Conditions: Hepatitis C Virus Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 204
Healthy volunteers: no

Brief summary:
The primary objectives of this study are to evaluate the efficacy, safety, and tolerability of sofosbuvir/velpatasvir (SOF/VEL) fixed-dose combination (FDC) and SOF/VEL FDC and ribavirin (RBV) for 12 weeks in participants with chronic genotype 3 hepatitis C virus (HCV) infection and compensated cirrhosis.

Detailed description:

Arms:
arm 1: SOF/VEL FDC for 12 weeks arm 2: SOF/VEL FDC + RBV for 12 weeks

Interventions: intervention 1: SOF/VEL intervention 2: RBV
Intervention descriptions: intervention 1: 400/100 mg FDC tablet administered orally once daily intervention 2: RBV tablets administered orally in a divided daily dose according to package insert weight-based dosing recommendations (\< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg)

Protocol document:
SAP_002.pdf: 
Study Title: 
Name of Test Drug: 
Study N urn ber: 
Protocol Version/Date: 
Analysis Type: 
Analysis Plan Version: 
Analysis Plan Date: 
Analysis Plan Author: 
~ GILEAU 
STATISTICAL ANALYSIS PLAN 
A Phase 2, Multicenter, Randomized, Open-Label Study to 
Evaluate the Efficacy and Safety of SofosbuvirNelpatasvir 
Fixed Dose Combination (FDC) and SofosbuvirNelpatasvir 
FDC and Ribavirin in Subjects with Chronic Genotype 3 HCV 
Infection and Cirrhosis 
Sofosbuvir/Velpatasvir Fixed-Dose Combination 
GS-US-342-2097 
Amendment 1: 04 April2016 
Final Analysis (SVR12) 
Version 1.0 
08 November 2017 
CONFIDENTIAL AND PROPRIETARY INFORMATION 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF ABBREVIATIONS........................................................................................................................................5
1.
INTRODUCTION ................................................................................................................................................7
1.1.
Study Objectives ......................................................................................................................................7
1.2.
Study Design............................................................................................................................................7
1.3.
Sample Size and Power............................................................................................................................8
2.
TYPE OF PLANNED ANALYSIS ......................................................................................................................9
2.1.
Interim Analysis.......................................................................................................................................9
2.2.
Final Analysis ..........................................................................................................................................9
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................10
3.1.
Analysis Sets..........................................................................................................................................10
3.1.1.
All Randomized/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.
Multiple Comparisons............................................................................................................................12
3.6.
Missing Data and Outliers......................................................................................................................12
3.6.1.
Missing Data ........................................................................................................................12
3.6.2.
Outliers.................................................................................................................................13
3.7.
Data Handling Conventions and Transformations .................................................................................13
3.8.
Analysis Visit Windows.........................................................................................................................14
3.8.1.
Definition of Study Day .......................................................................................................14
3.8.2.
Analysis Visit Windows.......................................................................................................14
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis
Window................................................................................................................................16
4.
SUBJECT DISPOSITION ..................................................................................................................................17
4.1.
Subject Enrollment and Disposition.......................................................................................................17
4.2.
Extent of Exposure and Adherence........................................................................................................18
4.2.1.
Duration of Exposure to Study Drug....................................................................................18
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.
Medical History......................................................................................................................................22
6.
EFFICACY ANALYSES ...................................................................................................................................23
6.1.
Primary Efficacy Endpoint.....................................................................................................................23
6.1.1.
Definition of the Primary Efficacy Endpoint .......................................................................23
6.1.2.
Primary Analysis of the Primary Efficacy Endpoint ............................................................23
6.1.3.
Subgroup Analysis of the Primary Efficacy Endpoint .........................................................23


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6.2.
Secondary Efficacy Endpoints ...............................................................................................................23
6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................23
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................24
6.3.
Exploratory Efficacy Endpoints.............................................................................................................25
6.3.1.
Definition of Exploratory Efficacy Endpoints......................................................................25
6.3.2.
Analysis Methods for Exploratory Efficacy Endpoints........................................................25
6.4.
Changes From Protocol-Specified Efficacy Analyses............................................................................25
7.
SAFETY ANALYSES........................................................................................................................................26
7.1.
Adverse Events and Deaths....................................................................................................................26
7.1.1.
Adverse Event Dictionary ....................................................................................................26
7.1.2.
Adverse Event Severity........................................................................................................26
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................26
7.1.4.
Serious Adverse Events........................................................................................................26
7.1.5.
Treatment-Emergent Adverse Events...................................................................................26
7.1.5.1.
Definition of Treatment-Emergent .................................................................26
7.1.5.2.
Incomplete Dates ............................................................................................27
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................27
7.2.
Laboratory Evaluations ..........................................................................................................................29
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................29
7.2.2.
Graded Laboratory Values ...................................................................................................30
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities.............................................30
7.2.2.2.
Summaries of Treatment-Emergent Laboratory 
Abnormalities .................................................................................................30
7.3.
HIV RNA for HIV Coinfected Subjects.................................................................................................30
7.4.
Body Weight, Height, and Vital Signs...................................................................................................31
7.5.
Prior and Concomitant Medications.......................................................................................................31
7.6.
Investigator Electrocardiogram Assessment ..........................................................................................32
7.7.
Other Safety Measures ...........................................................................................................................32
7.8.
Changes From Protocol-Specified Safety Analyses...............................................................................32
8.
PHARMACOKINETIC ANALYSES ................................................................................................................33
9.
REFERENCES ...................................................................................................................................................34
10.
SOFTWARE.......................................................................................................................................................35
11.
SAP REVISION..................................................................................................................................................36
12.
APPENDICES ....................................................................................................................................................37
Appendix 1.
Table of Contents for Statistical Tables, Figures, and Listings ..............................................38
Appendix 2.
Schedule of Assessments........................................................................................................44
Appendix 3.
Child-Pugh-Turcottea Classification of the Severity of Cirrhosis...........................................46


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LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Windows for On-treatment HCV RNA, Vital Signs, Safety Laboratory 
Data, HIV-1 RNA and CD4 Counts .......................................................................................15
Table 3-2.
Analysis Windows for Posttreatment HCV RNA, Vital Signs and Safety Laboratory 
Data, HIV-1 RNA and CD4 Counts .......................................................................................15


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate transaminase
ATC
anatomical therapeutic chemical
BMI
body mass index
BPM
beats per minute
CI
confidence interval
CSR
clinical study report
DAA
direct-acting antiviral
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
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ID
identification
INR
international normalized ratio
IWRS
interactive web response system
LLOQ
lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PT
preferred term
Q1
first quartile
Q3
third quartile
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SOC
system organ class
SOF
sofosbuvir (Sovaldi®)
SVR
sustained virologic response
SVRx
sustained virologic response x weeks after stopping study drug
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings


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TND
target not detected
ULN
upper limit of the normal range
VEL
velpatasvir (previously GS-5816)
WBC
white blood cell
WHO
World Health Organization


SOFNELFDC 
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Statistical Analysis Plan 
1. 
INTRODUCTION 
Version 1.0 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study rep01t (CSR) 
for Study GS-US-342-2097. This SAP is based on the study protocol Amendment 1 dated 
04 April 2016 and the electronic case rep01t form ( eCRF). The SAP will be fmalized before data 
finalization. Any changes made after fmalization of the SAP will be docmnented in the CSR. 
1.1. 
Study Objectives 
The primary objectives of this study are as follows: 
• 
To evaluate the efficacy of study treatment with sofosbuvir (SOF)/velpatasvir (VEL) 
fixed-dose combination (FDC) and SOFNEL FDC+ ribavirin (RBV) for 12 weeks as 
measured by the proportion of subjects with sustained virologic response (SVR) 12 weeks 
after cessation of treatment regimen (SVR12) 
• 
To evaluate the safety and tolerability of each treatment regimen 
The secondru.y objectives of this study ru.·e as follows: 
• 
To detemll.ne the prop01tion of subjects who attain SVR at 4 weeks after cessation of each 
treatment regimen (SVR4) 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
each treatment regimen 
• 
To evaluate the emergence of viral resistance to SOF and VEL dming treatment and after 
cessation of each treatment regimen 
The explorat01y objective of this study is as follows: 
• 
PPD 
1.2. 
Study Design 
This is a multicenter, randomized, open-label study that will evaluate the safety, tolerability, and 
antiviral efficacy of SOF NEL FDC±RBV for 12 weeks in subjects with chronic genotype 3 
HCV infection and compensated cinhosis with or without human immunodeficiency vims (HIV) 
co infection. 
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Approximately 200 subjects with chronic genotype 3 HCV infection and compensated cirrhosis 
will be randomized (1:1) to either:

Group 1 (n = 100): SOF/VEL (400/100 mg) once daily for 12 weeks
OR

Group 2 (n = 100): SOF/VEL (400/100 mg) once daily + RBV (1000 or 1200 mg divided 
into 2 daily doses) for 12 weeks 
Randomization will be stratified by prior treatment experience (treatment naive or treatment
experienced); treatment naive is defined as never having been exposed to an approved or 
experimental HCV-specific direct-acting antiviral (DAA) or having had prior treatment of HCV 
with interferon or RBV. All other subjects will be considered treatment experienced.
1.3.
Sample Size and Power
Approximately 200 subjects with chronic genotype 3 HCV infection and compensated cirrhosis 
will be enrolled in this study. This sample size is based on the number of subjects who meet the 
eligibility criteria and could practically be enrolled. With a sample size of 100 for each 
treatment, a 2-sided 95% exact confidence interval (CI) will extend 21% in length, at most, for 
each treatment group.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analysis
No formal interim analysis is planned.
2.2.
Final Analysis
The final analysis will be performed after all subjects have completed the posttreatment Week 12 
visit or have prematurely discontinued from the study, outstanding data queries have been 
resolved, and the database has been cleaned and finalized.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and proportion of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD) or standard error (SE), median, first 
quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
Data collected in the study will be presented in by-subject listings for all subjects in the Safety 
Analysis Set, unless otherwise specified. All by-subject listings will be presented by subject 
identification (ID) number in ascending order, unless otherwise specified.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The number of subjects eligible for each analysis set will be 
provided. Subjects who were excluded from each analysis set will be included in a by-subject 
listing with reasons for exclusion.
3.1.1.
All Randomized/Enrolled Analysis Set
The All Randomized Analysis Set includes all subjects who were randomized in the study.
Subjects will be grouped within the All Randomized Analysis Set by the treatment group to 
which they were randomized. 
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all randomized subjects who took at least 1 dose of any 
study drug. The study drugs in this study are SOF/VEL and RBV. Subjects will be grouped 
within the FAS by the treatment group to which they were randomized. This is the primary 
analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of any study drug. Subjects 
will be grouped within the Safety Analysis Set according to the treatment they received. This is 
the primary analysis set for safety analyses.
3.1.4.
Pharmacokinetic Analysis Set
The Pharmacokinetic (PK) Analysis Set includes all subjects who took at least 1 dose of study 
drug and have at least 1 nonmissing postdose plasma concentration value for the corresponding 
analyte. The analytes of interest may include SOF (and its metabolites GS-566500 and 
GS-331007), VEL, and RBV if applicable. The PK Analysis Set will be used for the listing of 
concentration data.


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3.2.
Subject Grouping
For analyses based on the All Randomized Analysis Set or FAS, subjects will be grouped 
according to the treatment group to which they were randomized. For analyses based on the 
Safety Analysis Set or the PK Analysis Set, subjects will be grouped according to the actual 
treatment received. The actual treatment received is defined as the randomized treatment except 
for subjects who received treatment that differed from the randomized treatment for the entire 
treatment duration. In such cases, the actual treatment received will be defined as the treatment 
received for the entire treatment duration.
3.3.
Strata and Covariates
Approximately 200 subjects with chronic genotype 3 HCV infection and compensated cirrhosis 
will be randomized in a 1:1 ratio to treatment Group 1 or Group 2 using an interactive web 
response system (IWRS). Randomization will be stratified by prior HCV treatment experience 
(treatment naive or treatment experienced).
If there are discrepancies in stratification factor values between the IWRS and the clinical
database, the values recorded in the clinical database will be used for analyses.   
3.4.
Examination of Subject Subsets
The following subject subsets will be explored for the primary efficacy endpoint:

Age (< 65 years, ≥65 years)

Sex (male, female)

Race (White, Asian)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Baseline body mass index (BMI) (< 30 kg/m2, ≥ 30 kg/m2)

IL28B genotype (CC, non-CC; with non-CC further broken down to CT, TT)

Baseline HCV RNA (< 800,000 IU/mL, ≥ 800,000 IU/mL)

Baseline alanine aminotransferase (ALT; ≤1.5 × upper limit of normal [ULN], > 1.5 × ULN)

Prior HCV treatment experience (treatment naive, treatment experienced)

HIV coinfection (yes, no, missing)

Prior HCV treatment response (nonresponder, relapse/breakthrough, other) for treatment-
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
Completed study treatment, discontinued study treatment 

Adherence to study regimen (< 80%, ≥ 80%)

Adherence to SOF/VEL (< 80%, ≥ 80%)
3.5.
Multiple Comparisons
No multiplicity adjustment will be made. 
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless imputation methods for handling missing 
data are specified. 
For missing last dosing date of a study drug, imputation rules are described in Section 3.8.1. 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 7.5.
For analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have the 
missing data imputed. Missing on-treatment HCV RNA will have missing data imputed up to the 
date of the last dose (for on-treatment displays). If the study day associated with the last dosing 
date of any study drug is greater than or equal to the lower bound of a visit window, and the 
value at the visit is missing, then the value will be imputed. If the study day associated with the 
last dosing date is less than the lower bound of a visit window then the on-treatment value at that 
visit will remain missing.
If an HCV RNA 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).
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
(ie, HCV RNA 14 IU/mL). No other imputation will be performed for continuous HCV RNA 
data. 
For the analyses of continuous HIV RNA data, for subjects with a missing HIV RNA value in a 
visit window that is bracketed by prior and subsequent values, the numerical value of HIV RNA 
will be imputed using the larger value. No other imputation will be performed for HIV RNA 
data.


