIONS ............................................................................6
1.
INTRODUCTION ................................................................................................................................................7
1.1.
Study Objectives ......................................................................................................................................7
1.2.
Study Design............................................................................................................................................8
1.3.
Sample Size and Power............................................................................................................................8
2.
TYPE OF PLANNED ANALYSIS ......................................................................................................................9
2.1.
DMC Analyses.........................................................................................................................................9
2.2.
Final Analysis ..........................................................................................................................................9
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................10
3.1.
Analysis Sets..........................................................................................................................................10
3.1.1.
All Enrolled Analysis Set.....................................................................................................10
3.1.2.
Full Analysis Set ..................................................................................................................10
3.1.3.
Safety Analysis Set...............................................................................................................10
3.1.4.
Pharmacokinetic Analysis Set..............................................................................................10
3.2.
Subject Grouping ...................................................................................................................................11
3.3.
Strata and Covariates..............................................................................................................................11
3.4.
Examination of Subject Subsets.............................................................................................................11
3.5.
Missing Data and Outliers......................................................................................................................12
3.5.1.
Missing Data ........................................................................................................................12
3.5.2.
Outliers.................................................................................................................................13
3.6.
Data Handling Conventions and Transformations .................................................................................13
3.7.
Visit Windows........................................................................................................................................15
3.7.1.
Definition of Study Day .......................................................................................................15
3.7.2.
Analysis Windows................................................................................................................15
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis 
Window................................................................................................................................16
4.
SUBJECT DISPOSITION ..................................................................................................................................18
4.1.
Subject Enrollment and Disposition.......................................................................................................18
4.2.
Extent of Exposure.................................................................................................................................19
4.2.1.
Durations of Exposure to Study Regimen ............................................................................19
4.2.2.
Adherence to Study Drug.....................................................................................................19
4.3.
Protocol Deviations................................................................................................................................20
5.
BASELINE CHARACTERISTICS....................................................................................................................21
5.1.
Demographics ........................................................................................................................................21
5.2.
Other Baseline Characteristics ...............................................................................................................21
5.3.
Swallowability Assessment for SOF/VEL/VOX FDC Placebo Tablets ................................................22
5.4.
Acceptability and Palatability of SOF/VEL/VOX FDC.........................................................................23
5.5.
Medical History......................................................................................................................................23
6.
EFFICACY ANALYSES ...................................................................................................................................24
6.1.
Key Efficacy Endpoint...........................................................................................................................24
6.1.1.
Definition of the Key Efficacy Endpoint..............................................................................24


Sofosbuvir/Velpatasvir/Voxilaprevir 
GS-US-367- 1175 
Statistical Analysis Plan - Final Analysis 
Version 1.0 
6.1.2. 
Analysis Methods for the Key Efficacy Endpoint ................................................................ 24 
6.1.3. 
Subgroup Analysis of the Key Efficacy Endpoint... ............................................................. 24 
6.2. 
Secondary Efficacy Endpoints ............................................................................................................... 24 
6.2.1. 
Definition of Secondary Efficacy Endpoints ........................................................................ 24 
6.2.2. 
Anal sis Methods for Seconda 
Efficac End oints .......................................................... 25 
6.4. 
7. 
SAFETY ANALYSES ........................................................................................................................................ 27 
7.1. 
Adverse Events and Deaths .................................................................................................................... 27 
7.1.1. 
Adverse Event Dictionary .................................................................................................... 27 
7.1.2. 
Adverse Event Severity ........................................................................................................ 27 
7.1.3. 
Relationship of Adverse Events to Study Drug .................................................................... 27 
7 .1.4. 
Serious Adverse Events ........................................................................................................ 27 
7.1.5. 
Treatment-Emergent Adverse Events ................................................................................... 27 
7 .1.6. 
Summaries of Adverse Events and Deaths ........................................................................... 28 
7 .2. 
Laboratory Evaluations .......................................................................................................................... 29 
7.2.1. 
Summaries ofNumeric Laboratory Results ......................................................................... 30 
7.2.2. 
Graded Laboratory Values ................................................................................................... 30 
7.3. 
Yitai Signs .............................................................................................................................................. 32 
7.4. 
Body Weight, Height and BM1 .............................................................................................................. 32 
7.5. 
Mid-Parental Height Assessment ........................................................................................................... 33 
7.6. 
Bone Age Assessment ............................................................................................................................ 33 
7.7. 
Tanner Pubertal Stage Assessment ......................................................................................................... 33 
7.8. 
Prior and Concomitant Medications ....................................................................................................... 34 
7 .9. 
Neuropsychiatric assessments as measured by PedsQUM Pediatric Quality of Life survey ................. 34 
7.10. 
Other Safety Measures ........................................................................................................................... 35 
7.11 . 
Changes From Protocol-Specified Safety Analyses ............................................................................... 35 
8. 
PHARMACOKINETICANALYSES ................................................................................................................ 36 
8.1. 
Population PK Analysis ......................................................................................................................... 36 
9. 
REFERENCES ................................................................................................................................................... 37 
10. SOFTWARE ....................................................................................................................................................... 38 
11 . SAP REYISION .................................................................................................................................................. 39 
12. APPENDICES .................................................................................................................................................... 40 
Appendix I. 
Appendix 2. 
Appendix 3. 
Table 3-1. 
Table 3-2. 
CONFIDENTIAL 
Study Procedures Table .......................................................................................................... 41 
Tanner Stages* ....................................................................................................................... 46 
PedsQUM Score Calculation Algorithms ............................................................................... 47 
LIST OF IN-TEXT TABLES 
Analysis Windows for On-treatment HCV RNA, Yitai Signs and Safety Laboratory 
Data ........................................................................................................................................ 16 
Analysis Windows for Posttreatment HCY RNA, Body Weight, Height, Yitai Sign 
and Safety Laboratoty Data .................................................................................................... 16 
Page 3 
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Statistical Analysis Plan - Final Analysis
Version 1.0
CONFIDENTIAL
Page 4
10 April 2020
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CDC 
Centers for Disease Control
CFR
Code of Federal Regulations
CI
confidence interval
CK
creatine kinase
CSR
clinical study report
CTX
C-type collagen sequence
DAA
direct-acting antiviral
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EOT
end of treatment
FAS
Full Analysis Set
FDC
Fixed Dose Combination
FU
follow-up
Gilead
Gilead Sciences, Inc.
Hb
hemoglobin
HCV
hepatitis C virus
HLT
high level term
HLGT
high level group term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
ID
identification
LLT
lower level term
LLOQ
lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
PedsQLTM
Pediatric Quality of Life Inventory™
PK
pharmacokinetics
PT
preferred term
P1NP
Procollagen type 1 N-terminal propeptide
Q1
first quartile
Q3
third quartile
RNA
ribonucleic acid


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Statistical Analysis Plan - Final Analysis
Version 1.0
CONFIDENTIAL
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SAE
serious adverse event
SAP
statistical analysis plan
SI (units)
International system of units
SOC
system organ class
SOF
sofosbuvir 
SVR
sustained virologic response
SVRx
sustained virologic response x weeks after stopping study drug
TEAE
treatment-emergent adverse events
TFLs
tables, figures, and listings
TND
target not detected
ULN
upper limit of normal
VEL
velpatasvir
VF
virologic failure
VOX
voxilaprevir
WBC
white blood cell
WHO
World Health Organization


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Statistical Analysis Plan - Final Analysis
Version 1.0
CONFIDENTIAL
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PHARMACOKINETIC ABBREVIATIONS AND DEFINITIONS
AUC
area under the plasma/serum concentration versus time curve
AUCtau
area under the plasma/serum concentration versus time curve over the dosing interval
Cmax
maximum observed plasma/serum concentration of drug
Ctau
observed drug concentration at the end of the dosing interval


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Statistical Analysis Plan - Final Analysis
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CONFIDENTIAL
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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) for Study GS-US-367-1175. This 
SAP is based on study Protocol Amendment 1 dated 27 March 2019 and electronic case report 
form (eCRF). Any changes made after the finalization of the SAP will be documented in the 
clinical study report (CSR).
1.1.
Study Objectives
The primary objectives of this study are as follows:

To evaluate the steady-state pharmacokinetics (PK) and confirm age-appropriate dose of 
SOF/VEL/VOX FDC in pediatric subjects with chronic HCV infection
The secondary objectives of this study are as follows:

To evaluate the safety and tolerability of SOF/VEL/VOX FDC in pediatric subjects with 
chronic HCV infection

To evaluate the antiviral efficacy of SOF/VEL/VOX FDC treatment in pediatric subjects 
with chronic HCV infection, as assessed by the proportion of pediatric subjects with 
sustained virological response (SVR) 12 weeks after cessation of treatment (SVR12)

To evaluate the antiviral efficacy SOF/VEL/VOX FDC treatment in pediatric subjects with 
chronic HCV infection, as assessed by the proportion of pediatric subjects with SVR 4 and 
24 weeks after cessation of treatment (SVR4 and SVR24)

To evaluate the proportion of pediatric subjects with virologic failure, including on-treatment 
virologic failure and relapse

To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment

To evaluate the emergence of viral resistance to SOF, VEL, and VOX during treatment and 
after cessation of treatment

To evaluate the effect of SOF/VEL/VOX FDC on growth and development of pediatric 
subjects during and after treatment

To evaluate acceptability, including palatability, and swallowability of formulations (as 
applicable) used in the study

To assess the effect of treatment with SOF/VEL/VOX FDC on quality of life as measured by 
PedsQL™ Pediatric Quality of Life survey including neuropsychiatric assessments


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1.2. 
Study Design 
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This is an open-label, multi-cohort study evaluating the PK, safety, and antiviral activity of 
SOFNELNOX FDC in pediatric subjects with chronic HCV infection. 
Overall, the study will enroll both direct-acting antiviral (DAA)-nai"ve and DAA-experienced 
pediatric subjects with chronic HCV infection of any HCV genotype. Three sequential age-based 
cohorts will be enrolled: 
• 
Cohort 1: at least 20 subjects 12 to < 18 years old 
• 
Cohort 2: at least 20 subjects 6 to< 12 years old 
• 
Cohort 3: at least 20 subjects 3 to< 6 years old 
Eligible DAA-naive subjects without cirrhosis will receive treatment for 8 weeks. Eligible DAA-
naive subjects with cirrhosis and DAA-experienced subjects with or without cirrhosis will 
receive treatment for 12 weeks. 
The total time to complete all study visits is up to approximately 36 weeks for subjects treated 
with 8 weeks of therapy and 40 weeks for subjects treated for 12 weeks of therapy including the 
following periods: 
• 
28-day (4-week) screening period 
• 
8 or 12-week treatment period 
• 
24-week posttreatment period 
The schedules of assessments for the study are provided as appendices to the SAP (see Study 
Procedures Table, Appendix 1). 
1.3. 
Sample Size and Power 
Assuming similar variability for SOF, GS-331007, VEL, or VOX AUCtau in the pediatric 
population compared to adults, a sample size of 20 pediatric subjects per cohort will provide at 
least 80% power to target a 90% confidence interval of the geometric mean ratio (GMR) within 
the bounds of 50% to 200% when comparing with the adult population. 
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2.
TYPE OF PLANNED ANALYSIS
2.1.
DMC Analyses
An external multidisciplinary Data Monitoring Committee (DMC) will review the progress of 
the study and perform interim reviews of the safety data in order to protect subject welfare and 
preserve study integrity. To ensure the best interests of the participants, the DMC will 
recommend to the sponsor if the nature, frequency, and severity of adverse effects associated 
with the study treatment warrant the early termination of the study, the continuation of the study, 
or the continuation of the study with modifications.
The DMC’s role and responsibilities and the scope of analysis to be provided to the DMC are 
provided in a mutually agreed upon charter, which defines the DMC membership, meeting 
logistics, and meeting frequency.
2.2.
Final Analysis
The European Medicines Agency (EMA) granted Gilead a waiver to study SOF/VEL/VOX in 
children under 12 years of age. As a result, after all adolescent subjects (12 to < 18 years of age) 
have completed through the post-treatment week 24 visit or have prematurely discontinued from 
the study, outstanding data queries have been resolved, and the database has been cleaned and 
finalized, the final analysis of the data will be performed.


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3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the nmnber of subjects [n], mean, standard deviation [SD] or standard error [SE], median, first 
quartile [Ql], third quartile [Q3], minimmn, and maximmn will be presented. 
Data collected in the study will be presented in by-subject listings for all subjects in the Safety 
Analysis Set, unless otherwise specified. All by-subject listings will be presented by subject 
identification (ID) number in ascending order, unless otherwise specified. 
3.1. 
Analysis Sets 
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The number of subjects eligible for each analysis set will be 
provided. Subjects who were excluded from Safety and Full Analysis Sets will be provided in a 
by-subject listing with reasons for exclusion. 
3.1.1. 
All Enrolled Analysis Set 
All Enrolled Analysis Set includes all adolescent subjects enrolled in the study after screening. 
3.1.2. 
Full Analysis Set 
The Full Analysis Set (FAS) includes HCV infected adolescent subjects who were enrolled into 
the study and received at least one dose of study drug. The study drug in this study is 
SOFNELNOX FDC. 
This is the primary analysis set for efficacy analyses. 
3.1.3. 
Safety Analysis Set 
The Safety Analysis Set includes all adolescent subjects who took at least 1 dose of study drug 
(ie, SOFNELNOX FDC). 
This is the primary analysis set for safety analyses. 
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Population PK Analysis Set
The Population PK Analysis Set includes all enrolled adolescent subjects who received at least 
one dose of study drug and for whom at least one non-missing PK concentration data value is
available from all types of PK sampling. This is the primary analysis set for the Population PK 
modeling and PK exposure analyses.
The PK Analysis Set is equivalent to the Population PK Analysis Set.
3.2.
Subject Grouping
For analyses based on the All Enrolled Analysis Set or FAS, subjects will be grouped according 
to the treatment to which they were enrolled. For analyses based on the Safety Analysis Set, 
subjects will be grouped according to the actual treatment received. The actual treatment 
received is defined as the enrolled treatment except for subjects who received treatment that 
differs from the enrolled treatment for the entire treatment duration. In this case, the actual 
treatment received is defined as the treatment received for the entire treatment duration. Given 
the fact that only DAA-naïve subjects without cirrhosis have been enrolled in this study, there 
will be only one treatment group (ie, SOF/VEL/VOX FDC 8 weeks).
The efficacy analyses will be performed on the FAS, and for selected efficacy analyses, by HCV 
genotype (1 [further broken down to 1a and 1b], 2, 3, 4, 5, 6, or other, as appropriate, and total). 
The safety analysis will be performed on the Safety Analysis Set.
For other selected analyses, for example, the summary of responses to the acceptability and 
palatability questionnaire, the analysis of tanner pubertal stage assessment data, please refer to 
the relevant sections for the detailed description of subject grouping.
3.3.
Strata and Covariates
This study does not use a stratified randomization schedule for enrolling subjects. No covariates 
will be included in efficacy and safety analyses.
3.4.
Examination of Subject Subsets
The efficacy endpoint SVR12 will be analyzed for the following subsets:

sex (male, female)

race (black, non-black)

ethnicity (Hispanic or Latino, non-Hispanic or Latino)

baseline weight (≤ median, > median)

IL28B (CC, non-CC [further broken down to CT, TT])