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Except for the imputation rules described above, values for other missing data (including all 
safety data) will not be imputed.
3.6.2.
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. 
3.7.
Data Handling Conventions and Transformations
By-subject listings will be presented for all subjects in the Safety Analysis Set 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, the date that the informed consent was signed 
will be used for age calculation as appropriate. For some countries, only birth year is collected on 
the eCRF. In those cases, “01 January” will be used for the unknown birth day and month for the 
purpose of age calculation, unless age is captured on the eCRF.
Non-PK data that are continuous in nature but are < LLOQ or above the upper limit of 
quantitation will be imputed as follows:

A value that is 1 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 as < 1. For the values reported as < 1 or < 0.1, values of 
0.9 or 0.09, respectively, will be used for calculation of summary statistics.

A value that is one unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “> x” (where x is considered the 
limit of quantitation). Values with decimal points will follow the same logic as above.

The limit of quantitation will be used for calculation of descriptive statistics if the datum is 
reported in the form of “≤ x” or “≥ x” (where x is considered the limit of quantitation).
The COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, version 2.0 will be used 
to determine HCV RNA results in this study. The LLOQ of the assay is 15 IU/mL.
When the calculated HCV RNA IU/mL is within the linear range of the assay, the result will be 
reported as the “<< numeric value>> IU/mL.” This result is referred to in this document as the 
numeric result or as “≥ LLOQ detected” for categorical results.


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When HCV RNA is not detected, the result will be reported as “No HCV RNA detected” or 
“target not detected.” This result is referred to in this document as “< LLOQ target not detected” 
or “< LLOQ TND.”
When the HCV RNA IU/mL is less than the LLOQ of the assay, the result will be reported as 
“< 15 IU/mL HCV RNA detected.” This result is 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 the LLOQ will be set to LLOQ – 1 IU/mL. HCV 
RNA values returned as “target not detected” will also be set to LLOQ – 1 IU/mL.
HIV RNA in this study will be measured using the AmpliPrep/COBAS® TaqMan® HIV-1 Test, 
v2.0. The LLOQ of the assay is 20 copies/mL.
For the analyses of continuous HIV RNA data, for missing HIV RNA values in a visit window 
that are bracketed by prior and subsequent values, the numerical value of HIV RNA will be 
imputed using the larger value. Values returned as “< 20 copies/mL HIV-1 RNA detected” or 
“No HIV-1 RNA detected” will be set to the LLOQ minus 1 (ie, HIV RNA 19 copies/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.
3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day is the day relative to the date of the first dose of any study drug. Study Day 1 will be 
defined as the day of first dose of any study drug.
Study day will be calculated from the date of the first dose of study drug 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
If there are subjects for whom the date of the last dose of study drug is unknown because the 
subject was lost to follow-up and not able to be contacted, the date of the 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 will not be included). 
3.8.2.
Analysis Visit Windows
Subject visits may not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.


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In general, the baseline value will be the last nonmissing value on or prior to the date of the first 
dose of study drug. 
HCV RNA, vital signs, safety laboratory data, HIV-1 RNA and CD4 counts (HIV-1 RNA and 
CD4 counts will be assessed for subjects with HIV coinfection only) collected up to the date of 
the last dose of study drug plus 3 days will be considered to be on-treatment data; HCV RNA, 
vital signs, safety laboratory data, and HIV-1 RNA and CD4 counts collected after the date of the 
last dose of study drug plus 3 days will be considered posttreatment data. The analysis windows 
for on-treatment HCV RNA, vital signs, safety laboratory data, and HIV-1 RNA and CD4 counts 
are provided in Table 3-1.
Table 3-1.
Analysis Windows for On-treatment HCV RNA, Vital Signs, Safety 
Laboratory Data, HIV-1 RNA and CD4 Counts
Nominal 
Visit
HCV RNA, Vital Signs, 
Safety Laboratory Data, HIV-1 RNA and CD4 Counts
Urinalysis, Coagulation Tests,
CPT Score and Body Weight
Nominal 
Day
Lower 
Limit
Upper 
Limit
Nominal 
Day
Lower 
Limit
Upper 
Limit
Baseline
1
(none)
1
1
(none)
1
Week 2
14
2
21
NA
NA
NA
Week 4
28
22
42
NA
NA
NA
Week 8
56
43
70
NA
NA
NA
Week 12
84
71
≥ 85
84
2
≥ 85
HCV RNA, vital signs, safety laboratory data, and HIV-1 RNA and CD4 counts collected after 
the date of the last dose of study drug plus 3 days will be assigned to the posttreatment follow-up 
(FU) visit. Visit windows will be calculated from the date of the last dose 
(ie, FU Day = collection date −the last dose date) as shown in Table 3-2.
Table 3-2.
Analysis Windows for Posttreatment HCV RNA, Vital Signs and 
Safety Laboratory Data, HIV-1 RNA and CD4 Counts
Nominal FUa
Visit
HCV RNA
Vital Signs, HIV-1 RNA, CD4 Counts and Other 
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
a
FU-x visit = posttreatment Week-x follow-up visit.
b
Posttreatment vital signs, safety labs, HIV-1 RNA, and CD4 counts will be summarized only for the FU-4 visit (ie, up to 30 
days after last dose).


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3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Window
Depending on the statistical analysis method, a single value 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 for each analysis window. 
If there are multiple valid nonmissing numeric observations in an analysis window, and a single 
value is needed, records will be chosen based on the following rules:

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 arithmetic mean will be used for the baseline value. 

For postbaseline visits: 
The record closest to the nominal day for that visit will be selected, except for HCV RNA 
posttreatment FU 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 arithmetic mean will be used, 
unless otherwise specified.

If there are multiple valid nonmissing categorical observations in an analysis 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, the same rules described above for postbaseline numeric 
observations will be followed, except if there are multiple records on the same day, in 
which case 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 all enrolled subjects will be provided for each investigator by treatment group and 
overall. The summary will present the number and proportion of subjects in all enrolled subjects. 
For each column, the denominator for the percentage calculation will be the total number of 
subjects for that column. 
A similar enrollment table will be provided by treatment group and overall by prior HCV 
treatment (treatment naive or treatment experienced). The denominator for the proportion of 
subjects in the stratum will be the total number of subjects in the Safety Analysis Set within that 
stratum. If there are discrepancies in the value used for stratification assignment between the 
IWRS and the clinical database, the value collected in the clinical database will be used for the 
summary. A listing of subjects with the IWRS randomization strata that differ from stratification 
factor data entered in the clinical database at the time of data finalization will be provided. 
The randomization schedule used for the study will be provided as an appendix to the CSR.
A summary of subject disposition will be provided for each treatment group and overall for all 
screened subjects. The summary will present the number of subjects screened, the number of 
subjects not randomized, the number of subjects randomized, the number of subjects randomized 
but never treated, and the number of subjects in each of the categories listed below:

Treated (Safety Analysis Set) 

In the FAS

In the PK Analysis Set

Completed study treatment

Did not complete study treatment with reasons for premature discontinuation of study 
treatment

Completed study

Did not complete study with reasons for premature discontinuation of study
For the proportion of subjects who completed or did not complete study treatment or the study, 
the denominator for the percentage calculation will be the total number of subjects in the Safety 
Analysis Set. Among subjects who completed study treatment or discontinued study treatment, 
the number of subjects will be summarized for the following:

No HCV posttreatment Week 4 assessment and thereafter (No HCV FU-4 and thereafter)

With HCV posttreatment Week 4 assessment but no HCV posttreatment Week 12 and 
thereafter (With HCV FU-4 but No FU-12 and thereafter)


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If a subject did not have any HCV RNA assessment ≥21 days after the last dose of study drug
(ie, lower bound of FU-4 visit for HCV RNA data), the subject will be categorized as having 
“No HCV FU-4 and thereafter.” If a subject had the HCV FU-4 assessment but did not have any 
HCV RNA assessment ≥70 days after the last dose of any study drug (ie, lower bound of 
FU-12 visit for HCV RNA data), the subject will be categorized as having “With HCV FU-4 but 
No FU-12 and thereafter.”
The total number of subjects who were randomized and the number of subjects in each of the 
disposition categories listed above will be depicted by a flowchart.
A summary of reasons for screen failure will also be provided.  
The following by-subject listings will be provided by subject ID number in ascending order to 
support the above summary tables:

Disposition for subjects who complete study treatment and study

Disposition for subjects who did not complete study treatment and/or study with reasons for 
premature discontinuation of study treatment and/or study

Lot number and kit ID (if applicable)
4.2.
Extent of Exposure and Adherence
The extent of exposure to study drug will be examined by assessing the total duration of study 
drug exposure and the level of adherence to the study regimen/drug specified in the protocol for 
subjects in Safety Analysis Set.
4.2.1.
Duration of Exposure to Study Drug
Total duration of exposure to the study regimen is defined as the date of the last dose of study 
regimen – the date of the first dose of study regimen + 1, regardless of any temporary 
interruptions in study drug dosing, and will be expressed in weeks using up to 1 decimal place
(eg, 4.5 weeks). The date of first/last dose of study regimen is defined as the date of first/last 
dosing of SOV/VEL for subjects who were assigned to SOF/VEL treatment group, and the date 
of the earliest/latest dosing of SOF/VEL or RBV for subjects who were assigned to 
SOF/VEL+RBV treatment group.
The total duration of exposure to individual study drug is defined as the date of the last dose of 
study drug (either SOF/VEL or RBV) – the date of the first dose of study drug (either SOF/VEL 
or RBV) + 1, regardless of any temporary interruptions in study drug administration, and will be 
expressed in weeks using up to 1 decimal place.
The total duration of exposure to the study regimen and to each individual study drug will be 
summarized using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) and the number (ie, cumulative counts). The proportion of subjects exposed to the 


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study regimen through the following time periods: baseline /Day 1, Week 2 (Day 14), Week 4 
(Day 28), Week 8 (Day 56), and Week 12 (Day 84) will also be presented. A 3-day window was 
applied to the last planned on-treatment visit to match the protocol-specified visit window.
Summaries will be provided by treatment group and overall for the Safety Analysis Set.
4.2.2.
Adherence to Study Drug
The presumed total number of tablets administered to a subject will be determined by the data 
collected on the drug accountability eCRF using the following formula:







 Returned
Tablets
of
No.
 Dispensed
Tablets
of
No.
ed
Administer
 Doses
of
Number 
Total
The level of adherence to study drug will be assessed based on the total amount of study drug 
administered relative to the total amount of study drug prescribed at baseline. 
The level of adherence will be expressed as a percentage using the following formula:
100
  
Baseline
at 
Prescribed
Drug
Study 
of
Amount 
Total
  
ed
Administer
Drug
Study 
of
Amount 
Total
(%)
Adherence
of
Level








Note: If calculated adherence is greater than 100%, the result will be set to 100%.
In this study, the total amount of SOF/VEL (400/100 mg) prescribed for 12 weeks would require 
84 SOF/VEL (400/100 mg) tablets. For Group 2 subjects, the prescribed weight-based RBV 
(200 mg tablet) would require 420 tablets (5 tablets/day × 84 days for subjects with baseline 
weight < 75 kg) or 504 tablets (6 tablets/day × 84 days for subjects with baseline weight ≥ 75 kg)
for the 12 week treatment period.
Subjects who prematurely discontinue study drug due to 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. Study drug bottles that were dispensed on or after the 
subject first met virologic failure criteria will not be included in the calculation of adherence. If a 
bottle was dispensed and the bottle was returned empty, the number of tablets returned will be 
entered as zero. If a bottle was 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 proportion of subjects belonging to adherence categories 
(e.g., < 80%, ≥ 80 to < 90%, ≥ 90%) will be provided by treatment group for the Safety Analysis 
Set. No inferential statistics will be provided.


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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 treatment assignment at randomization will be 
listed with the start and stop dates that they received incorrect study treatment.
A by-subject listing will be provided for those subjects who violate at least 1 inclusion or 
exclusion criterion. The listing will present the entry criterion (or criteria if more than 
1 violation) that subjects did not meet and related comments, if collected.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic variables ie, age, sex, race, and ethnicity) will be summarized for each 
treatment group and overall. Age will be summarized by descriptive statistics (n, mean, SD, 
median, Q1, Q3, minimum, and maximum). Age categories (< 65 years, ≥65 years), sex, race, 
and ethnicity will be summarized by the numbers and percentages of subjects. Age will be 
calculated in years at the date of the first dose of study drug. If a subject did not receive study 
drug after randomization, 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, which includes the date the informed consent was signed, will 
be provided by subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include: 

BMI (kg/m2) as a continuous variable and as categories (< 30 kg/m2, ≥30 kg/m2)

HCV genotype/subtype

IL28B genotype (CC, non-CC; further broken down to CT, TT ) 

Baseline HCV RNA (log10 IU/mL) as a continuous variable and as categories 
(< 800,000 IU/mL, ≥800,000 IU/mL)

Baseline ALT (U/L) as a continuous variable and as categories (≤1.5 × ULN, > 1.5 × ULN)

Prior HCV treatment (treatment naive, treatment experienced)

Prior HCV treatment (DAA±Peg-IFN±RBV, Peg-IFN+RBV, Other) and treatment response 
to the last prior HCV treatment (non responder, relapse/breakthrough, other) for treatment-
experienced subjects

HIV coinfection (yes, no, missing)

Baseline HIV RNA (subjects with HIV coinfection) as a continuous variable and as 
categories (<50 copies/mL, >=50 copies/mL)

Baseline CD4 T-cell counts (subjects with HIV coinfection)


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
Baseline CD4 T-cell counts by category for subjects with HIV coinfection 
(100−200 cells/uL, 201−350 cells/uL, 351−500 cells/uL, > 500 cells/uL)

Estimated glomerular filtration rate (eGFR) 

Baseline Cirrhosis status (yes, no, not determined)

Cirrhosis determination method (FibroTest and APRI, Liver Biopsy, and Transient 
Elastography) 
Estimated glomerular filtration rate will be calculated by the Cockcroft-Gault method: eGFRCG
(mL/min) =[(140 – age (yrs)) × weight (kg) × (0.85 if female)] / (serum creatinine (mg/dL) × 
72), where weight is total body mass in kilograms.
Baseline BMI will be calculated using the following method:
BMI = (baseline weight in kilograms)/(baseline height in meters)2
These baseline characteristics will be summarized for each treatment group and overall.
Continuous variables will be summarized using descriptive statistics (n, mean, SD, median, Q1, 
Q3, minimum, and maximum) and categorical variables using the number and percentage of 
subjects. The summary of baseline characteristics will be provided for the Safety Analysis Set.
A by-subject listing of baseline characteristics will be provided by subject ID number in 
ascending order. A separate by-subject data listing for cirrhosis determination will be provided
for all subjects at screening.
A separate by-subject listing for prior HCV treatment and response will be provided for
treatment-experienced subjects. The listing will display the prior HCV treatment experience for 
all subjects as well as the prior HCV regimen and treatment, the treatment duration, and the prior 
HCV treatment response for treatment-experienced subjects.
5.3.
Medical History
General medical history data will be collected at screening and a by-subject listing will be 
provided for Safety Analysis Set. 


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
6.1.1.
Definition of the Primary Efficacy Endpoint
The primary efficacy endpoint is SVR12 defined as HCV RNA < LLOQ (ie, < 15 IU/mL) 
12 weeks after discontinuation of the study drug for the FAS.
6.1.2.
Primary Analysis of the Primary Efficacy Endpoint
The point estimates of SVR12 and the 2-sided 95% exact CIs based on the Clopper-Pearson 
method {Clopper 1934} will be provided for each treatment group.
6.1.3.
Subgroup Analysis of the Primary Efficacy Endpoint
Point estimates and the 2-sided 95% exact CIs based on the Clopper-Pearson method will be 
provided for the SVR12 rate for each subgroup by treatment group. Subsets are outlined in 
Section 3.4.
SVR12 rates will be summarized by categories of early viral response to explore possible early 
on-treatment predictors of SVR12. The relationship between SVR12 and study drug modification 
may also be explored.
A Forest plot will graphically present the point estimates and the 2-sided 95% exact CIs of
SVR12 rates for each subgroup by treatment group.
6.2.
Secondary Efficacy Endpoints  
6.2.1.
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints include the following:

The proportion of subjects with HCV RNA < LLOQ at 4 weeks after discontinuation of
treatment (SVR4 )

The proportion of subjects with HCV RNA < LLOQ while on treatment by study visit

HCV RNA (log10 IU/mL) and change from baseline in HCV RNA (log10 IU/mL) through the 
end of treatment (EOT)

The proportion of subjects with virologic failure, defined as follows:
On-treatment virologic failure
o
HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ while on 
treatment, confirmed with 2 consecutive values (note, second confirmation value may 
be posttreatment), or last available on-treatment measurement with no subsequent 
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o
> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment confirmed with 
2 consecutive values (note, second confirmation value may be posttreatment), or last 
available on-treatment measurement with no subsequent follow-up values
ie, rebound)
o
HCV RNA persistently ≥ LLOQ through 8 weeks of treatment ie, nonresponse)
Relapse
o
HCV RNA ≥ LLOQ during the posttreatment period, having achieved HCV RNA 
< LLOQ at EOT, confirmed with 2 consecutive values or last available posttreatment 
measurement

Characterization of HCV drug resistance substitutions at baseline, during, and after study 
treatment, as applicable.
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 3.8.2. Missing values will be imputed based on the categorical 
imputation rules described in Section 3.6.1. The 2-sided 95% exact CI based on the 
Clopper-Pearson method will be provided for the proportion of subjects with HCV RNA 
< LLOQ at each visit for each treatment group. The overall category for “HCV RNA < LLOQ” 
will be divided into the following 2 subcategories: “< LLOQ TND” for subjects with target not 
detected and “< LLOQ detected” for subjects with < LLOQ HCV RNA detected in tabular 
displays. 
A plot of the proportion of subjects with HCV RNA < LLOQ over time during treatment will be 
provided.
Summary statistics will be presented for absolute values and change from baseline in HCV RNA 
(log10 IU/mL) by visit through the EOT. Imputation rules described in Section 3.6.1 will be used 
to assign HCV RNA values for missing values at visits 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) absolute values and changes from baseline in HCV RNA 
through EOT will be provided.
For the virologic outcome analysis, a summary table of the number and proportion of subjects 
with SVR12, virologic failure, and other ie, subjects who did not achieve SVR12 and did not 
meet criteria for virologic failure) will be created. All subjects who achieve SVR12 will be 
categorized as SVR12. Virologic failure will be descriptively summarized as “on-treatment 
virologic failure” and relapse (which will be broken down by study drug completed yes/no). The 
denominator for relapse will be the number of subjects who had HCV RNA < LLOQ on their last 
observed on-treatment HCV RNA measurement; otherwise, the denominator will be the number 
of subjects in the FAS. Virologic outcomes will also be provided by randomization stratum by 
treatment group and overall for the FAS.


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In addition, a summary table of the number and proportion of subjects with HCV RNA 
< LLOQ and~ LLOQ at each posttreatment follow-up visit (observed and imputed, with reasons 
for imputed) will be provided. Two-sided 95% exact Cis based on the Clopper-Pearson method 
will be presented for the proportion of subjects with HCV RNA < LLOQ by treatment group. 
By-subject data listings will be provided for the HCV RNA change from baseline for subjects 
with virologic failure and subjects with other virologic outcomes. 
Dmg-resistant substitutions will be summarized and listed as applicable. 
6.3. 
Exploratory Efficacy Endpoints 
6.3.1. 
Defmition of Exploratory Efficacy Endpoints 
PO 
I 
I 
6.3.2. 
Analysis Methods for Exploratory Efficacy Endpoints 
PO 
6.4. 
Changes From Protocol-Specified Efficacy Analyses 
There are no planned changes from protocol-specified efficacy analyses. 
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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory AEs will be coded using the current version of the Medical Dictionary 
for Regulatory Activities (MedDRA). System organ class (SOC), high level group term, high 
level term, preferred term (PT), and lower level term will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events were graded by the investigator as Grade 1 (mild), 2 (moderate), 3 (severe), or 
4 (life threatening) according to toxicity criteria specified in the GSI Grading Scale for Severity 
of Adverse Events and Laboratory Abnormalities (01 April 2015). 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 will be considered the least severe for the purposes of sorting for 
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 the 
relationship to study drug will be considered to be related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing from that captured on the 
eCRF.
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 Drug Safety and 
Public Health Department before database finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent
Treatment-emergent adverse events (TEAEs) are defined as 1 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 an 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 only) of the 
first dose date of study drug

The AE onset date is the same as or before the month and year (or year only) 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 treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
A brief high-level summary of TEAEs will show, by treatment group, the number and 
proportion of subjects who had the following: (1) any AE, (2) any AE of Grade 3 or above, (3) 
any AE of Grade 2 or above, (4) any treatment-related AE, (5) any treatment-related AE of 
Grade 3 or above, (6) any treatment-related AE of Grade 2 or above, (7) any SAE, (8) any
treatment-related SAE, (9) any AE that led to premature discontinuation of any study drug, (10) 
any AE that led to modification or interruption of any study drug, (11) any AE that led to 
premature discontinuation of SOF/VEL, (12) any AE that led to interruption of SOF/VEL, (13) 
any AE that led to discontinuation of RBV, (14) any AE that led to modification or interruption 
of RBV, and (15) all deaths.
Summaries (number and percentage of subjects) of TEAEs (by SOC and PT) will be provided by 
treatment group using 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 any study drug

AEs leading to modification or interruption of any study drug
Multiple events will be counted once only per subject in each summary. The SOCs will be 
presented alphabetically and the PTs within each SOC will be presented by descending order of 
the total frequencies. In summaries by severity grade, the most severe grade will be used for 
those AEs that occurred more than once in an individual subject during the study. 
In addition to the above summary tables, TEAEs will also be summarized by PT only, in order of 
descending incidence within the overall treatment group for:

All AEs

AEs that occurred in at least 5% of subjects within any treatment group

AEs of Grade 3 or above

All treatment-related AEs

All SAEs

AEs leading to premature discontinuation of any study drug

AEs leading to modification or interruption of any study drug

AEs leading to premature discontinuation of SOF/VEL

AEs leading to interruption of SOF/VEL

AEs leading to modification or interruption of RBV

AEs leading to discontinuation of RBV
Data listings, with a variable indicating whether the event is treatment emergent, will be
provided for the following:

All AEs

AEs of Grade 3 or above

SAEs

Deaths

AEs leading to premature discontinuation of any study drug


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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 date of the last dose of study drug
plus 30 days. The analysis will be based on values reported in conventional units. When values 
are below the limit of quantitation, the closest imputed value will be used for the purpose of 
calculating summary statistics, but the original values will be presented in listings. For example, 
if “< 0.2” was recorded, a value of 0.1 will be used for the purpose of calculating summary 
statistics; if “< 0.1” was recorded, a value of 0.09 will be used for the purpose of calculating 
summary statistics.
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and urinalysis separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher, based on the 
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities, will be 
flagged in the data listings, as appropriate.
No inferential statistics will be generated.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided 
by treatment group for ALT, aspartate aminotransferase (AST), total bilirubin, alkaline 
phosphatase, white blood cells (WBC) counts, neutrophils, lymphocytes, hemoglobin, platelets,
CD4 T-cell counts (absolute and percentage for HIV coinfected subjects only), reticulocytes, and 
international normalized ratio (INR) as follows:

Baseline values 

Values at each postbaseline visit

Change from baseline at each postbaseline visit
A baseline laboratory value will be defined as the final assessment performed on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
values will be displayed to the reported number of digits and the SD to the reported number of 
digits plus 1.
Median (Q1, Q3) of the observed values for ALT, AST, total bilirubin, alkaline phosphatase, 
WBC, neutrophils, lymphocytes, hemoglobin, platelets, CD4 T-cell counts (absolute and 
percentage for HIV coinfected subjects only), and reticulocytes will be plotted using a line plot 
by treatment group and visit. In the case of multiple values in an analysis window, data will be 
selected for analysis as described in Section 3.8.3.


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A by-subject listing of subjects with any hemoglobin values < 10 g/dL and < 8.5 g/dL will be 
provided. All laboratory test data will be listed. Central Laboratory (Covance) Reference Ranges 
will also be listed. 
7.2.2.
Graded Laboratory Values
The GSI Scale for Severity of Adverse Events and Laboratory Abnormalities (01 April 2015)
will be used for assigning toxicity grades (0 to 4) to laboratory results for analysis. 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.
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 the date of the last dose of
study drug plus 30 days. If the relevant baseline laboratory value is missing, then any 
abnormality of at least Grade 1 at a postbaseline time point will be considered treatment 
emergent.
7.2.2.2.
Summaries of Treatment-Emergent Laboratory Abnormalities
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by analyte and treatment group; subjects will be categorized 
according to the most severe postbaseline abnormality grade for a given analyte:

Graded laboratory abnormalities

Grade 3 or above laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after the date of the last dose of study drug for the 
laboratory parameter of interest.
A by-subject listing of treatment-emergent Grade 3 or above laboratory abnormalities will be 
provided by subject ID number and visit in chronological order. This listing will include all test 
results that were collected throughout the study for the analyte of interest, with all applicable 
severity grades or abnormal flags displayed.
7.3.
HIV RNA for HIV Coinfected Subjects
The analysis of HIV RNA will be performed for HIV coinfected subjects in Safety Analysis Set
using data collected up to the date of the last dose of any study drug plus 30 days.
The proportion of subjects with HIV virologic rebound during the study will be summarized.
Subjects with HIV virologic rebound are defined as those with HIV RNA ≥400 copies/mL at at 
least 2 consecutive postbaseline on-treatment visits which are at least 2 weeks apart based on 
actual dates.


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By-subject listings of HIV virologic rebound will be provided and include HIV RNA, CD4 
counts (absolute and percentage), HCV RNA, HIV current antiretroviral medication, and HCV 
treatment during the study.
A contingency table of the number of subjects with HIV RNA < 400 or ≥ 400 copies/mL at 
baseline and postbaseline visits by CD4 count < 200 cells/μL or ≥ 200 cells/μL at baseline will 
be generated. The number and proportion of subjects with HIV RNA < 50 or ≥ 50 copies/mL 
will be summarized by visit. Median (Q1, Q3) and mean (± SD) change from baseline in HIV 
RNA (copies/mL) will be summarized and plotted by visit for subjects with detectable HIV RNA 
at baseline. A listing of subjects with HIV RNA ≥ 50 copies/mL will be provided.
The denominator for proportion of subjects with HIV rebound, the contingency table of HIV 
RNA by CD4 counts, and the proportion of subjects with HIV RNA < 50 or ≥ 50 copies/mL will 
be the number of subjects in the Safety Analysis Set with HIV coinfection.
7.4.
Body Weight, Height, and Vital Signs
Vital signs (systolic and diastolic blood pressure [mmHg], pulse [beats/min]) at each visit, and 
change from baseline in vital signs at each visit will be summarized for the Safety Analysis Set 
using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) by 
treatment group. The baseline value will be defined as the last available value collected on or 
prior to the date/time of the 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 3.8.3. 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. In the same manner, a by-subject listing of 
body weight, height, and BMI will be provided separately.
7.5.
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 prior to the date of the first dose of study drug 

Concomitant medications: any medications taken on or after the date of the first dose of 
study drug and up to the date of the last dose of study drug
Concomitant medications will be summarized by Anatomical Therapeutic Chemical (ATC) drug 
class Level 2, and preferred name using the number and percentage of subjects for each 
treatment group and overall. A subject reporting the same medication more than once will be 


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counted only once when calculating the number and percentage of subjects who received that 
medication. The summary of concomitant medications will be ordered by descending frequency 
of ATC drug classes for overall, and then preferred names within an ATC medical class. For 
drugs with the same frequency, sorting will be done alphabetically.
Concomitant medication 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 date of the first 
dose of study drug or with a start date that is after the date of the last dose of study drug will be 
excluded from the 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 date of the first dose of study drug will be excluded from the concomitant medication 
summary. If a partial start date is entered, any medication with the month and year (if day is 
missing) or year (if day and month are missing) after the date of the last dose of study drug will 
be excluded from the concomitant medication summary. Medications with completely missing 
dates will be included in the concomitant medication summary. 
All collected 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.
For HIV coinfected subjects, the proportion of subjects who were treated with HIV antiretroviral 
therapy at baseline will be summarized. The prior and current HIV antiretroviral therapy will be 
provided in a by-subject listing sorted by subject ID number and administration date in 
chronological order.
7.6.
Investigator Electrocardiogram Assessment
A by-subject listing for electrocardiogram (ECG) assessment results will be provided by subject 
ID number and visit in chronological order.
7.7.
Other Safety Measures
A data listing will be provided for subjects who become pregnant during the study. A data listing 
of Child-Pugh-Turcotte (CPT) scores will be provided. 
7.8.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC ANALYSES
Plasma concentrations of SOF (and its metabolites GS-566500 and GS-331007), and VEL will 
be determined using validated bioanalytical assays. All plasma concentrations will be provided 
in a by-subject listing sorted by subject ID number and study drug administration date in 
chronological order.