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
baseline HCV RNA (< 800,000 IU/mL, ≥ 800,000 IU/mL)

baseline alanine aminotransferase (ALT) (≤1.5 × ULN, > 1.5 × ULN)

prior HCV treatment experience (treatment naive, treatment experienced - DAA-naïve, DAA 
experienced)

number of prior HCV treatments

most recent response to prior DAA-naïve and DAA HCV treatment (non-response, 
relapse/breakthrough) for treatment experienced subjects

study treatment status (completed study treatment, discontinued study treatment)

adherence to study drug (< 80%, ≥ 80%)
3.5.
Missing Data and Outliers
3.5.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. 
For missing last dosing date of study drug, imputation rules are described in Section 3.7.1. The 
handling of missing or incomplete dates for adverse event (AE) onset is described in 
Section 7.1.5.2, and for prior and concomitant medications in Section 7.8.
For analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have the 
missing data imputed. Missing on-treatment HCV RNA will have the missing data imputed up to 
the time of the last dose (for on-treatment displays). If the study day associated with the last 
dosing date is greater than or equal to the lower bound of a visit window, and the value at the 
visit is missing, the value will be imputed. If the study day associated with the last dosing date is 
less than the lower bound of a visit window, then the on-treatment value at that visit will remain 
missing. 
If a data point is missing and is preceded and followed in time by values that are “< lower limit 
of quantitation (LLOQ) target not detected (TND)”, then the missing data point will be set to 
“< LLOQ TND”. If a data point is missing and preceded and followed by values that are 
“< LLOQ detected”, or preceded by “< LLOQ detected” and followed by “< LLOQ TND”, or 
preceded by “< LLOQ TND” and followed by “< LLOQ detected”, then the missing value will 
be set to “< LLOQ detected”. In these situations, the data point will be termed a bracketed 
success; otherwise, the data point will be termed a bracketed failure (ie, ≥LLOQ detected). If a 
data point is missing and is not bracketed, the missing data point will also be termed a failure 
(ie, ≥LLOQ detected) except for SVR24, which will be imputed according to SVR12 status. 
Success for SVR12 who have no further HCV RNA measurements collected will be counted as a 
success for SVR24 due to the high correlation between these 2 endpoints.


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For the analyses of continuous HCV RNA efficacy data, when and only when a missing HCV 
RNA value is imputed as < LLOQ TND or < LLOQ detected according to the imputation rule 
described above, the corresponding continuous value will be imputed to LLOQ - 1 IU/mL. No 
other imputation will be performed for continuous HCV RNA data.
In the analysis of the PedsQL™Pediatric Quality of Life Inventory V4.0 Short Form (SF15) 
questionnaire, missing data at on-treatment visits and posttreatment follow-up Week 12 (FU-12) 
visit will not be imputed. Last posttreatment observation carried forward will be used for 
imputation of missing data at posttreatment follow-up Week 24 visit.
3.5.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis..
3.6.
Data Handling Conventions and Transformations
By-subject listings will be presented for all subjects in the Safety Analysis Set and sorted by 
subject ID number, visit date, and time (if applicable) unless otherwise specified. Data collected 
on log forms, such as AEs, will be presented in chronological order within subject. 
Age (in years) on the date of the first dose of study drug and sex at birth will be used for analyses 
and presentation in listings.
If a subject was not dosed with study drug at all, then the date the informed consent was signed 
will be used instead of the first dose date of study drug. Unless age is captured on the eCRF, the 
following conventions will be used for the imputation of date of birth when it is partially missing 
or not collected:

If only month and year of birth is collected, then “15” will be imputed as the day of birth

If only year of birth is collected, then “01 July” will be imputed as the day and month of birth

If year of birth is missing, then date of birth will not be imputed
Non-PK data that are continuous in nature but are less than the LLOQ or above the upper LOQ
will be imputed as follows:

A value that is one unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “x” (where x is considered the 
limit of quantitation). For example, if the values are reported as < 50 and < 5.0, values of 
49 and 4.9, respectively, will be used for calculation of summary statistics. An exception for 
this rule is any value reported < 1. For the values reported as < 1 or < 0.1, value of 0.9 or 
0.09 will be used for calculation of summary statistics.


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
A value that is one unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “> x” (where x is considered the 
limit of quantitation). Values with decimal points will follow the same logic as above.

The limit of quantitation will be used for calculation of descriptive statistics if the datum is 
reported in the form of “≤ x” or “≥ x” (where x is considered the limit of quantitation).
The COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 for use with the High Pure 
System was used to determine HCV RNA results in this study. The LLOQ of the assay is 
15 IU/mL.
When the calculated HCV RNA value is within the linear range of the assay, then the result will 
be reported as the “<< numeric value>> IU/mL”. This result will be referred to in this document 
as the numeric result or as “≥ LLOQ detected” for categorical result.
When HCV RNA is not detected, the result is reported as “No HCV RNA detected” or “target 
not detected”. This result will be referred to in this document as “< LLOQ target not detected” or 
“< LLOQ TND”.
When the HCV RNA IU/mL is less than LLOQ of the assay, the result is reported as 
“< 15 IU/mL HCV RNA detected”. This result will be referred to in this document as “< LLOQ 
detected”.
The overall category of HCV RNA < LLOQ includes “< LLOQ TND” and “< LLOQ detected.”
For numerical HCV RNA data, values below LLOQ will be set to the LLOQ 1 IU/mL 
(ie, 14 HCV RNA IU/mL). HCV RNA values returned as “No HCV RNA detected” will also be 
set to 14 IU/mL.
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data (eg, log10 scale) or nonparametric analysis 
methods may be used, as appropriate.
Natural logarithm transformation will be used for plasma/blood concentrations and analysis of 
PK parameters. Plasma concentration values that are below the lower limit of quantitation (BLQ) 
will be presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated 
as 0 at predose time points, and one-half the value of the LLOQ at postdose time points for 
summary purposes.
For the presentation of summary and order statistics, if at least 1 subject has a concentration 
value of BLQ for the time point, then the minimum value will be displayed as “BLQ” If more 
than 25% of the subjects have a concentration data value of BLQ for a given time point, then the 
minimum and Q1 values will be displayed as “BLQ” If more than 50% of the subjects have a 
concentration data value of BLQ for a given time point, then the minimum, Q1, and median 
values will be displayed as “BLQ” If more than 75% of the subjects have a concentration data 
value of BLQ for a given time point, then the minimum, Q1, median, and Q3 values will be 
displayed as “BLQ” If all subjects have concentration data values of BLQ for a given time point, 
then all order statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ”.


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3.7.
Visit Windows
3.7.1.
Definition of Study Day
Study day is the day relative to the date of the first dose of study drug. Study Day 1 will be 
defined as the day of first dose of study drug administration.
Study day will be calculated from the date of first dose of study drug administration and derived 
as follows:

For postdose study days: Assessment Date First Dose Date + 1

For days prior to the first dose: Assessment Date First Dose Date
The last dose date for the study drug will be the end date on study drug administration eCRF for 
the record where the “subject permanently discontinued” flag is ‘Yes’.
If there are subjects for whom the date of last study drug is unknown due to the reason that the 
subject was lost to follow-up and not able to be contacted, the date of last dose will be estimated 
using the maximum of nonmissing study drug start or stop dates, visit dates and laboratory 
collection dates (posttreatment visits and unscheduled visits are not included).
3.7.2.
Analysis Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.
In general, the baseline value will be the last nonmissing value on or prior to the first dose date 
of study drug. 
HCV RNA, vital signs, and safety laboratory data collected up to the last dose date + 3 days are 
considered to be on-treatment data and HCV RNA, vital signs and safety laboratory data 
collected after the last dose date + 3 days are considered posttreatment data. Given the fact that 
only DAA-naïve subjects without cirrhosis have been enrolled in this study, the analysis 
windows for on-treatment HCV RNA, vital signs and safety laboratory data are provided in
Table 3-1.


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Table 3-1.
Analysis Windows for On-treatment HCV RNA, Vital Signs and 
Safety Laboratory Data
Nominal Visit
SOF/VEL/VOX 8 Weeks
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 1
7
2
11
Week 2
14
12
21
Week 4
28
22
42
Week 8
56
43
≥57
HCV RNA, vital sign, and safety laboratory data collected after the last dose date + 3 days will 
be assigned to the posttreatment follow-up (FU) visits. Visit windows will be calculated from the 
last dose date (ie, FU Day  collection date minus the last dose date) as shown in Table 3-2.
Table 3-2.
Analysis Windows for Posttreatment HCV RNA, Body Weight, 
Height, Vital Sign and Safety Laboratory Data
Nominal 
FUa Visit
HCV RNA, Body weight and Height
Vital Signs and Safety Laboratory Datab
Nominal FU Day
Lower Limit
Upper Limit
Nominal FU Day
Lower Limit
Upper Limit
FU 4
28
21
69
28
4
30
FU 12
84
70
146
NA
NA
NA
FU 24
168
147
210
NA
NA
NA
a
FU x visit  posttreatment Week x follow up visit.
b
Vital signs (blood pressure, pulse, respiratory rate, and temperature) and safety labs will only be summarized for the FU 4
visit (up to 30 days after last dose).
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window. 
If multiple valid nonmissing numeric observations exist in an analysis window, records will be 
chosen based on the following rules if a single value is needed:

For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, average (arithmetic mean) will be used for the baseline value. 