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9.
REFERENCES
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the Case of the 
Binomial. Dec. Biometrika 1934;26 (4):pp. 404-13.


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


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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.
Table of Contents for Statistical Tables, Figures, and Listings
Appendix 2.
Schedule of Assessments
Appendix 3.
Child-Pugh-Turcottea Classification of the Severity of Cirrhosis


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Appendix 1.
Table of Contents for Statistical Tables, Figures, and Listings
Table Number
Title
Analysis Set
15.8.1.1
Enrollment by Country and Investigator
All Enrolled Subjects
15.8.1.2
Subjects Randomized and Treated by Randomization Stratum
Safety Analysis Set
15.8.1.3
Subject Disposition
Screened Subjects
15.8.1.4
Reasons for Screen Failure
Screened Subjects
15.8.3.1
Demographics
Safety Analysis Set
15.8.3.2
Baseline Characteristics
Safety Analysis Set
15.8.4
Adherence to Study Drug
Safety Analysis Set
15.9.1
SVR12
Full Analysis Set
15.9.2.1.1
Virologic Outcomes
Full Analysis Set
15.9.2.1.2
Virologic Outcomes by Randomization Stratum
Full Analysis Set
15.9.2.1.3
Virologic Outcomes by Visit During Posttreatment Follow Up
Full Analysis Set
15.9.2.2
SVR by Visit During Posttreatment Follow Up
Full Analysis Set
15.9.2.3
Proportion of Subjects with HCV RNA Less than LLOQ (15 
IU/mL) while on Treatment by Visit
Full Analysis Set
15.9.2.4
HCV RNA (log10 IU/mL) and Change from Baseline by Visit 
Through End of Treatment
Full Analysis Set
15.9.3.1
Proportion of Subjects with ALT Normalization by Visit
Full Analysis Set with 
ALT > ULN at Baseline
15.9.4.1
SVR12 by Subgroup
Full Analysis Set
15.9.4.2
SVR12 by Early Viral Response
Full Analysis Set
15.9.4.3
SVR12 by Dose Modifications
Full Analysis Set
15.11.1
Duration of Exposure to Study Regimen
Safety Analysis Set
15.11.2.1.1
Adverse Events: Brief Summary
Safety Analysis Set
15.11.2.1.2
All Treatment-Emergent Adverse Events
Safety Analysis Set
15.11.2.1.3
Treatment-Emergent Adverse Events that Occurred in at Least 5% 
of Subjects in Any Treatment Group by Preferred Term
Safety Analysis Set
15.11.2.2.1
Treatment-Emergent Adverse Events of Grade 3 or Above
Safety Analysis Set
15.11.2.2.2
Treatment-Emergent Adverse Events of Grade 3 or Above by 
Preferred Term
Safety Analysis Set
15.11.2.2.3
Treatment-Emergent Adverse Events of Grade 2 or Above
Safety Analysis Set
15.11.2.3.1
Treatment-Emergent Treatment-Related Adverse Events
Safety Analysis Set
15.11.2.3.2
Treatment-Emergent Treatment-Related Adverse Events by 
Preferred Term
Safety Analysis Set


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Table Number
Title
Analysis Set
15.11.2.3.3
Treatment-Emergent Treatment-Related Adverse Events of 
Grade 3 or Above
Safety Analysis Set
15.11.2.3.4
Treatment-Emergent Treatment-Related Adverse Events of 
Grade 2 or Above
Safety Analysis Set
15.11.4.1
Treatment-Emergent Serious Adverse Events
Safety Analysis Set
15.11.4.2
Treatment-Emergent Serious Adverse Events by Preferred Term
Safety Analysis Set
15.11.4.3
Treatment-Emergent Treatment-Related Serious Adverse Events
Safety Analysis Set
15.11.5.1
Adverse Events Leading to Premature Discontinuation of Any 
Study Drug
Safety Analysis Set
15.11.5.2
Adverse Events Leading to Premature Discontinuation of Any 
Study Drug by Preferred Term
Safety Analysis Set
15.11.5.3
Adverse Events Leading to Modification or Interruption of Any 
Study Drug
Safety Analysis Set
15.11.5.4
Adverse Events Leading to Modification or Interruption of Any 
Study Drug by Preferred Term
Safety Analysis Set
15.11.5.5
Adverse Events Leading to Premature Discontinuation of 
SOF/VEL by Preferred Term
Safety Analysis Set
15.11.5.6
Adverse Events Leading to Interruption of SOF/VEL by Preferred 
Term
Safety Analysis Set
15.11.5.7
Adverse Events Leading to Modification or Interruption of RBV 
by Preferred Term
Safety Analysis Set
15.11.5.8
Adverse Events Leading to Premature Discontinuation of RBV 
by Preferred Term
Safety Analysis Set
15.11.6.1.1
ALT (U/L) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.1.2
AST (U/L) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.1.3
Total Bilirubin (mg/dL) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.1.4
Alkaline Phosphatase (U/L) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.1.5.1
Hemoglobin (g/dL) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.1.5.2
Subjects with Postbaseline Hemoglobin < 10 g/dL and < 8.5 g/dL
Safety Analysis Set
15.11.6.1.6
Reticulocytes (× 103 /μL) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.1.7
WBC (× 103 /μL) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.1.8
Neutrophils (× 103 /μL) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.1.9
Lymphocytes (× 103 /μL) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.1.10
Platelets (× 103 /μL) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.1.11
INR and Change from Baseline by Visit
Safety Analysis Set
15.11.6.1.12.1
CD4 Counts (cells/μL) and Change from Baseline by Visit
Safety Analysis Set with 
HIV Coinfection


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Table Number
Title
Analysis Set
15.11.6.1.12.2
CD4 Counts (%) and Change from Baseline by Visit
Safety Analysis Set with 
HIV Coinfection
15.11.6.2.1
Proportion of Subjects with HIV Virologic Rebound
Safety Analysis Set
with HIV Coinfection
15.11.6.2.2
Contingency Table of HIV RNA by CD4 Counts at Baseline
Safety Analysis Set with 
HIV Coinfection
15.11.6.2.3
HIV RNA (copies/mL) and Change from Baseline by Visit
Safety Analysis Set with 
HIV Coinfection
15.11.6.2.4
Subjects with HIV RNA < 50 or ≥ 50 copies/mL by Visit
Safety Analysis Set with 
HIV Coinfection
15.11.6.3.1
Treatment-Emergent Graded Laboratory Abnormalities
Safety Analysis Set
15.11.6.3.2
Treatment-Emergent Grade 3 or Above Laboratory Abnormalities
Safety Analysis Set
15.11.7.1
Systolic Blood Pressure (mmHg) and Change from Baseline by 
Visit
Safety Analysis Set
15.11.7.2
Diastolic Blood Pressure (mmHg) and Change from Baseline 
by Visit
Safety Analysis Set
15.11.7.3
Pulse (bpm) and Change from Baseline by Visit
Safety Analysis Set
15.11.7.4.1
Concomitant Medications
Safety Analysis Set
15.11.7.4.2
Summary of Antiretroviral Therapy at Baseline
Safety Analysis Set with 
HIV Coinfection


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Figure Number
Title
Analysis Set
15.8.1
Subject Disposition
Screened Subjects
15.9.2.3
Proportion of Subjects with HCV RNA < LLOQ while on 
Treatment by Visit
Full Analysis Set
15.9.2.4.1
Mean ± SD Change from Baseline in HCV RNA (log10 IU/mL) 
by Treatment Group by Visit Through End of Treatment
Full Analysis Set
15.9.2.4.2
Median (Q1, Q3) Change from Baseline in HCV RNA 
(log10 IU/mL) by Treatment Group by Visit Through End of 
Treatment
Full Analysis Set
15.9.2.4.3
Mean ± SD HCV RNA (log10 IU/mL) by Treatment Group by 
Visit Through End of Treatment
Full Analysis Set
15.9.2.4.4
Median (Q1, Q3) HCV RNA (log10 IU/mL) by Treatment Group
by Visit Through End of Treatment
Full Analysis Set
15.9.4.1
Forest Plot of  SVR12 by Subgroup
Full Analysis Set
15.11.6.1.1
Median (Q1, Q3) ALT (U/L) by Visit
Safety Analysis Set
15.11.6.1.2
Median (Q1, Q3) AST (U/L) by Visit
Safety Analysis Set
15.11.6.1.3
Median (Q1, Q3) Total Bilirubin (mg/dL) by  Visit
Safety Analysis Set
15.11.6.1.4
Median (Q1, Q3) Alkaline Phosphatase (U/L) by Visit
Safety Analysis Set
15.11.6.1.5
Median (Q1, Q3) Hemoglobin (g/dL) by Visit
Safety Analysis Set
15.11.6.1.6
Median (Q1, Q3) Reticulocytes (× 103 /μL) by Visit
Safety Analysis Set
15.11.6.1.7
Median (Q1, Q3) WBC (× 103 /μL) by Visit
Safety Analysis Set
15.11.6.1.8
Median (Q1, Q3) Neutrophils (× 103 /μL) by Visit
Safety Analysis Set
15.11.6.1.9
Median (Q1, Q3) Lymphocytes (× 103 /μL) by Visit
Safety Analysis Set
15.11.6.1.10
Median (Q1, Q3) Platelets (× 103 /μL) by Visit
Safety Analysis Set
15.11.6.1.12.1
Median (Q1, Q3) CD4 Counts (cells/μL) by Visit
Safety Analysis Set with 
HIV Coinfection
15.11.6.1.12.2
Median (Q1, Q3) CD4 Counts (%) by Visit
Safety Analysis Set with 
HIV Coinfection
15.11.6.2.3.1
Median (Q1, Q3) HIV RNA Change from Baseline by Visit for 
Subjects Who Had Detectable HIV RNA at Baseline
Safety Analysis Set with 
HIV Coinfection
15.11.6.2.3.2
Mean ±SD HIV RNA Change from Baseline by Visit for Subjects 
Who Had Detectable HIV RNA at Baseline
Safety Analysis Set
with HIV Coinfection


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Listing Number
Title
Analysis Set
16.1.6
Lot Number and Kit ID
Safety Analysis Set
16.1.7
Randomization Scheme and Code
All Randomized Analysis 
Set
16.2.1.1
Disposition for Subjects Who Completed Study Treatment and 
Study
Safety Analysis Set
16.2.1.2
Disposition for Subjects Who Did Not Complete Study 
Treatment and/or Study with Reasons for Premature 
Discontinuation of Study Treatment and/or Study
Safety Analysis Set
16.2.2.1
Inclusion and Exclusion Criteria
Subjects Not Treated
16.2.2.2
Subjects Randomized and Treated Who Did Not Meet 
Eligibility Criteria
Safety Analysis Set
16.2.2.3
Randomization Stratification Discrepancies Between IWRS and 
Database Values
Safety Analysis Set
16.2.2.4
Subjects Who Received Incorrect Study Drug Based on 
Randomized Treatment Assignment
Safety Analysis Set
16.2.3
Subjects Who Were Excluded from Safety and Full Analysis 
Sets
All Randomized Analysis 
Set
16.2.4.1
Demographics
Safety Analysis Set
16.2.4.2.1
Baseline Characteristics
Safety Analysis Set
16.2.4.2.2
Cirrhosis Determination
Safety Analysis Set
16.2.4.3.1
Medical History
Safety Analysis Set
16.2.4.3.2
Prior HCV Treatment and Response
Safety Analysis Set
16.2.4.4.1
Prior and Concomitant Medications
Safety Analysis Set
16.2.4.4.2
Prior and Current HIV Medications
Safety Analysis Set with 
HIV Coinfection
16.2.5.1
Study Drug Administration
Safety Analysis Set
16.2.5.2
Study Drug Accountability and Adherence
Safety Analysis Set
16.2.5.3
Plasma PK Sampling Details and PK Concentrations
PK Analysis Set
16.2.6.1
HCV RNA (log10 IU/mL) and Change from Baseline
Safety Analysis Set
16.2.6.2
Subjects with Virologic Failure
Safety Analysis Set
16.2.6.3
Subjects with “Other” Virologic Outcome
Safety Analysis Set
16.2.7.1
All Adverse Events
Safety Analysis Set
16.2.7.2
Adverse Events of Grade 3 or Above
Safety Analysis Set
16.2.7.3
Deaths
Safety Analysis Set
16.2.7.4
Serious Adverse Events
Safety Analysis Set


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Listing Number
Title
Analysis Set
16.2.7.5
Adverse Events Leading to Premature Discontinuation of Any 
Study Drug
Safety Analysis Set
16.2.7.6
Adverse Events Leading to Modification or Interruption of Any 
Study Drug
Safety Analysis Set
16.2.8.1.1
Subjects with Postbaseline Hemoglobin < 10 g/dL and < 8.5 
g/dL
Safety Analysis Set
16.2.8.1.2
Central Laboratory (Covance) Reference Ranges
Safety Analysis Set
16.2.8.1.3
Subjects with Treatment-Emergent Grade 3 or Above
Laboratory Abnormalities
Safety Analysis Set
16.2.8.1.4
Screen Labs: HBsAg, Anti-HIV Ab, Anti-HCV Ab, HbA1c, 
and Serum Beta hCG
Safety Analysis Set
16.2.8.1.5.1
Hematology: Hematocrit, Hemoglobin, Reticulocytes, MCV, 
RBC, WBC, and Platelets
Safety Analysis Set
16.2.8.1.5.2
Hematology: WBC, Neutrophils, and Lymphocytes
Safety Analysis Set
16.2.8.1.5.3
Hematology: Eosinophils, Basophils, and Monocytes
Safety Analysis Set
16.2.8.1.6
Coagulation: INR, Prothrombin Time, and APTT
Safety Analysis Set
16.2.8.1.7.1
Serum Chemistry: Sodium, Potassium, Uric Acid, Creatine 
Kinase, Serum Creatinine, Estimated GFR (Cockcroft-Gault), 
and Glucose
Safety Analysis Set
16.2.8.1.7.2
Serum Chemistry: AST, ALT, Total Bilirubin, Direct Bilirubin, 
Alkaline Phosphatase, GGT, Albumin, and Lipase
Safety Analysis Set
16.2.8.1.8
Urinalysis: Urine Blood, Glucose, pH, Protein, Urobilinogen, 
and Leukocyte Esterase
Safety Analysis Set
16.2.8.1.9
Microscopic Urinalysis for Subjects with Abnormal Leukocyte 
Esterase
Safety Analysis Set
16.2.8.1.10
Subjects with HIV Virologic Rebound During Study
Safety Analysis Set with 
HIV Coinfection
16.2.8.1.11
HIV RNA by Visit for Subjects with HIV RNA ≥50 copies/mL
Safety Analysis Set with 
HIV Coinfection
16.2.8.1.12
CD4 T-Lymphocyte Absolute Count (cells/μL and %) and HIV 
RNA (copies/mL)
Safety Analysis Set with 
HIV Coinfection
16.2.8.2.1
Vital Signs
Safety Analysis Set
16.2.8.2.2
Height, Weight, and BMI
Safety Analysis Set
16.2.8.2.3.1
12-Lead Electrocardiogram Results
Safety Analysis Set
16.2.8.3
Pregnancy
Safety Analysis Set
16.2.8.4
Child-Pugh-Turcotte (CPT) scores by Visit
Safety Analysis Set


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Appendix 2.
Schedule of Assessments
Screen
Baseline/Day 1b
On-treatment Week
Post-treatment Week
2
4
8
12/ET
4
12
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
X
X
Height
X
Weight
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
12-Lead ECG
X
CPT score
X
X
Adverse Events and 
Concomitant Medications
X
X
X
X
X
X
X
Pregnancy Prevention 
Counseling
X
X
X
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
Study Drug Dispensinga
X
X
X
Laboratory Assessments
Hematology, Chemistry g
X
X
X
X
X
X
X
X
Coagulation Tests
X
X
X
Urinalysis
X
X
X
HCV RNAc
X
X
X
X
X
X
X
Xf


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Screen
Baseline/Day 1b
On-treatment Week
Post-treatment Week
2
4
8
12/ET
4
12
HIV-1 RNAh
X
X
X
X
X
X
X
X
Viral Sequencingc  
X
X
X
X
X
X
Xf
Single PK
X
X
X
X
Serum β-hCG or Urine 
Pregnancy Testd
X
X
X
X
X
X
X
Urine Drug Screen
X
HCV Genotyping, IL28B 
X
HCV, HIV, HBV Serology
X
HbA1c, Fibrotest®
X
Archive Samplee
X
X
Pharmacogenomic Samplee
X
a
The IWRS will provide direction on the specifics of each subject’s study drug dispensing
b
Baseline/Day 1 assessments must be performed prior to dosing
c
Viral sequencing samples for virologic sequencing required at baseline and after any visit where a previously undetectable HCV RNA becomes detectable 
d
Serum β-hCG pregnancy test performed at screening and for confirmation of positive urine pregnancy test.
e
Only for subjects who have provided consent for this sample and testing. The Week 12 / Early Termination visit will be the last opportunity for this to be collected.
f
Only for subjects with HCV RNA ≥LLOQ at post-treatment week 12 visit will be asked to return after for a confirmatory visit where additional samples are collected.
g
CrCl will be calculated at all visits where a blood sample is drawn
h
HIV-1 RNA will only be collected and analyzed for coinfected subjects


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Appendix 3.
Child-Pugh-Turcottea Classification of the Severity of Cirrhosis
POINTS*
1
2
3
Encephalopathy
None
Grade 1-2
(or precipitant-induced)
Grade3-4
(or chronic)
Ascites
None
Mild/Moderate
(diuretic-responsive)
Severe
(diuretic-refractory)**
Bilirubin (mg/dL)
< 2
2-3
> 3
Albumin (g/dL)
> 3.5
2.8-3.5
< 2.8
PT (sec 
prolonged)
or  INR***
< 4
< 1.7
4-6
1.7-2.3
> 6
> 2.3
*
CPT score is obtained by adding the score for each parameter
CPT class: A = 5-6 points
B = 7-9 points
C = 10-15 points
**
Note: If a subject is taking medications to control ascites or encephalopathy which has controlled the symptoms, the scoring
should be 2 points (not 1 point).
*** Either PT or INR can be used to determine the CPT Score; however, if both tests have been performed, INR will be chosen 
as the primary test for the calculation.
a
U.S. Department of Veterans Affairs. Child -Pugh-Turcotte Classification of the severity of cirrhosis. 
Available at http://www hepatitis.va.gov/provider/tools/child-pugh-calculator.asp, Accessed May 29, 2012.

Prot_001.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Study Director 
or Medical Monitor: 
Protocol Version/Date: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Multicenter, Randomized, Open-Label Study to Evaluate 
the Efficacy and Safety of SofosbuvirN elpatasvir Fixed Dose 
Combination (FDC) and SofosbuvirN elpatasvir FDC and Ribavirin 
in Subjects with Cln·onic Genotype 3 HCV Infection and Cinhosis 
Gilead Sciences, Inc. 
This is a non-IND study 
2016-000417-73 
Not Available 
Hepatitis C Virus Infection 
GS-US-342-2097 
Name: 
Brian McNabb, MD 
Telephone: 
PPD 
Fax: 
PPD 
Cell Phone: PPD 
Original: 
Amendment 1: 
16 March 2016 
04 April 20 16 
CONFIDENTIALITY STATEMENT 
The infotmation contained in this docmnent, pruiicularly unpublished data, is the propetty or 
under contl'ol of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infotmation is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the infotmation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaty to obtain infonned consent from those 
persons to whom the drug may be administered. 


SOF/VEL FDC
Protocol GS-US-342-2097
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Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................10
1.
INTRODUCTION ..............................................................................................................................................13
1.1.
Background ............................................................................................................................................13
1.2.
Sofosbuvir/Velpatasvir Fixed Dose Combination..................................................................................14
1.2.1.
General Information .............................................................................................................14
1.2.2.
Additional Clinical Experience ............................................................................................15
1.3.
Ribavirin (RBV).....................................................................................................................................39
1.4.
Rationale for This Study ........................................................................................................................40
1.5.
Rationale for Dose Selection..................................................................................................................40
1.6.
Overall Risk/Benefit Assessment...........................................................................................................41
1.7.
Compliance ............................................................................................................................................42
2.
OBJECTIVES.....................................................................................................................................................43
3.
STUDY DESIGN................................................................................................................................................44
3.1.
Treatment Plan and Regimen .................................................................................................................44
3.2.
Visit Schedule ........................................................................................................................................44
3.3.
Virologic Response ................................................................................................................................44
3.3.1.
HCV Virologic Response-Based Treatment Stopping Criteria ............................................44
3.3.2.
HIV Virologic Rebound Criteria..........................................................................................45
3.4.
Stopping Rules for Individual Subjects..................................................................................................47
3.5.
Discontinuations.....................................................................................................................................47
3.6.
Assessments for Premature Discontinuation from Study.......................................................................48
3.7.
Criteria for Discontinuation of Study Treatment....................................................................................48
3.8.
Biomarker Testing..................................................................................................................................48
3.8.1.
Biomarker Samples for Optional Future Research...............................................................48
3.8.2.
Biomarker Samples for Optional Pharmacogenomic Research............................................49
4.
SUBJECT POPULATION..................................................................................................................................50
4.1.
Number of Subjects and Subject Selection ............................................................................................50
4.2.
Inclusion Criteria....................................................................................................................................50
4.3.
Exclusion Criteria...................................................................................................................................52
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................55
5.1.
Randomization, and Study Drug Supply................................................................................................55
5.2.
Description and Handling of SOF/VEL FDC ........................................................................................55
5.2.1.
Formulation..........................................................................................................................55
5.2.2.
Packaging and Labeling .......................................................................................................55
5.2.3.
Storage and Handling...........................................................................................................55
5.3.
Dosage and Administration of SOF/VEL FDC......................................................................................56
5.4.
Description and Handling of Ribavirin (RBV) ......................................................................................56
5.4.1.
Formulation..........................................................................................................................56
5.4.2.
Packaging and Labeling .......................................................................................................56
5.4.3.
Storage and Handling...........................................................................................................56
5.4.4.
Dosage and Administration..................................................................................................57


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5.5.
Prior and Concomitant Medications.......................................................................................................58
5.6.
Acceptable HIV Antiretroviral Regimens..............................................................................................59
5.7.
Study Drug Adherence and Drug Accountability...................................................................................60
5.8.
Study Drug Return or Disposal ..............................................................................................................61
6.
STUDY PROCEDURES ....................................................................................................................................62
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................62
6.2.
Screening Assessments ..........................................................................................................................62
6.2.1.
Screening Visit (Day 28 to Day 0) .......................................................................................62
6.3.
Treatment Assessments..........................................................................................................................64
6.3.1.
Baseline/Day 1 Visit.............................................................................................................64
6.3.2.
Week 2 (±3 days) .................................................................................................................65
6.3.3.
Weeks 4 and 8 (3 days) .....................................................................................................66
6.3.4.
Week 12 or Early Termination (3 days)............................................................................66
6.3.5.
Unscheduled Visit ................................................................................................................67
6.4.
Posttreatment Assessments ....................................................................................................................67
6.4.1.
Post-treatment Week 4 (±5 days) .........................................................................................67
6.4.2.
Post-treatment Week 12 (± 5 days) ......................................................................................68
6.5.
Confirmatory Visit .................................................................................................................................69
6.6.
End of Study...........................................................................................................................................69
6.7.
Procedures and Specifications................................................................................................................69
6.7.1.
Clinical Laboratory Analytes ...............................................................................................69
6.7.2.
Medical History....................................................................................................................70
6.7.3.
Complete Physical Examination...........................................................................................70
6.7.4.
Vital Signs............................................................................................................................70
6.7.5.
Creatinine Clearance ............................................................................................................70
6.7.6.
12-Lead ECGs......................................................................................................................71
6.7.7.
HCV Viral RNA Sequencing / Phenotyping Sample (Archive)...........................................71
6.7.8.
HIV Viral RNA Genotyping/Phenotyping Sample (Archive)..............................................71
6.7.9.
Single Pharmacokinetic (PK) Sample ..................................................................................71
6.7.10.
Pharmacogenomics Testing..................................................................................................71
6.7.11.
Sample Storage.....................................................................................................................72
6.7.12.
Pregnancy Testing................................................................................................................72
7.
TOXICITY MANAGEMENT............................................................................................................................73
7.1.
Dose Modification Due to Toxicity........................................................................................................73
7.2.
Group 1:  Subjects administered SOF/VEL ...........................................................................................73
7.3.
Group 2:  Subjects administered SOF/VEL+ RBV................................................................................73
7.3.1.
Subject Stopping Rules ........................................................................................................73
7.4.
Subject Stopping Rules ..........................................................................................................................73
7.5.
Special Situations Reports......................................................................................................................73
7.5.1.
Definitions of Special Situations..........................................................................................73
8.
ADVERSE EVENTS MANAGEMENT ............................................................................................................75
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................75
8.1.1.
Adverse Events.....................................................................................................................75
8.1.2.
Serious Adverse Events........................................................................................................75
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................76
8.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................76
8.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................76
8.2.2.
Assessment of Severity ........................................................................................................77
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................77


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8.4.
Gilead Reporting Requirements.............................................................................................................78
8.5.
Toxicity Management ............................................................................................................................79
8.5.1.
Instructions for Reporting Special Situations.......................................................................79
9.
STATISTICAL CONSIDERATIONS................................................................................................................81
9.1.
Analysis Objectives and Endpoints........................................................................................................81
9.1.1.
Analysis Objectives..............................................................................................................81
9.1.2.
Primary Endpoints................................................................................................................81
9.1.3.
Secondary Endpoints............................................................................................................81
9.1.4.
Other Endpoints of Interest ..................................................................................................82
9.2.
Analysis Conventions.............................................................................................................................82
9.2.1.
Analysis Sets ........................................................................................................................82
9.3.
Data Handling Conventions ...................................................................................................................82
9.4.
Demographic Data and Baseline Characteristics ...................................................................................84
9.5.
Efficacy Analysis ...................................................................................................................................84
9.5.1.
Primary Analysis..................................................................................................................84
9.5.2.
Secondary Analyses .............................................................................................................84
9.6.
Safety Analysis.......................................................................................................................................85
9.6.1.
Extent of Exposure...............................................................................................................85
9.6.2.
Adverse Events.....................................................................................................................85
9.6.3.
Laboratory Evaluations ........................................................................................................86
9.6.4.
Other Safety Evaluations......................................................................................................86
9.6.5.
HIV RNA Analysis ..............................................................................................................86
9.7.
Pharmacokinetic Analysis......................................................................................................................86
9.8.
Sample Size............................................................................................................................................86
10.
RESPONSIBILITIES..........................................................................................................................................87
10.1.
Investigator Responsibilities ..................................................................................................................87
10.1.1.
Good Clinical Practice..........................................................................................................87
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................87
10.1.3.
Informed Consent.................................................................................................................87
10.1.4.
Confidentiality......................................................................................................................88
10.1.5.
Study Files and Retention of Records ..................................................................................88
10.1.6.
Case Report Forms...............................................................................................................89
10.1.7.
Investigational Medicinal Product Accountability and Return.............................................90
10.1.8.
Inspections............................................................................................................................90
10.1.9.
Protocol Compliance............................................................................................................90
10.2.
Sponsor Responsibilities ........................................................................................................................91
10.2.1.
Protocol Modifications.........................................................................................................91
10.2.2.
Study Report and Publications .............................................................................................91
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................91
10.3.1.
Payment Reporting...............................................................................................................91
10.3.2.
Access to Information for Monitoring..................................................................................92
10.3.3.
Access to Information for Auditing or Inspections ..............................................................92
10.3.4.
Study Discontinuation..........................................................................................................92
11.
REFERENCES ...................................................................................................................................................93
12.
APPENDICES ....................................................................................................................................................96
Appendix 1.
Investigator Signature Page....................................................................................................97
Appendix 2.
Study Procedures Table..........................................................................................................98
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............100