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
For postbaseline visits: 
The record closest to the nominal day for that visit will be selected except for HCV RNA 
posttreatment follow-up visits, for which the latest record in the analysis window will be 
selected. 
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken, unless 
otherwise specified.
If multiple valid nonmissing categorical observations exist in a window, records will be selected
as follows:

For baseline, the last available record on or prior to the date of the first dose of study drug
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, the value with the lowest severity will be selected (eg, normal will be selected over 
abnormal).

For postbaseline visits, follow the same rules described above for postbaseline numeric 
observations, except that if there are multiple records on the same day, the most conservative 
value will be selected (eg, abnormal will be selected over normal).


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided for each country, investigator within a 
country, and overall. The summary will present the number and percentage of subjects in the 
Safety Analysis Set. For each column, the denominator for the percentage calculation will be the 
total number of subjects analyzed for that column. 
A summary of subject disposition will be provided. This summary will present the number of 
subjects screened, enrolled, enrolled but never treated, and the number and percentage of 
subjects in each of the categories listed below. For the “Treated” category, the denominator for 
the percentage calculation will be the total number of subjects enrolled. For all other categories, 
the denominator for the percentage calculation will be the total number of subjects in the Safety 
Analysis Set. 

Treated (Safety Analysis Set) 

In FAS

In Intensive PK Analysis Set

In Population PK Analysis Set

Completed study treatment

Did not complete study treatment with reasons for premature discontinuation of study 
treatment

Completed the study

Did not complete the study with reason for premature discontinuation of study
Among subjects who completed the study treatment and who discontinued study treatment, the 
following number and percentage of subjects will be summarized:

Subjects who had no HCV posttreatment Week 4 assessment and thereafter (No HCV FU-4 
and thereafter)

Subjects who had HCV posttreatment Week 4 assessment but no HCV posttreatment 
Week 12 assessment and thereafter (With HCV FU-4 but no FU-12 and thereafter)
If a subject did not have any HCV RNA assessment ≥ 21 days after the last dose of any study 
drug (ie, lower bound of FU-4 visit for HCV RNA data), the subject is categorized as having 
“No HCV FU-4 and thereafter”. If a subject had the HCV FU-4 assessment but did not have any 


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HCV RNA assessment ≥ 70 days after the last dose of any study drug (ie, lower bound of FU-12 
visit for HCV RNA data), the subject is categorized as having “With HCV FU-4 but No FU-12 
and thereafter”.
In addition, the total number of subjects who were enrolled, and the number of subjects in each 
of the disposition categories listed above will be displayed in a flowchart.
The following by-subject listings will be provided by subject ID number in ascending order to 
support the above summary tables:

Disposition of subjects who complete study treatment and study

Disposition of subjects who did not complete study treatment and/or study with reasons for 
premature discontinuation of study drug and/or study

Lot number and kit ID (if applicable)
4.2.
Extent of Exposure
Extent of exposure to study drug will be examined by assessing the total durations of study drug 
exposure and the level of adherence to the study drug regimen specified in the protocol. 
4.2.1.
Durations of Exposure to Study Regimen 
Total duration of exposure to study drug will be defined as last dose date minus first dose date 
plus 1, regardless of any temporary interruptions in study drug administration, and will be 
expressed in weeks using up to 1 decimal place (eg, 4.5 weeks).
The total durations of exposure to study drug will be summarized using descriptive statistics 
(n, mean, SD, median, Q1, Q3, minimum, and maximum) and using the number (ie, cumulative 
counts) and percentage of subjects exposed through the following time periods: Baseline 
(Day 1), Week 1 (Day 7), Week 4 (Day 28), and Week 8 (Day 56) given the fact that only DAA-
naïve subjects without cirrhosis have been enrolled in this study. A 3-day window is applied to 
the last planned on-treatment visit to match with the protocol-specified visit window. Summaries 
will be provided for the Safety Analysis Set. 
4.2.2.
Adherence to Study Drug
The level of adherence to the study drug regimen will be assessed based on the total amount of 
study drug administered relative to the total amount of study drug prescribed.
The adherence will be calculated based on the amount of SOF/VEL/VOX (mg) by the following 
formula:
100
  
baseline
at 
Prescribed
Drug
Study 
of
Amount 
Total
  
ed
Administer
Drug
Study 
of
Amount 
Total
(%)
Adherence
of
Level










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Where the presumed total amount of study drug (mg) administered to a subject will be 
determined by the data collected on the drug accountability eCRF using the following formula:





Returned
(mg)
Drug
Study 
  
of
Amount 
Total
Dispensed
(mg)
Drug
Study 
  
of
Amount 
Total
ed
Administer
(mg)
Drug
Study 
of
Amount 
Total
Note: If calculated adherence is greater than 100%, the result will be set to 100%.
For adolescent subjects aged 12 to < 18 years receiving the SOF/VEL/VOX 400/100/100 mg 
once daily, the total amount of drug prescribed for 8 weeks would require 33,600 mg 
(ie, 400+100+100 mg/day, 56 days).
Subjects who prematurely discontinue study drug for lack of efficacy (ie, virologic failure) will 
have the total amount of study drug prescribed calculated up to the first date when virologic 
failure criteria were met. For virologic failure confirmed by 2 consecutive measurements the date 
of the first measurement will be used. If there are study drug bottles dispensed on or after the 
subject first met virologic failure criteria, these bottles will not be included in the calculation of 
adherence. If a bottle is dispensed and the bottle is returned empty, then the number of tablets 
returned will be entered as zero. If a bottle is dispensed but not returned (missing), the number of 
tablets taken from that bottle will be counted as zero.
Descriptive statistics for the level of adherence (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) with the number and percentage of subjects belonging to adherence categories 
(e.g. < 80%, ≥ 80 to < 90%, ≥ 90%) will be provided for the Safety Analysis Set. No inferential 
statistics will be provided for duration of exposure and adherence to study drug. 
A separate by-subject listing of study drug administration and drug accountability will be 
provided by subject ID number (in ascending order) and visit (in chronological order).
4.3.
Protocol Deviations
A summary of important protocol deviations will be provided by the Clinical Operations group 
for subjects in the Safety Analysis Set.
Subjects who received study drug other than their enrolled treatment assignment will be listed 
with the start and stop dates that they received incorrect study treatment.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized by HCV 
genotype (1 [further broken down to 1a and 1b], 2, 3, 4, 5, 6, or other, as appropriate, and total)
using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for age, and 
using the numbers and percentages of subjects for sex, race, and ethnicity. Age is calculated in 
years at the date of initial study drug administration. If a subject did not receive study drug after 
enrollment, the subject’s age will be calculated from the date that the subject signed the informed 
consent form. The summary of demographic data will be provided for the Safety Analysis Set.
A by-subject demographic listing will be provided by subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include:

weight in kg

height in cm

body mass index (BMI; in kg/m2)

HCV genotype (1 [further broken down to 1a and 1b], 2, 3, 4, 5, 6, or other, as appropriate,
and as determined by sequencing if available)

cirrhosis (presence, absence, not determined)

primary assessment method used to make the cirrhosis determination (liver biopsy, transient 
elastography, Fibrotest and APRI, APRI, Fibrotest, liver imaging, other)

transient elastography in kPa

Fibrotest as a continuous and as categorical variable

APRI

FIB-4 (,
	 (	) ×  (/)
		  (^ /) × ! (/) )

IL28B (CC, CT, TT) 

baseline HCV RNA (IU/mL) (< 800,000 IU/mL, ≥800,000 IU/mL)