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Appendix 4.
Child-Pugh-Turcotte Classification of the severity of cirrhosis ...........................................122
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................123
Appendix 6.
Opportunistic Infections .......................................................................................................126
LIST OF IN-TEXT TABLES
Table 1-1.
GS-US-342-1138: SVR12 Overall and by HCV Genotypes ..................................................16
Table 1-2.
NGMN, NG, EE, and VEL Plasma PK Parameters Following Administration of 
NGM/EE alone or with VEL..................................................................................................32
Table 1-3.
Summary of LH, FSH, and Progesterone Concentrations Following Administration 
of NGM/EE alone or with VEL..............................................................................................32
Table 1-4.
Summary of Changes in SOF/VEL PK following administration with 
Representative H2RAs and PPIs ............................................................................................34
Table 1-5.
GS-US-342-1167: Summary of Changes in PK Parameters of SOF, its Metabolites 
GS-566500 and GS-331007, GS-5816, and Evaluated ARVs (EFV, RPV, DTG, 
EVG, COBI, FTC, TAF, and TFV) (PK Analysis Sets).........................................................35
Table 1-6.
GS-US-342-1326: Preliminary Summary of Changes in PK Parameters of SOF, its 
Metabolites GS-566500 and GS-331007, GS-5816, and Evaluated ARVs (EVG, 
COBI, DRV, ATV, LPV, RTV, RAL, FTC, and TFV)..........................................................37
Table 5-1.
List of Disallowed /Use with Caution Medications................................................................59
Table 7-1.
Ribavirin Dose Modification Guideline for Coadministration with SOVALDI.....................73
LIST OF IN-TEXT FIGURES
Figure 3-1.
HIV Virologic Rebound Schema............................................................................................46


SOF/VEL FDC
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Amendment 1
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Multicenter, Randomized, Open-Label Study to Evaluate 
the Efficacy and Safety of Sofosbuvir/Velpatasvir Fixed Dose 
Combination (FDC) and Sofosbuvir/Velpatasvir FDC and Ribavirin 
in Subjects with Chronic Genotype 3 HCV Infection and Cirrhosis
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
This is a non-IND study
2016-000417-73
Not Available
Study Centers:
Approximately 30 centers in Spain
Number of Subjects 
Planned:
Approximately 200 subjects with chronic genotype 3 HCV infection 
and compensated cirrhosis
Target Population:
Male and non-pregnant/non-lactating female subjects with chronic 
genotype 3 HCV infection and compensated cirrhosis, ages 18 years 
or older with and without HIV-1 coinfection. 
Duration of 
Treatment:
Following randomization, enrolled subjects will receive assigned 
study treatment for 12 weeks
Objectives:
The primary objectives of this study are:

To evaluate the efficacy of study treatment with 
Sofosbuvir(SOF)/Velpatasvir(VEL, GS-5816) FDC and
SOF/VEL FDC and Ribavirin (RBV) for 12 weeks as measured 
by the proportion of subjects with sustained virologic response 
12 weeks after cessation of treatment regimen (SVR12) 

To evaluate the safety and tolerability of each treatment regimen 
The secondary objectives of this study are: 

To determine the proportion of subjects who attain SVR at 
4 weeks after cessation of each treatment regimen (SVR4)

To evaluate the kinetics of circulating HCV RNA during 
treatment and after cessation of each treatment regimen

To evaluate the emergence of viral resistance to SOF and VEL
during treatment and after cessation of treatment


SOFNELFDC 
Protocol GS-US-342-2097 
Gilead Sciences, Inc. 
Study Design: 
Substudy 
Diagnosis and Main 
Eligibility Criteria: 
Study Procedmes/ 
Frequency: 
CONFIDENTIAL 
The explorat01y objective of this study is: 
• 
PD 
Final 
Amendment 1 
Approximately 200 subjects with chronic genotype 3 HCV infection 
and compensated cinhosis will be randomized (1: 1) to either: 
1. Group 1 (n = 100): 
SOFNEL once daily for 12 weeks 
or 
2. Group 2 (n = 100): 
SOFNEL + RBV for 12 weeks 
Randomization will be stratified by prior treatment experience 
(treatment naive/treatment -experienced). 
Phannacogenomics (PG) Substudy 
In consenting pruiicipants, a blood sample will be drawn at baseline 
or dming the study for phmmacogenomics resem·ch. 
Chronic genotype 3 HCV infected, male and non-pregnant/ 
non-lactating female subjects with compensated cinhosis, ages 
18 years or older. 
HIV -1 co infected patients at·e eligible to pa1ticipate. They must meet 
the HIV specific eligibility criteria. 
Refer to Sections 4.2 and 4.3 of the protocol for detailed Inclusion 
and Exclusion Criteria 
Screening assessments will be completed within 28 days of the 
Baseline/Day 1 visit. The screening window can be extended to 
42 days for subjects requiring liver biopsy, additional HCV genotype 
testing, or for extenuating circumstances. 
All subjects will complete the following study visits: Screening, 
Baseline/Day 1, on-treatment visits at the end of Weeks 2, 4, 8, and 
12, and posttreatment Week 4. Patients who achieve SVR4 will also 
be required to attend a posttreatment Week 12 visit. 
Screening assessments will include physical examination, medical 
hist01y, height, weight, vital signs, 12-lead ECG, adverse events 
related to screening procedmes, concomitant medications, safety 
laborat01y tests (including hematology, chemistty, and coagulation), 
Page 7 
04 April2016 


SOFNELFDC 
Protocol GS-US-342-2097 
Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
CONFIDENTIAL 
Final 
Amendment 1 
HCV RNA, HIV-1 RNA, CD4 T-cell count and percent, serology 
(HIV, HCV, HBV), hemoglobin Ale (HbAlc), assessment of the 
presence or absence of cinhosis, screening for hepatocellular 
carcinoma (HCC), senun ~-hCG (females of child bearing potential 
only), IL28B genotyping, urinalysis and urine dmg screen. Subjects 
with HIV co-infection will also have the following laboratoty tests: 
HIV -1 RNA, CD4 T -cell cmmt and percent. 
On-treatment assessments include adverse events (AEs ), concomitant 
medications, study medication pill count, physical examination, 
weight, vital signs, safety laboratoty tests, HCV RNA, 
phannacokinetic samples, and urine pregnancy tests (females of child 
bearing potential only). Subjects with HIV co-infection will also have 
the following laboratmy tests: HIV-1 RNA, CD4 T-cell count and 
percent. 
Post-treatment assessments include AEs, concomitant medications, 
vital signs, safety laboratoty tests, HCV RNA, and mine pregnancy 
tests (females of child bearing potential only). Subjects with HIV 
co-infection will also have the following laboratoty tests: HIV-1 
RNA, CD4 T -cell count and percent. 
Samples for HCV RNA sequencing I phenotyping will be collected at 
Baseline and eve1y visit thereafter. Subects' with HIV co-infection 
will also have samples for HIV RNA genotyping/phenotyping 
collected at Baseline/Day 1 and at Weeks 2, 4, 8, 12, ET and 
Posttreatment Week 4. Samples will be collected during on-treatment 
visits for pharmacokinetic (PK) analysis of study dmgs. 
For subjects who provide their additional and specific consent, an 
appropriate blood sample will be collected at the Baseline/Day 1 visit 
for PG (this sample may be drawn after Baseline/Day 1 ifnecessmy). 
For subjects who provide their additional atld specific consent, 
PPD 
SOF /VEL fixed dose combination (FDC) is manufactured as a 
400/100mg FDC tablet for oral administration. All subjects will take 
1 tablet daily with or without food. 
Subjects in Group 2 will take RBV with food at a total daily oral dose 
of 1000 or 1200 mg (1000 mg for subjects weighing < 75 kg and 
1200 mg for subjects weighing 2. 75 kg) in a divided daily dose. 
Page8 
04 April2016 


SOF/VEL FDC
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Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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Criteria for 
Evaluation:
Safety:
AEs and laboratory tests will be collected throughout the study
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV RNA 
performed using COBAS® AmpliPrep®/COBAS® TaqMan® HCV 
Quantitative Test, v2.0
Pharmacokinetics:
A single PK blood sample will be collected at each on-treatment visit 
for all subjects. 
The PK of SOF (and metabolites), VEL and RBV may be assessed.
Statistical Methods:
The primary efficacy endpoint for the study is SVR12 in all 
randomized and treated subjects. 
In the primary efficacy analysis, point estimate and 95% confidence 
interval of SVR12 will be computed for each treatment group.
Secondary efficacy endpoints include SVR4 and the proportion of 
subjects with virologic failure.
All continuous endpoints (except for safety endpoints) will be 
summarized using an 8-number summary (n, mean, standard 
deviation, median, Q1, Q3, minimum, maximum) by treatment group 
and stratification within group (as appropriate). All categorical 
endpoints will be summarized by number and percentage of subjects 
who meet the endpoint definition.
Safety endpoints will be analyzed by the number and percent of 
subjects with events or abnormalities for categorical values or 
8-number summary (n, mean, standard deviation, median, Q1, Q3, 
minimum, maximum) for continuous data by treatment group.
With a sample size of 100 for each treatment, a two-sided 95% exact
confidence interval will extend at most 21% in length for each 
treatment.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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Amendment 1
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil counts
APRI
AST: platelet ratio index
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the curve
AUCtau
area under the plasma concentration versus time curve over the dosing interval (tau)
ß-hCG
ß-human chorionic gonadotropin
BLQ
below the lower limit of quantification
BMI
body mass index
CD4
cluster of differentiation 4
CI
confidence interval
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
CK
creatine kinase
CPT
Child-Pugh-Turcotte Classification
CRF
case report form(s)
CRO
Contract (or clinical) research organization 
CSA
colony stimulating agents
DAA
direct acting antiviral
DCV
daclatasvir (HCV NS5A Inhibitor)
DDI
drug-drug interaction
DSPH
Drug Safety and Public Health
EC
Ethics committee
ECG
electrocardiogram
EDC
electronic data capture
eCRF
Electronic case report form(s)
ESA
Erythropoiesis-stimulating agents 
ET
early termination
EU
European Union
EudraCT
European clinical trials database
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
fixed dose combination


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FSH
follicle stimulating hormone
GCP
Good Clinical Practice (Guidelines)
GM-CSF
Granulocyte macrophage colony stimulating factor
GSI
Gilead Sciences, Inc.
GT
genotype (viral)
H2RA
Histamine-2 receptor antagonist
Hb
Hemoglobin
HBV
Hepatitis B virus
HbA1C
Hemoglobin A1C
HCC
Hepatocellular carcinoma
hCG
human chorionic gonadotropin
HDPE
high-density polyethylene
HCV
Hepatitis C virus
HIV
Human Immunodeficiency Virus
HLGT
high-level group term
HLT
high-level term
IB
investigator’s brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IFN
interferon
IL28B
interleukin-28B gene
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
INR
international normalized ratio of prothrombin time
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
LAM
lactational amenorrhea method
LDV
ledipasvir
LFT
liver function test
LH
luteinizing hormone
LLN
lower limit of the normal range
LLOQ
lower limit of quantification
LLT
lower-level term
LT
liver transplantation
MELD
Model for End Stage Liver Disease
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute


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mL
milliliter
mmHg
millimeters mercury
MCV
mean cellular volume
NDA
New Drug Application
ng
nanogram
ng•h/mL
nanograms times hours per milliliter
NG
norgestrel
NGM
norgestimate
NGM/EE
norgestimate/ethinyl estradiol
NGMN
norelgestromin
NS (3/4A/5A/5B)
Non-structural protein
OC
oral contraceptive
PCR
Polymerase chain reaction
Peg-IFN
Pegylated-Interferon-
pg
pictogram
pg•h/mL
picograms times hours per milliliter
P-gp
P-glycoprotein
PK
pharmacokinetic
PPI
Proton pump inhibitor
PT
Preferred term or prothrombin time
RBV
ribavirin
RNA
ribonucleic acid
SADR
serious adverse drug reaction
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
Standard deviation
SOC
System Organ Class
SOF
Sovaldi® or Sofosbuvir, formerly GS-7977
SOF/VEL
SOF/VEL fixed dose combination
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained virologic response
tmax
The time (observed time point) of Cmax
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant (λz)
ULN
upper limit of the normal range
US
United States
VA
Veterans Affairs
VEL
Velpatasvir, formerly GS-5816
WBC
White blood cell count


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Amendment 1
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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) infection is a global health challenge with estimates ranging up to 
150 million individuals infected worldwide {World Health Organization (WHO) 2014}. In the 
United States (US), approximately 2.7 million people have chronic HCV infection {Denniston et 
al 2014} and HCV infection causes over 15,000 deaths each year {Ly et al 2012}, although 
under-reporting of HCV infection on death certificates may contribute to as much as a 5-fold 
underestimation of the actual number of deaths {Mahajan et al 2014}. Successful treatment of 
chronic HCV infection reduces the need for liver transplantation, the incidence of HCC, and 
overall mortality {Backus et al 2011}. Thus, the public health benefit of safe and effective HCV 
treatment regimens is high.
The development of sofosbuvir (Sovaldi®, SOF), a nucleotide analog HCV NS5B polymerase 
inhibitor, represents a major advance in the treatment of HCV as SOF-based regimens are shorter 
in duration, better tolerated, and result in higher SVR rates than prior therapies. SOF is currently 
approved in the US for the treatment of genotype (GT) 1, 2, 3 and 4 HCV infection and in the 
European Union for GT1-6 with different regimens and durations dependent on the HCV 
genotype and the presence or absence of cirrhosis {Gilead Sciences Inc 2013}.The next wave of 
therapies for the treatment of HCV includes combinations of direct acting antivirals (DAAs) 
including SOF in Peg-IFN and RBV free regimens. The first of these treatments, a fixed dose 
combination (FDC) of SOF and the HCV nonstructural protein 5A (NS5A) inhibitor ledipasvir 
(LDV), has been approved in the US and Europe. The Phase 3 studies GS-US-337-0102 (ION 1), 
GS-US-337-0109 (ION 2), and GS-US-337-0108 (ION 3) demonstrated that treatment with 
LDV/SOF with or without RBV for 8, 12 or 24 weeks resulted in high SVR12 rates in subjects 
with GT1 HCV infection {Afdhal et al 2014b}, {Afdhal et al 2014a}, {Kowdley et al 2014}.
LDV/SOF with RBV is currently approved as a 24 week regimen for the treatment of genotype 3 
HCV infection in Europe, but is not approved for GT3 HCV infections in the US.
Despite the recent advances of DAA based therapy for HCV, there remains room for 
improvement in therapy for certain subgroups of patients based on genotype, previous HCV 
treatment experience, and the presence or absence of cirrhosis.  For example, while there are 
good treatment options available for patients with GT3 HCV infections without cirrhosis 
(12 weeks of SOF plus daclatasvir has been shown to lead to SVR12 rates as high as 98% in 
patients with GT 3 HCV infections) {Nelson et al 2015}, this regimen has not been as effective
in patients with concomitant cirrhosis, where SVR12 rates are around 60%.  Treatment options 
for patients with GT 3 HCV infections and cirrhosis are limited to longer regimens (24 weeks) 
that include the use of ribavirin or 12 week regimens that require the use of ribavirin and 
pegylated interferon {Gilead Sciences Inc 2013}. Considering these subgroups is critical as over 
half of all HCV infections are non-GT1: estimates from 2 recent meta-analyses indicate GT3 
HCV is the next most common after GT1 accounting for 22-30% of HCV infections. The 
availability of a well-tolerated, all oral, ribavirin-free, pegylated interferon-free, short duration 
therapy that is effective in all HCV genotypes, including patients with GT3 HCV and cirrhosis


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would be a major advance for the treatment of HCV infection globally.  Moreover, a 
pangenotypic regimen that does not require HCV genotyping, response guided therapy, or 
intensive safety monitoring due to use of Peg-IFN or RBV would allow a greater number of 
patients to be treated in regions where HCV genotyping or careful safety monitoring of treated 
patients is not part of routine medical care for HCV infection.
1.2.
Sofosbuvir/Velpatasvir Fixed Dose Combination
SOF/ velpatasvir (VEL) fixed-dose combination (SOF/VEL FDC) combines two HCV specific 
DAAs into a single tablet for the treatment of chronic HCV infection.
SOF is a nucleotide analog HCV NS5B polymerase inhibitor currently approved in the US and 
other regions for the treatment of HCV infection as described in Section 1.1. VEL (formerly 
known as GS-5816) is a HCV NS5A inhibitor that has demonstrated activity against HCV in 
phase 1, phase 2, and phase 3 studies.  VEL showed activity against genotypes 1, 2, 3 and 4 HCV 
in a phase 1, 3 day, monotherapy study. Phase 2 studies of SOF + VEL administered as single 
agents have demonstrated that the combination of SOF 400 mg and VEL 100 mg administered 
for 12 weeks is well tolerated and results in high SVR rates across a broad range of HCV 
genotypes. In the Phase 2 study GS-US-342-0109 all patients with GT3 HCV infections without 
cirrhosis achieved SVR12, regardless of the addition of RBV. Patients with compensated 
cirrhosis achieved higher SVR12 rates with the addition of RBV, suggesting that RBV provides 
additional efficacy when added to regimens of SOF + VEL in these patients. The SOF/VEL FDC 
(400/100 mg) is a co-formulation of SOF 400 mg and VEL 100 mg has been shown to be 
effective in the treatment of GT1-6 HCV in four Phase 3 trials (ASTRAL 1-4), including patients 
with GT3 HCV infections and cirrhosis.{Feld et al 2015, Foster et al 2015} {Curry et al 2015}.
The ASTRAL studies and several ongoing phase 3 trials are described in detail in 
Section 1.2.2.1.
The development of SOF/VEL may have a major impact on the global prevalence and burden of 
HCV as it may represent a simple, well tolerated, highly efficacious, pangenotypic treatment for 
all HCV infected patients.
1.2.1.
General Information
Please refer to the SOF/VEL FDC Investigator’s Brochure (IB) for additional information on 
SOF/VEL, and the individual components, including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience


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1.2.2.
Additional Clinical Experience
1.2.2.1.
Sofosbuvir/Velpatasvir Phase 3 Studies
Four Phase 3 studies have been completed evaluating the efficacy and safety of SOF/VEL in 
subjects with genotype 1-6 HCV infection. Three studies enrolled subjects without cirrhosis or 
with compensated cirrhosis, GS-US-342-1138 (ASTRAL-1), GS-US-342-1139 (ASTRAL-2) 
and GS-US-342-1140 (ASTRAL-3); and one study enrolled subjects with decompensated 
cirrhosis GS-US-342-1137 (ASTRAL-4). Three Phase 3 trials enrolling patients with HIV-1 
coinfection (GS-US-342-1202 [ASTRAL-5]), patients who failed to achieve SVR12 in previous 
Gilead sponsored HCV treatment studies (GS-US-342-1553), and patients who received placebo 
during ASTRAL-1 (GS-US-342-1446) are currently ongoing.  Summaries of results from the 
completed Phase 3 studies and descriptions of the ongoing Phase 3 studies are presented below.
1.2.2.1.1.
Study GS-US-342-1138 (ASTRAL-1)
Design
This ongoing Phase 3, randomized, double-blind, placebo-controlled, multicenter, international 
study is assessing the antiviral efficacy, safety, and tolerability of 12 weeks of SOF/VEL  
treatment compared with 12 weeks of  SOF/VEL placebo treatment in subjects with chronic 
genotype 1, 2, 4, 5, or 6 hepatitis C virus (HCV) infection. This study was conducted in Begium, 
Canada, France, Germany, Hong Kong, Italy, United Kingdom and United States.
Subjects with genotype 1, 2, 4, or 6 HCV infection were randomized in a 5:1 ratio to treatment 
with SOF/VEL for 12 weeks (SOF/VEL 12 Week group) or SOF/VEL placebo for 12 weeks 
(Placebo 12 Week group). Subjects with genotype 5 HCV infection were enrolled to the 
SOF/VEL 12 Week group. Randomization was stratified by HCV genotype (1, 2, 4, 6, and 
indeterminate) and the presence or absence of cirrhosis at screening.
Disposition
A total of 740 subjects were enrolled and treated; 624 subjects in the SOF/VEL 12 Week group 
and 116 subjects in the Placebo 12 Week group.
The majority of subjects (99.3%) completed study treatment. Five subjects (0.7%) prematurely 
discontinued study treatment; 2 subjects in the SOF/VEL group and 3 subjects in the placebo 
group. The reasons for premature discontinuation of study drug for subjects in the SOF/VEL
12 Week group were an AE (1 subject) and lost to follow-up (1 subject) and for subjects in the 
Placebo 12 Week group were AEs (2 subjects) and investigator discretion (1 subject).
Demographics and Baseline Characteristics
Demographics and baseline disease characteristics were generally balanced between the 
SOF/VEL 12 Week and Placebo 12 Week groups.


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In the SOF/VEL 12 Week group, the majority of subjects were male (59.9%), and 21.6% of 
subjects had a body mass index (BMI) 30 kg/m2, 19.4% had cirrhosis and most subjects 
(73.9%) had baseline HCV RNA ≥800,000 IU/mL. Of the 624 subjects who received SOF/VEL, 
328 subjects (52.6%) had genotype 1 HCV infection (210 subjects [33.7%] with HCV 
genotype 1a and 118 subjects [18.9%] with HCV genotype 1b), 104 subjects (16.7%) had 
genotype 2 HCV infection, 116 subjects (18.6%) had genotype 4 HCV infection, 35 subjects 
(5.6%) had genotype 5 HCV infection, and 41 subjects (6.6%) had genotype 6 HCV infection.
Efficacy Results 
The SOF/VEL  12 Week group met the primary endpoint of an SVR12 rate that was statistically 
superior relative to the prespecified performance goal of 85% (p < 0.001). The SVR12 rate was 
as follows:
SOF/VEL 12 Week group: 99.0% (95% CI: 97.9% to 99.6%) of subjects (618 of 624) achieved 
SVR12.
Table 1-1 presents the SVR12 results for the SOV/VEL FDC12 Week group overall and by HCV 
genotype. A total of 6 of 624 subjects (1.0%) who received SOF/VEL did not achieved SVR12. 
Two subjects had relapse determined at posttreatment week 4; one treatment-naïve subject with 
genotype 1a HCV infection without cirrhosis and one treatment experienced subject with 
genotype 1b infection and cirrhosis. Four additional subjects (3 with genotype 1 and 1 with 
genotype 5) did not achieve SVR12 (1 subject withdrew consent, 2 subjects had not returned for 
the posttreatment Week 12 visit, and 1 subject died prior to the posttreatment Week 4 visit). 
Table 1-1.
GS-US-342-1138: SVR12 Overall and by HCV Genotypes 
SOF/VEL
12 Weeks
Total
(All 
Genotypes)
(N = 624)
GT-1a
(N = 210)
GT-1b
(N = 118)
GT-1
Total
(N = 328)
GT-2
(N = 104)
GT-4
(N = 116)
GT-5
(N = 35)
GT-6
(N = 41)
SVR12
618/624 
(99.0%)
206/210 
(98.1%)
117/118 
(99.2%)
323/328 
(98.5%)
104/104 
(100.0%)
116/116 
(100.0%)
34/35 
(97.1%)
41/41 
(100.0%)
GT = genotype
The SVR4 results for subjects with genotype 1, 2, 4, 5, or 6 HCV infection were the same as the 
SVR12 results with the exception of 1 subject with genotype 1a HCV infection who achieved 
SVR4 but had not returned for his posttreatment Week 12 visit at the time of the interim analysis.
HCV RNA declined rapidly with similar decreases in HCV RNA observed across all HCV 
genotypes in the SOF/VEL 12 Week group. Consistent with the rapid and sustained decline in 
HCV RNA, > 88.5% of subjects in the SOF/VEL 12 Week group had HCV RNA LLOQ at 
Week 4. Time to virologic suppression was not associated with treatment outcome overall or in 
any genotype.


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Virologic Resistance
Deep sequence analyses indicated that subjects in the SOF/VEL 12 Week group had a diverse 
population of HCV with more than 30 subtypes across genotypes 1, 2, 4, 5, 6, and 7. 
Approximately 42% and 9% of subjects in the SOF/VEL 12 Week group had baseline NS5A 
resistance-associated variants (RAVs) and NS5B RAVs, respectively. Baseline NS5A or NS5B 
RAVs had no impact on SVR12, with high SVR12 across all subtypes/genotypes regardless of 
the presence of NS5A RAVs or NS5B RAVs. Two subjects had virologic failure and both had 
baseline NS5A RAVs. At virologic failure time points, both subjects developed additional NS5A 
RAVs (Y93N and Y93H) that conferred a high (> 700) fold shift in EC50 to VEL. No NS5B 
RAVs were detected at baseline or posttreatment in either subject with virologic failure.
Safety Results
Treatment with SOF/VEL was well tolerated. Subjects in the SOF/VEL 12 Week treatment 
group had similar type, incidence, and severity of AEs as subjects in the Placebo 12 Week group.
Grade 3 (severe) and Grade 4 (life-threatening) AEs were rare, 19 of 624 (2.9%) in the SOF/VEL
12 Week group and 1 of 116 (0.9%) in the Placebo 12 Week group. Two subjects (0.3%) in the 
SOF/VEL 12 Week group had Grade 4 AEs. One subject had a Grade 4 AE of malignant lung 
neoplasm and 1 subject had a Grade 4 AE of sudden death. Both events were assessed by the 
investigators as unrelated to study drugs.
SAEs were rare and occurred in 15 subjects (2.4%) in the SOF/VEL 12 Week group. All SAEs 
were assessed by the investigators as unrelated to study drugs. No placebo treated subjects had 
SAEs. No trends in SAE type or onset time were observed, and no SAE was reported in 
> 1 subject. No SAEs led to treatment discontinuation. One subject death was reported in the 
study. This subject completed 12 weeks of treatment with SOF/VEL and died in his sleep on 
posttreatment Day 8. The death was assessed as not related to study drug by the investigator. One 
subject (0.2%) in the SOF/VEL 12 Week group discontinued study treatment due to a Grade 3 
AE of anxiety and 2 subjects (1.7%) in the Placebo 12 Week group discontinued study treatment 
due to meeting the prespecified stopping criteria of elevated ALT and/or AST levels ≥5 nadir.
Most laboratory abnormalities were Grade 1 or 2 in severity. Subjects in the SOF/VEL 12 Week 
group had Grade 3 or 4 chemistry abnormalities of elevated AST (Grade 3; 1 subject [0.2%]), 
elevated creatine kinase (Grade 3; 2 subjects [0.3%], Grade 4; 2 subjects [0.3%]), hyperglycemia 
(Grade 3, 15 subjects [2.4%]), and elevated lipase (Grade 3; 14 subjects [2.2%], Grade 4, 
2 subjects [0.3%]). Among subjects in the SOF/VEL 12 Week, all Grade 3 or 4 creatinine kinase 
elevations were transient, all Grade 3 or 4 lipase elevations were asymptomatic and generally 
transient, and Grade 3 or 4 hyperglycemia occurred in subjects with a medical history of 
diabetes. The most frequently observed Grade 3 or 4 laboratory abnormalities observed in 
placebo treated subjects were elevated ALT (Grade 3; 6 subjects [5.2%] and Grade 4; 2 subjects 
[1.7%]) consistent with ongoing HCV infection.


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No notable changes from baseline in vital signs (systolic blood pressure, diastolic blood pressure, 
or pulse) were observed during the study. No trends in ECG findings suggestive of cardiotoxicity 
were observed.
Conclusions 
The conclusions from this interim analysis were as follows:

The study met its primary efficacy endpoint demonstrating that the SVR12 rate of 99.0% 
(95% CI: 97.9% to 99.6%) in genotype 1, 2, 4, 5, and 6 HCV-infected subjects treated for 
12 weeks with SOF/VEL was statistically superior to the prespecified SVR12 performance 
goal of 85% (p<0.001).