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
baseline HCV RNA (log10 IU/mL) as a continuous variable and as categories (< 6 log10
IU/mL, ≥ 6 log10 IU/mL)

baseline ALT (U/L) as a continuous variable and as categories (≤1.5 × ULN, > 1.5 × ULN)

estimated glomerular filtration rate (eGFR) using Schwartz Formula (mL/min/1.73m2)

prior treatment experience (treatment naïve, treatment experienced[ DAA-naïve, DAA-
experienced])

number of prior HCV treatments

most recent response to prior HCV treatment (non-response, relapse/breakthrough) for 
treatment experienced subjects

mode of HCV Infection

bone age in years

Tanner Stage 
Estimated glomerular filtration rate will be calculated using Schwartz Formula (mL/min/1.73m2) 
 k L/Scr [(k is a proportionality constant, for adolescent females ≥12 years old is 0.55; for 
adolescent males ≥ 12 years old is 0.70); L is height in centimeters (cm); and Scr is serum 
creatinine (mg/dL)]
These baseline characteristics will be summarized by HCV genotype (1 [further broken down to 
1a and 1b], 2, 3, 4, 5, 6, or other, as appropriate, and as determined by sequencing, and total) 
using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for 
continuous variables and using the numbers and percentages of subjects for categorical variables. 
The summary of baseline characteristics will be provided for the Safety Analysis Set.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Swallowability Assessment for SOF/VEL/VOX FDC Placebo Tablets
For subjects in the 12 to <18 years of age group, swallowability of SOF/VEL/VOX FDC placebo 
tablets will be summarized using the numbers and percentages of subjects in each swallowability 
category (ie, Able to Swallow, Unable to Swallow). 
A by-subject listing of Swallowability of SOF/VEL/VOX FDC placebo tablets will be provided 
by subject ID number in ascending order.


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5.4.
Acceptability and Palatability of SOF/VEL/VOX FDC
A questionnaire will be administered to subjects to assess acceptability and palatability of the 
formulation they received on Day 1, End of Treatment and Early Termination (as applicable). If 
the subject is unable to complete the questionnaires, the parent/legal guardian will assist to 
complete the questionnaire on their behalf. The subject’s parent/legal guardian will also 
complete a questionnaire on End of Treatment or Early Termination (as applicable) for their 
assessment of acceptability of the formulation the subject received.
Acceptability and palatability will be assessed by character response to questions about how the 
study drug tasted, how easy it was to swallow the study drug, and also at the end of treatment 
about how it was to take the study drug and, for those who received that tablet formulation, how 
they felt about the number of tablets they had to swallow in the following categories, as 
applicable:

Did Not Taste the Study Drug (for question regarding study drug taste only)

Very Bad/Hard

Bad/Hard

Maybe Bad/Hard or Maybe Good/Easy

Good/Easy

Very Good/Easy
Responses to the acceptability and palatability questionnaire by subjects and their parent/legal 
guardian at Day 1, End of Treatment and Early Termination (as applicable) will be respectively 
summarized using the numbers and percentages of subjects in the corresponding categories, as 
applicable, for each question.
A by-subject listing of acceptability and palatability of SOF/VEL/VOX FDC will be provided by 
subject ID number in ascending order.
5.5.
Medical History
General medical history (ie, conditions not specific to the disease being studied) data will be 
collected at screening and listed only. General medical history data will not be coded. A 
by-subject listing of disease-specific medical history will be provided by subject ID number 
(in ascending order) and medical history of abnormalities (in chronological order).


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6.
EFFICACY ANALYSES
6.1.
Key Efficacy Endpoint
6.1.1.
Definition of the Key Efficacy Endpoint
The key efficacy endpoint is SVR12 defined as HCV RNA < LLOQ (ie, < 15 IU/mL) 12 weeks 
after discontinuation of the study drug in the FAS. The COBAS® AmpliPrep/COBAS® TaqMan®
HCV Test, v2.0 for use with the High Pure System will be used to measure HCV RNA.
6.1.2.
Analysis Methods for the Key Efficacy Endpoint
No inferential statistics will be provided for efficacy endpoints. No statistical comparison will be 
conducted.
The point estimates of SVR12 rate and 2-sided 95% exact CI based on Clopper-Pearson method 
{Clopper 1934} will be provided by HCV genotype (1 [further broken down to 1a and 1b], 2, 3, 
4, 5, 6, or other, as appropriate, and total).
6.1.3.
Subgroup Analysis of the Key Efficacy Endpoint
The point estimates of SVR12 rate and 2-sided 95% exact CIs based on Clopper-Pearson method 
{Clopper 1934} will be provided within each subgroup specified in Section 3.4
A Forest plot will graphically present estimates and 95% confidence intervals of SVR12 rates 
within each subgroup.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints

The percentage of subjects who attain SVR at 4 and 24 weeks after stopping therapy, defined 
as HCV RNA < LLOQ (ie, < 15 IU/mL) 4 and 24 weeks after stopping treatment (SVR 4 and 
SVR 24)

The percentage of subjects with HCV RNA below LLOQ by study visit

HCV RNA (log10 IU/mL) and change from baseline in HCV RNA (log10 IU/mL) through end 
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
The percentage of subjects with virologic failure as the following:
On-treatment virologic failure
HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ, while on 
treatment, confirmed with 2 consecutive values (note, second confirmation value can be 
posttreatment), or last available on-treatment measurement with no subsequent follow-up
values (ie, breakthrough)
> 1 log10IU/mL increase in HCV RNA from nadir while on treatment, confirmed with 
2 consecutive values (note, second confirmation value can be posttreatment), or last 
available on-treatment measurement with no subsequent follow-up values (ie, rebound)
HCV RNA persistently ≥ LLOQ through 8 weeks of treatment (ie, nonresponse)
Relapse 
HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA 
< LLOQ at end of treatment, confirmed with 2 consecutive values or last available 
posttreatment measurement

The proportion of subjects with ALT normalization (defined as ALT > ULN at baseline and 
ALT ≤ ULN at each visit), presented by study visit

Characterization of HCV drug resistance substitutions at baseline, during, and after therapy 
with SOF/VEL/VOX
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
For analyses of HCV RNA < LLOQ by visit while on treatment and during the posttreatment 
(SVR) follow-up period, subjects will be assigned a value at each visit based on the analysis visit 
windows specified in Section 3.7.2. Missing values will be imputed based on the categorical 
imputation rules described in Section 3.5.1. The 2-sided 95% exact confidence interval based on 
Clopper-Pearson method will be provided for the percentage of subjects with HCV RNA 
< LLOQ at each visit. The overall category for “HCV RNA < LLOQ” will be split into the 
following 2 subcategories: “< LLOQ TND” for subjects with target not detected and “< LLOQ 
detected” for subjects with < LLOQ detected in tabular displays. 
Graphs for the percentage of subjects with HCV RNA < LLOQ over time during treatment will 
be displayed.
Summary statistics will be presented for absolute values and change from baseline in HCV RNA 
(log10 IU/mL) by visit through EOT. Imputation rules described in Section 3.5.1 will be used to 
assign HCV RNA values for missing values at a visit that are bracketed by “< LLOQ TND” 
and/or “< LLOQ detected”. Otherwise, a missing  excluded analysis will be performed. Plots of 
the mean ± SD and median (Q1, Q3) of absolute values and changes from baseline in HCV RNA 
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For the SVRl 2 endpoint analysis, a smmnary table of the number and percentage of subjects 
with SVR12, virologic failure (VF), and Other will be created by HCV genotype (1 [further 
broken down to 1 a and 1 b ], 2, 3, 4, 5, 6, or other, as appropriate, and total). All subjects who 
achieve SVR12 will be categorized as SVR12. Virologic failure will be descriptively 
smmnarized as "on-treatment virologic failure" and relapse (which will be broken down by study 
drug completed yes/no). Subjects who do not achieve SVR12 and do not meet criteria for VF 
will be categorized as Other. The denominator for relapse will be the number of subjects who 
had HCV RNA < LLOQ on their last observed on-treatment HCV RNA measurement; 
otherwise, the denominator will be the nmnber of subjects in the FAS. 
A concordance table between SVR12 and SVR24 will be provided. Subjects with both observed 
SVR12 and observed SVR24 data will be included for this analysis. 
In addition, a smmnary table of the number and percentage of subjects with HCV RNA < LLOQ 
and 
LLOQ at the posttreatment follow-up visit ( observed and imputed, with reasons for 
imputed) will be provided for each posttreatment follow-up visit. 95% Clopper-Pearson exact 
Cls will be presented for the overall proportion of subjects with HCV RNA < LLOQ. 
Tables for ALT nonnalization by visit will use similar methodology to the analyses of HCV 
RNA< LLOQ, but will use a missing 
excluded analysis. Only those subjects with ALT greater 
than the ULN range at baseline ( defined as the last ALT value collected prior to first dose of 
study drug) will be included in the analysis of ALT nonnalization. 
Drug resistant substitutions will be analyzed as part of the Virology Study Report. 
-
I 
-
6.4. 
Changes From Protocol-Specified Efficacy Analyses 
There are no changes from protocol-specified efficacy analyses. 
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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA). System organ class (SOC), high-level group term (HLGT), 
high-level term (HLT), preferred term (PT), and lower-level term (LLT) will be provided in the 
AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity criteria 
specified in the protocol. The severity grade of events for which the investigator did not record 
severity will be categorized as “missing” for tabular summaries and data listings and the most 
severe will be considered (for sorting purpose only) in data presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE eCRF to the 
question of “Related to Study Treatment”. Events for which the investigator did not record 
relationships to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing from that captured on the 
CRF.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAE specified in the study protocol. Serious adverse events captured and stored in the clinical 
database will be reconciled with the SAE database from the Gilead Pharmacovigilance and 
Epidemiology Department before database finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment Emergent
Treatment-emergent adverse events (TEAEs) are defined as one or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug.

Any AEs leading to premature discontinuation of study drug.


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7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete, then the month and year (or year alone if month is not 
recorded) of onset determine whether an AE is treatment emergent, as long as the AE stop date is 
not prior to the first dose date of study drug. The event is considered treatment emergent if both
of the following 2 criteria are met:

The AE onset and end dates are the same as or after the month and year (or year) of the first 
dose date of study drug

The AE onset date is the same as or before the month and year (or year) of the 30th day after
the date of the last dose of study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dose date of study drug, will be considered to be treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
A brief high-level summary of TEAEs will be provided by presenting the number and percentage 
of subjects who had the following: any AE; any AE of Grade 3 or above; any AE of Grade 2 or 
above; any treatment-related AE; any treatment-related AE of Grade 3 or above; any 
treatment-related AE of Grade 2 or above; any SAE; any treatment-related SAE; any AE that led 
to premature discontinuation of SOF/VEL/VOX; any AE that led to interruption of 
SOF/VEL/VOX. All deaths (including those that are treatment emergent and those that are not 
treatment emergent) observed during the study will also be summarized and included in this 
table.
Adverse event summaries will provide the number and percentage of subjects with TEAEs by 
SOC and PT, based on the Safety Analysis Set as follows:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

All SAEs

All treatment-related SAEs 


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
AEs leading to premature discontinuation of SOF/VEL/VOX

AEs leading to interruption of SOF/VEL/VOX
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC and then by PT in order of descending
incidence overall within each SOC. In summaries by severity grade, the most severe grade will 
be used for those AEs that occurred more than once in an individual subject during the study. 
In addition to the above summary tables, TEAEs will be summarized by PT only, in order of 
descending incidence for:

AEs that occurred in at least 5% of subjects within this age group

AEs of Grade 3 or above

All treatment-related AEs

All SAEs

AEs leading to premature discontinuation of SOF/VEL/VOX

AEs leading to interruption of SOF/VEL/VOX
In addition to the summaries described above, data listings will be provided for the following:

All AEs (with a variable indicating whether the event is treatment emergent)

AEs of Grade 3 or above

SAEs

Deaths

AEs leading to premature discontinuation of SOF/VEL/VOX

AEs leading to interruption of SOF/VEL/VOX
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days
for subjects who have permanently discontinued study drug. The analysis will be based on values 
reported in conventional units. When values are below the limit of quantitation, they will be 
listed as such, and the closest imputed value will be used for the purpose of calculating summary 
statistics. For example, if “< 0.2” was recorded, a value of 0.1 will be used for the purpose of 
calculating summary statistics; if “< 0.1” was recorded, a value of 0.09 will be used for the 
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A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and urinalysis separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on the 
Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
flagged in the data listings, as appropriate.
No inferential statistics will be generated.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided 
for ALT, aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, hemoglobin, 
reticulocytes, white blood cell (WBC), neutrophils, lymphocytes, platelets, and international 
normalized ratio (INR) as follows:

Baseline values

Values at each postbaseline analysis window

Change from baseline at each postbaseline analysis window
A baseline laboratory value will be defined as the final assessment performed on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
will be displayed to the reported number of digits; SD to the reported number of digits plus 1.
Median (Q1, Q3) of the observed values for these laboratory parameters will be plotted using a 
line plot by visit. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3 (Selection of Data in the Event of Multiple Records in a Window). 
The number of subjects with hemoglobin < 10 g/dL and < 8.5 g/dL at any postbaseline visits 
(up to 30 days after the last dose of any study drug) will be summarized.
7.2.2.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
used for assigning toxicity grades to laboratory results for analysis as Grade 0, Grade 1, Grade 2, 
Grade 3, or Grade 4. Grade 0 includes all values that do not meet the criteria for an abnormality 
of at least Grade 1. Some laboratory tests have criteria for both increased and decreased levels; 
analyses for each direction (ie, increased, decreased) will be presented separately. 


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7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days for subjects who permanently discontinued study drug. If the 
relevant baseline laboratory value is missing, then any abnormality of at least Grade 1 will be 
considered treatment emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by analyte; subjects will be categorized according to the most 
severe postbaseline abnormality grade for a given analyte:

Graded laboratory abnormalities

Grade 3 or above laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after last dose for the laboratory parameter of 
interest.
A by-subject listing of treatment-emergent Grade 3 or above laboratory abnormalities will be 
provided by subject ID number and visit in chronological order. This listing will include all test 
results that were collected throughout the study for the analyte of interest, with all applicable 
severity grades or abnormal flags displayed.
For subjects with at least one event of treatment-emergent Grade 3 or above laboratory 
abnormality of creatine kinase (CK) or lipase, a listing of AEs will be provided.
7.2.2.3.
On-Treatment Liver-Related Laboratory Events
The following liver-related laboratory events will be summarized using data from all the 
on-treatment postbaseline visits (up to 3 days after the last dose of any study drug):

AST or ALT > 3 × ULN and total bilirubin > 2 × ULN

ALT > 5 × ULN

Total bilirubin > 2 × ULN
For the composite criterion of AST or ALT and total bilirubin, AST or ALT and total bilirubin 
must meet the specified cut-offs at a given postbaseline time point; subjects will be counted once 
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Set with at least 1 postbaseline value of AST or ALT and total bilirubin at the same time point. 
For individual laboratory tests, subjects will be counted once based on the most severe 
postbaseline values when the criterion is met. The denominator will be the number of subjects in 
the Safety Analysis Set with at least 1 nonmissing postbaseline value for the test. A listing will 
be provided including ALT, AST, total bilirubin, direct bilirubin, alkaline phosphatase, HCV 
RNA (log10) and yes/no flag for subjects meeting at least 1 of the 3 criteria. All the available data 
for the subjects will be listed.
7.3.
Vital Signs
Vital signs (systolic and diastolic blood pressure [mmHg], pulse [beats/min]) at each visit and 
change from baseline at each visit will be summarized for the Safety Analysis Set using 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum). The baseline 
value will be defined as the last available value collected on or prior to the date/time of first dose 
of study drug. Change from baseline to a postbaseline visit will be defined as the postbaseline 
value minus the baseline value.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3 (Selection of Data in the Event of Multiple Records in a Window). No 
inferential statistics will be generated.
A by-subject listing of vital signs (systolic and diastolic blood pressure [mmHg], pulse 
[beats/min], respiration [breaths/min], and body temperature [°C]) will be provided by subject ID 
number and visit in chronological order. 
7.4.
Body Weight, Height and BMI
An age- and sex-specific percentile will be derived for each weight, height and BMI measurement 
according to the downloadable SAS program available on the Centers for Disease Control (CDC) 
website using the year 2000 growth charts. Methods and SAS program published on the following 
CDC website will be applied to calculate the percentile {Centers for Disease Control and 
Prevention (CDC) 2016a, Centers for Disease Control and Prevention (CDC) 2016b}.
Body weight, height, BMI and percentiles for body weight, height, BMI at each visit, and change 
from baseline at each visit will be summarized for the Safety Analysis Set using descriptive 
statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum). 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3 (Selection of Data in the Event of Multiple Records in a Window). No 
inferential statistics will be generated.
A by-subject listing of body weight, weight percentile, height, height percentile, BMI and BMI 
percentile will be provided by subject ID number and visit in chronological order.


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7.5.
Mid-Parental Height Assessment
The calculation of mid-parental height has been a standard procedure for assessing individual 
child’s future adult height since it was first described by Tanner {Tanner 1970}. Mid-parental 
height will be calculated as the average of father's and mother's height. For boys, the 
sex-adjusted mid-parental height will be calculated by adding 2.5 inch or 6.5 cm from the mean 
of the parents' heights. For girls, will be calculated by subtracting 2.5 inch or 6.5 cm from the 
mean of the parents' heights. If any one of parents’ heights is missing, the calculation will be 
excluded.
A by-subject listing of parents’ heights and derived mid-parental height will be provided by 
subject ID number in ascending order.
7.6.
Bone Age Assessment
Radiographic bone age assessment is performed on Day 1 and End of Treatment. 
Radiographic bone age at baseline visit, End of Treatment and change from baseline visit will be 
summarized for the Safety Analysis Set using descriptive statistics (n, mean, SD, median, Q1, 
Q3, minimum, and maximum). 
Fasting blood samples for bone age biomarkers CTX (C-type collagen sequence) and 
Procollagen type 1 N-terminal propeptide (P1NP), will be collected at Day 1, Early Termination 
(if applicable) and posttreatment Week 24.
Each of bone age biomarkers (CTX and P1NP) at baseline visit, Early Termination (if 
applicable), FU-24 visit and change from baseline visit will be summarized respectively for the 
Safety Analysis Set using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and 
maximum).
A by-subject listing of radiographic bone age assessment and bone age biomarkers will be 
provided by subject ID number in ascending order and visit in chronological order.
7.7.
Tanner Pubertal Stage Assessment
The Tanner stages will be used to evaluate the onset and progression of pubertal changes. 
Females will be rated for pubic hair growth and breast development, and males will be rated for 
pubic hair growth and genitalia development. If the subject is at a Tanner 5 at Day 1, no further 
Tanner Pubertal Stage Assessments are to be completed. The Tanner stages (Pubic Hair and 
Breasts for female; Pubic Hair and Genitalia for male) at EOT, FU-12 and FU-24 visit will be 
summarized by baseline Tanner stages using frequency count and percentage by sex.
Tanner stage results at baseline and during the study will be listed.


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7.8.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version
of the World Health Organization (WHO) Drug dictionary. The medications will be categorized 
as prior or concomitant using the following definitions:

Prior medications: any medications taken and stopped prior to or on the date of first study 
drug administration

Concomitant medications: any medications taken after the date of first study drug 
administration and up to the last dosing date of study drug
Concomitant medications will be summarized by preferred name using the number and 
percentage of subjects for the Safety Analysis Set. A subject reporting the same medication more 
than once will be counted only once when calculating the number and percentage of subjects 
who received that medication. The summary of concomitant medications will be ordered by 
preferred term in descending frequency. For drugs with the same frequency, sorting will be done 
alphabetically.
Summaries will be based on the Safety Analysis Set. No inferential statistics will be generated. 
For purposes of analysis, any medication with a stop date that is on or prior to the initial study 
drug dosing date or a start date that is after the last study drug dosing date will be excluded from 
a concomitant medication summary. If a partial stop date is entered, any medication with the 
month and year (if day is missing) or year (if day and month are missing) prior to the initial 
study drug dosing date will be excluded from the concomitant medication summary. If a partial 
start date is entered, then any medication with the month and year (if day is missing) or year (if 
day and month are missing) after the study drug stop date will be excluded from the concomitant 
medication summary. Medications with completely missing dates will be included in the 
concomitant medication summary.
A summary of prior medications will not be provided.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.9.
Neuropsychiatric assessments as measured by PedsQL™ Pediatric Quality of 
Life survey
The Pediatric Quality of Life (PedsQL™ SF 15) Questionnaires will be completed by all subjects 
and their parent/legal guardian up to 24-Week Posttreatment visits. The transformed scale scores 
(0 to 100 scale) at baseline, EOT, or at Early Termination, if applicable, 12-Week Post-
Treatment, and 24-Week Post-Treatment visits and change from baseline, change from EOT to 
posttreatment will be presented for each of the 4 domains of the SF-15 (physical functioning, 
emotional functioning, social functioning, and school functioning), the psychosocial health 
summary (emotional, social, and school functioning domains), and the Total Score. Scoring of 


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the SF15 scales will be performed as described in Scaling and Scoring of the Pediatric Quality of 
Life Inventory™ (PedsQLTM) by James W. Varni. A Wilcoxon signed rank test will be used to 
explore changes in status from baseline to EOT, or at Early Termination, if applicable, and from 
EOT to each of the posttreatment time points. Results (p values) will be presented but should be 
interpreted with caution as multiple endpoints are being tested, and the study has not been 
powered to test these endpoints. Plot of the mean ± SD of change from baseline in SF15 
summary scores will be presented.
7.10.
Other Safety Measures
A data listing will be provided for subjects who become pregnant during the study.
7.11.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC ANALYSES
8.1.
Population PK Analysis
Population PK modeling will be applied on 
 
 sparse PK samples to characterize the PK of SOF,
GS-331007, VEL and VOX using mixed-effect modeling techniques. SOF, GS-331007, VEL
and VOX exposures (AUCtau, Cmax, and Ctau, if applicable) in pediatric subjects will be 
summarized using descriptive statistics (n, arithmetic mean, geometric mean and its 95% 
confidence interval, coefficient of variation [%CV], SD, median, Q1, Q3, minimum, and 
maximum), and will be compared with SOF/VEL/VOX adult populations. The primary PK
endpoint of this analysis will be evaluated by carrying out an analysis of variance (ANOVA) for 
log-transformed SOF, GS-331007, VEL and VOX AUCtau. The secondary PK endpoints of this 
analysis will be the Cmax and Ctau (if applicable), of SOF, GS-331007, VEL and VOX. The 90% 
confidence intervals will be constructed for the ratio of geometric means of each PK parameter. 
Population PK Analysis will be performed in ad hoc fashion upon estimated PK parameters 
using the population PK model are available.
CCI


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


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


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


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


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Appendix 1.
Study Procedures Table
Appendix Table 1.
Screening and On-Treatment Study Visits
Screening
Day 1a
On-Treatment
Study Week (±3 Days)
Early 
Terminationa
Week 1
Week 2t,v
Week 4 s
Week 8b
End of 
Treatmentc
Clinical Assessments
Informed Consent/Assent
X
Determine Eligibility
X
X
Medical History
X
Parental Height, if known
X
Complete Physical Examination
X
X
X
X
Symptom Directed Physical Examination
X
X
X
X
Tanner Pubertal Stage Assessment
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
Body Weight and Height
X
X
X
X
X
X
X
X
Radiographic Bone Age Assessment
X
X
X
AEs and Concomitant Medications
Xe
X
X
X
X
X
X
X
FibroScan® (if available)
Xf
Xf
Pregnancy Prevention Counselingg
X
X
X
X
X
SOF/VEL/VOX Swallowability Assessment 
Xh
Xh
SOF/VEL/VOX Acceptability Questionnairei
X
X
X
Quality of Life Surveyj
X
X
X
Review of Study Medication Compliance
Xk
X
X
X
X
Study Drug Dispensing 
X
X
X
Return of Study Drug Bottles 
X
X
X
X
Review Dosing Diary 
Xk
Xk


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Screening
Day 1a
On-Treatment
Study Week (±3 Days)
Early 
Terminationa
Week 1
Week 2t,v
Week 4 s
Week 8b
End of 
Treatmentc
Laboratory Assessments
Hematology, Chemistry 
X
X
X
X
X
X
X
X
Coagulation 
X
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
HBV DNAl
X
X
X
X
X
X
X
Viral Sequencingm
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testingn
X
X
Xo
X
X
X
X
Single sparse PK sample collected at anytime 
X
X
X
X
Two sparse PK Samples collected pre dose and 
between 15 minutes and up to 4 hours postdose
Xp
Xp
Pharmacogenomics Sampler
X
X
X
X
X
X
X
Urinalysis
X
X
Xk
Xk
Urine Drug Screen 
X
IL28B Genotyping
Xf
Xf
Bone Age Biomarkers
X
Xw
HCV Genotyping
X
HIV testing, HAV Antibody, HCV Antibody, 
HBsAg, HBsAb, HBcAb 
X
HbA1c, Fibrotest®, APRI
X
TSH
X
X
X
Alpha 1 anti trypsin
X
CCI


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Statistical Analysis Plan - Final Analysis 
Approximate amount of 
blood drawn (mL) 
Cohort I 
Approximate amount of 
blood drawn (mL) 
Cohort 2 
Approximate amount of 
blood drawn (mL) 
Cohort 3 
Screening 
22. 1 
22. [U 
22. [U 
Day t• 
Week i 
Week 21,v 
11.3 
12.3 
9.3 
(no IPK) 
23.3 
(ifIPK)• 
12.3 
9.3 
[81 
12.3 
8.3 
8v 
Version 1.0 
On-Treatment 
Study Week (±3 Days) 
End of 
Early 
Week4 • 
Week Sb 
Treatment" 
Termination• 
11.3 
9.3 
13.2 
16.8 
11.3 
9.3 
13.2 
16.8 
9.3 
8.3 
12.2 
12.2 
a 
Subjects should be instmcted to fast (no food or drink, except water), starting from midnight (00:00) or earlier, as appropriate, on the evening prior to Day I and Early 
Tem1ination (if applicable) to ensure an approximate 8 hour fast prior to the blood sample collection the next morning. 
b 
The Week 8 Visit will only be completed for subject DAA na'ive with cirrhosis or DAA experienced with or without cirrhosis, who are on 12 weeks of treatment. 
c 
For subjects that are DAA naive without cirrhosis, who are on 8 weeks of treatment, the End of Treatment visit will occur at Week 8. 
For subjects that are DAA naive with cirrhosis or DAA experienced with or without cirrhosis, who are on 12 weeks of treatment, the End of Treatment Visit will occur at 
Week 12. 
d 
Vital signs include blood pressure, pulse, respiratory rate, and temperature. 
e 
From the time of obtaining infom1ed consent through the first administration of investigational medicinal product, record all serious adverse events (SAEs), as well as any 
adverse events related to protocol mandated procedures. 
f 
FibroScan® and IL28B genotyping may be perfom1ed at Day I if not completed at Screening. 
g 
Including partner pregnancy prevention for male participants (all subjects 2:: 12 years old and subjects < 12 years old at the discretion of the Investigator based on subject's 
pubertal status). 
h 
Swallowability may occur at Day I if not completed during Screening. 
I 
Ill 
A questionnaire will be administered to subjects to assess acceptability, including palatability, on Day I, EOT (Week 8 or Week 12), or Early Tem1ination (as applicable). If 
the subject is unable to complete the questionnaires, the parent/legal guardian will assist to complete the questionnaire. The subjects' parent/legal guardian will also complete 
a questionnaire on EOT (Week 8 or Week 12) or Early Tem1ination (as applicable). 
Quality of life survey will be completed by all subjects and their parent/legal guardian. Subject and parent/legal guardian is to review questionnaire and write/mark answers 
direct! onto the uestionnaire. 
n 
All females of childbearing potential will have a semm pregnancy test at Screening. In addition, all females of childbearing potential will perfom1 a urine pregnancy test at 
Da I and eve 
4 weeks during the dosin 
eriod and for a minimum of30 da s following the last dose of SOFNEL/VOX FDC. 
I' 
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p 
I' 
F 
Version 1.0 
u 
In cohort 2 and cohort 3, for subject weighing :5 25 kg, the screening visit will be perfom1ed in two different days. Samples for chemistry, hematology, coagulation, TSH, 
1-IIV/HAV/HCV testing will be perfom1ed on one day ( 12 ml of blood will be collected) and all other samples including for 1-ICV RNA, 1-ICV genotype and IL28B will be 
collected on a different day within the screening window ( 10. 1 ml of blood will be collected). If the subject's weight is > 25 kg, the screening visit blood draw can be 
com leted in one da . 
I' 
w 
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Appendix Table 2.
Posttreatment Visits
Posttreatment
Study Week (±5 Days)
4 Weeks Posttreatment
12 Weeks Posttreatment
24 Weeks Posttreatmenta
Clinical Assessments
Symptom directed Physical Exam
X
X
X
Tanner Pubertal Stage assessment 
X
X
Vital Signs
X
X
X
Body weight and Height
X
X
X
AEs
X
Xb
Xb
Concomitant Medications
X
Pregnancy Prevention Counselingc
X
Quality of Life Survey
X
X
Laboratory Assessments
Hematology, Chemistry
X
HCV RNA
X
X
X
HBV DNAd
X
X
X
Viral Sequencinge
X
X
X
Pharmacogenomics Samplef
X
X
X
Urine Pregnancy Test
X
Bone Age Biomarkers
X
Approximate amount of
blood drawn (mL)  All Cohorts
7.3
5
8.6
a
Subjects should be instructed to fast (no food or drink, except water), starting from midnight (00:00) or earlier, as appropriate, on the evening prior to posttreatment Week 24 
to ensure an approximate 8 hour fast prior to the blood sample collection the next morning.  
b
Only SAEs will be captured at posttreatment Week 12 and 24 
c
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years old and subjects < 12 years old at the discretion of the Investigator based on subject’s 
pubertal status) 
d
HBV DNA testing for subjects HBcAb positive at Screening
e
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
f
Only for subjects that have provided consent, an appropriate blood sample for PG analysis will be collected at Day 1. If the sample was not collected Day 1 visit, the sample 
may be drawn at subsequent visits CCI


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Appendix 2.
Tanner Stages*
1. Pubic hair (male and female)
Tanner I
no pubic hair at all (prepubertal Dominic state)
Tanner II
small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females)
Tanner III
hair becomes more coarse and curly, and begins to extend laterally
Tanner IV
adult-like hair quality, extending across pubis but sparing medial thighs
Tanner V
hair extends to medial surface of the thighs
2. Genitals (male) (One standard deviation around mean age)
Tanner I
Testes, scrotum, and penis about same size and proportion as in early childhood
Tanner II
Enlargement of scrotum and testes; skin of scrotum reddens and changes in texture; little or no enlargement of penis (10.5-12.5)
Tanner III
Enlargement of penis, first mainly in length; further growth of testes and scrotum (11.5-14)
Tanner IV
Increased size of penis with growth in breadth and development of glans; further enlargement of testes and scrotum and increased darkening 
of scrotal skin (13.5-15)
Tanner V
Genitalia adult in size and shape
3. Breasts (female)
Tanner I
no glandular tissue: areola follows the skin contours of the chest
Tanner II
breast bud forms, with small area of surrounding glandular tissue; areola begins to widen 
Tanner III
breast begins to become more elevated, and extends beyond the borders of the areola, which continues to widen but remains in contour with 
surrounding breast 
Tanner IV
increased breast size and elevation; areola and papilla form a secondary mound projecting from the contour of the surrounding breast
Tanner V 
breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla. 
*
Chart referenced from Marshall WA, Tanner JM, variations in the pattern of pubertal changes in boys and girls {Marshall 1969, Marshall 1970}


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


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