High SVR12 rates were achieved across all HCV genotypes and subgroups
— Among subjects with cirrhosis, the SVR rate was 99.2%
— Among subjects with prior treatment failure, the SVR rate was 99.5%
— Among subjects with baseline NS5A RAVs, the SVR12 rate was 99.2%

Treatment with SOF/VEL for 12 Weeks was generally well tolerated with a safety profile 
similar to that of placebo treatment. There was a low incidence of SAEs, discontinuations 
due to AEs and no clinically relevant laboratory abnormalities.
1.2.2.1.2.
Study GS-US-342-1139 (ASTRAL-2)
Study Design
This ongoing Phase 3, randomized, open-label, multicenter study is assessing the antiviral 
efficacy, safety, and tolerability of 12 weeks of SOF/VEL treatment compared with 12 weeks of 
SOF+RBV treatment in subjects with chronic genotype 2 HCV infection. The study was 
conducted in the United States (US).
Subjects with genotype 2 HCV infection were randomized (1:1) to treatment with SOF/VEL for 
12 weeks (SOF/VEL 12 Week group) or SOF+RBV for 12 weeks (SOF+RBV 12 Week group). 
Randomization was stratified by the presence or absence of cirrhosis at screening and prior 
treatment experience (treatment naive vs treatment experienced).
Disposition
A total of 266 subjects were randomized and treated; 134 in the SOF/VEL 12 Week group and 
132 in the SOF+RBV 12 Week group. The majority of subjects (99.2%) completed study 
treatment. Two subjects (0.8%), 1 in each treatment group, prematurely discontinued study 
treatment. One subject in the SOF/VEL 12 Week group discontinued study treatment on Day 1 
(after receiving 1 dose of study drug) due to AEs of disturbance in attention, headache, and 
anxiety. One subject in the SOF+RBV 12 Week group completed the Week 10 study visit, but 


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did not return for any subsequent study visits and was assumed to be lost to follow-up; the last 
confirmed dosing date was Day 71.
Demographics and Baseline Characteristics
Overall, demographics and baseline disease characteristics were balanced across both treatment 
groups. The majority of subjects were male (59.4%), and 32.7% of subjects had a BMI 
30 kg/m2. A total of 38 subjects (14.3%) had cirrhosis at screening. Overall, the majority of 
subjects had HCV RNA 800,000 IU/mL (79.7%). Overall, 14.7% (39 subjects) were treatment 
experienced.
Efficacy Results
The SOF/VEL 12 Week group met the primary endpoint of an SVR12 rate that was noninferior 
to the SVR12 rate in the SOF+RBV 12 Week group. The SVR12 rates were as follows:

SOF/VEL 12 Week group: 99.3% (95% CI: 95.9% to 100%) of subjects (133 of 134) 
achieved SVR12

SOF+RBV 12 Week group: 93.9% (95% CI: 88.4% to 97.3%) of subjects (124 of 132) 
achieved SVR12
The strata-adjusted difference (95% CI) in the proportions was 5.2% (0.2% to 10.3%). Since the 
lower bound of the 2-sided 95% CI for the difference between groups was greater than the 
prespecified noninferiority margin of −10%, the efficacy of SOF/VEL for 12 weeks was 
demonstrated to be statistically noninferior to SOF+RBV for 12 weeks. There was sufficient 
evidence to demonstrate the statistical superiority of treatment with SOF/VEL for 12 weeks over 
SOF+RBV for 12 weeks for SVR12 (p = 0.018; CMH test stratified by cirrhosis status and prior 
treatment experience).
In the SOF/VEL 12 Week group, 1 of 134 subjects (0.7%) did not achieve SVR12: the subject 
discontinued study treatment on Day 1 (after receiving 1 dose) due to AEs of difficulty 
concentrating, headache, and anxiety. The subject never achieved HCV RNA LLOQ. In the 
SOF+RBV 12 Week group, 8 of 132 subjects (6.1%) did not achieve SVR12. Of these, 
6 subjects relapsed and 2 were lost to follow-up. Four relapses occurred by the posttreatment 
Week 4 visit and 2 relapses occurred between the posttreatment Week 4 and 12 visits. The low 
number of virologic failures in the study precluded meaningful subgroup analysis of SVR.
The SVR4 results were similar to the SVR12 results with the exception of 3 subjects in 
SOF+RBV 12 Week group: 1 subject was lost to follow-up after posttreatment Week 4 and 
2 subjects relapsed between the posttreatment Week 4 and Week 12 visits.
HCV RNA levels (log10 IU/mL) declined rapidly with similar decreases in HCV RNA observed 
in both treatment groups. After 1 week of treatment, the mean change from baseline in HCV 
RNA levels was 4.51 log10 IU/mL in both treatment groups. The decreases in HCV RNA were 
maintained from Weeks 2 through 12. Consistent with the rapid and sustained decline in 


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HCV RNA, 90.2% of subjects in both treatment groups had HCV RNA LLOQ at Week 4. 
There was a lack of correlation of time to suppression with virologic outcome in the SOF/VEL
12 week group as all subjects who completed treatment achieved SVR regardless of the time to 
suppression.
Virologic Resistance
Deep sequencing analyses indicated that genotype 2a and 2b were the predominant HCV 
subtypes in subjects who were randomized and treated in this study. Approximately 60% and 
10% of subjects in the SOF/VEL 12 Week group had pretreatment NS5A and NS5B RAVs, 
respectively. The most prevalent NS5A RAV observed was L31M in 51% of subjects. Despite 
the presence of pretreatment NS5A and NS5B RAVs, no subjects in the SOF/VEL 12 Week 
group experienced virologic failure in this study. Two of the 6 subjects who relapsed in the 
SOF+RBV 12 Week group had low levels of the NS5B NI RAV L159F detectable at failure.
Safety Results
Overall, treatment with SOF/VEL or SOF+RBV for 12 weeks was generally safe and well 
tolerated. A smaller percentage of subjects in the SOF/VEL 12 Week group experienced any AE 
(68.7%, 92 of 134) compared with the SOF+RBV 12 Week group (76.5%, 101 of 132), 
including treatment-related AEs (SOF/VEL, 33.6%; SOF+RBV, 56.8%) and AEs leading to 
modification or interruption of any study drug (SOF/VEL, 0; SOF+RBV, 9.8%).
The most common AEs (ie, AEs reported in > 10% of subjects in either group) were reported by 
a smaller percentage of subjects in the SOF/VEL 12 Week group compared with the SOF+RBV 
12 Week group, including fatigue (14.9% vs 35.6%), headache (17.9% vs 22.0%), nausea 
(10.4% vs 14.4%), and insomnia (4.5% vs 13.6%). 
Most AEs were Grade 1 (mild) or Grade 2 (moderate) in severity. Grade 3 (severe) AEs were 
rare (SOF/VEL, 2.2%; SOF+RBV, 2.3%). No Grade 4 (life-threatening) AEs were reported. 
Anxiety was the only Grade 3 AE reported in > 1 subject in the SOF/VEL 12 Week group (n = 2, 
1.5%).
Serious adverse events (SAEs) were also rare (1.5%, 4 of 266 subjects [2 in each treatment 
group]). No SAE was reported in 1 subject. All SAEs were considered by the investigators to 
be not related to study drug. Two non-treatment-emergent deaths were reported during the study 
(metastatic lung cancer and cardiac arrest after treatment completion). No pregnancies were 
reported during the study. Only 1 subject permanently discontinued any study drug (SOF/VEL) 
due to AEs. After receiving 1 dose of SOF/VEL, the subject, who had a medical history of 
depression, insomnia and post-traumatic stress disorder, discontinued study treatment due to 
Grade 3 AEs of difficulty concentrating, headache, and anxiety that were assessed as related to 
study drugs by the investigator.
Most subjects had at least 1 laboratory abnormality reported, with the majority being Grade 1 
(104 of 266 subjects, 39.1%) or Grade 2 (70 of 266 subjects, 26.3%) in severity. A smaller 
percentage of subjects had Grade 3 laboratory abnormalities in the SOF/VEL 12 Week group 


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(7.5%, 10 subjects) compared with the SOF+RBV 12 Week group (13.6%, 18 subjects). This
difference was accounted for primarily by the expected decreases in hemoglobin observed with 
RBV therapy. No subjects in the SOF/VEL 12 Week group had a Grade 3 or 4 hematology 
laboratory abnormality. The only Grade 3 hematology laboratories abnormality in the SOF+RBV 
12 Week group were decreased hemoglobin (5.3%, 7 subjects) and increased lymphocytes 
(0.8%, 1 subject). The most common Grade 3 or 4 chemistry laboratory abnormalities in both 
treatment groups were increased serum glucose (hyperglycemia) and increased lipase. Grade 3 
increases in lipase were reported for 7 subjects (5.3%) in the SOF/VEL 12 Week group and 
2 subjects (1.5%) in the SOF+RBV 12 Week group. Grade 4 increases in lipase were reported for 
1 subject (0.8%) in each treatment group. All of the Grade 3 lipase elevations were transient and 
asymptomatic, with no cases of clinical pancreatitis. In the SOF/VEL 12 Week group, 1 subject 
each experienced a Grade 3 or 4 increase in creatine kinase following workout sessions. Grade 3 
hyperbilirubinemia was only observed in the SOF+RBV 12 Week group and was consistent with 
RBV-associated hemolysis. Grade 4 chemistry laboratory abnormalities were reported for lipase 
and creatine kinase.
No notable changes in vital signs (systolic blood pressure, diastolic blood pressure, and pulse) or 
ECGs were reported during the study.
Conclusions 
The conclusions from this interim analysis were as follows:

The study met its predefined primary efficacy endpoint, demonstrating that the SVR12 rate 
of 99.3% with SOF/VEL for 12 weeks was noninferior to the SVR12 rates of 93.9% with 
SOF+RBV for 12 weeks.

Treatment with SOF/VEL for 12 weeks led to a statistically superior SVR12 rate compared 
with SOF+RBV for 12 weeks (p = 0.018). 

No subjects treated with SOF/VEL experienced virologic failure, including subjects with 
cirrhosis (14%), prior treatment failure (14%), and baseline NS5A RAVs (60%).

SOF/VEL was generally well tolerated and, compared with SOF+RBV, lacked toxicities 
associated with RBV. No treatment-emergent deaths, Grade 4 AEs, treatment-related SAEs, 
or clinically relevant laboratory abnormalities were observed.
1.2.2.1.3.
Study GS-US-342-1140 (ASTRAL-3)
Study Design
This ongoing, Phase 3, randomized, open-label, multicenter study is assessing the antiviral 
efficacy, safety, and tolerability of 12 weeks of SOF/VEL treatment compared with 24 weeks of 
SOF+RBV treatment in subjects with chronic genotype 3 HCV infection. This study was 
conducted in Australia, Canada, France, Germany, Italy, New Zealand, United Kingdom and 
United States.


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Subjects with genotype 3 HCV infection were randomized (1:1) to treatment with SOF/VEL for 
12 weeks (SOF/VEL 12 Week group) or SOF+RBV for 24 weeks (SOF+RBV 24 Week group). 
Randomization was stratified by the presence or absence of cirrhosis at screening and prior 
treatment experience (treatment naive vs treatment-experienced).
Disposition
A total of 552 subjects were randomized and treated (277 subjects in the SOF/VEL 12 Week 
group and 275 subjects in the SOF+RBV24 Week group). A total of 21 subjects (7.6%) in the 
SOF+RBV 24 Week group discontinued treatment compared with 2 subjects (0.7%) in the 
SOF/VEL 12 Week group. The most common reason for discontinuation of treatment for 
subjects in the SOF+RBV 24 Week group was AEs (9 subjects, 3.3%).
Demographics and Baseline Characteristics
The majority of subjects were male (62.3%), and 20.3% of subjects had a BMI ≥30 kg/m2. 
Overall, the majority of subjects had HCV RNA ≥800,000 IU/mL (69.7%). A total of 
163 subjects (29.5%) had cirrhosis at screening. Overall, 25.7% (142 subjects) were treatment 
experienced.
Efficacy Results
The study met the primary efficacy endpoint. The SVR12 rate for the SOF/VEL 12 Week group 
was statistically noninferior to the SVR12 rate for the SOF+RBV 24 Week group. The SVR12 
rates were as follows:

SOF/VEL 12 Week group: 95.3% (95% CI: 92.1% to 97.5%) of subjects (264 of 277) 
achieved SVR12.

SOF+RBV 24 Week group: 80.4% (95% CI: 75.2% to 84.9%) of subjects (221 of 275) 
achieved SVR12.
The strata-adjusted difference (95% CI) in the proportions was 14.8% (9.6% to 20.0%). The 
superiority of treatment with SOF/VEL for 12 weeks over SOF+RBV for 24 weeks for SVR12 
was also demonstrated (p < 0.001; CMH test stratified by cirrhosis status and prior treatment 
experience).
In the SOF/VEL 12 Week group, 13 of 277 subjects (4.7%) did not achieve SVR12. Of these, 
no subjects had on-treatment virologic failure, 11 subjects relapsed, and 2 subjects were lost to 
follow-up. In the SOF+RBV 24 Week group, 54 of 275 subjects (19.6%) did not achieve SVR12. 
Of these, 1 subject had on-treatment virologic failure (nonresponse), 38 subjects relapsed, and 
15 subjects did not achieve SVR12 for reasons other than virologic failure. These 15 subjects 
included 6 subjects who were lost to follow-up or who did not attend a posttreatment Week 12 
visit, 4 subjects who withdrew from the study due to AEs, 2 subjects who withdrew consent from 
the study, 2 subjects who died, and 1 subject who only received 2 days of study drug, did not 


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achieve HCV RNA < LLOQ on treatment, and did not meet the protocol definition for virologic 
failure.
Most relapses occurred by the posttreatment Week 4 visit. In the SOF/VEL 12 Week group, 8 of 
11 relapses occurred by posttreatment Week 4, and 3 of 11 relapses occurred between 
posttreatment Weeks 4 and 12. 
Across the 2 treatment groups, the SVR12 rates consistently favored the SOF/VEL 12 Week 
group over the SOF+RBV 24 Week group. Within each treatment group, the SVR12 rates for 
most subgroups were generally consistent with those observed in the overall population. In the 
SOF/VEL 12 Week group, the SVR12 rates for subjects with and without cirrhosis were 91.3% 
(73 of 80) and 97.0% (191 of 197), respectively, and the SVR12 rates for treatment-naive and 
treatment-experienced subjects were 97.1% (200 of 206) and 90.1% (64 of 71), respectively. In 
the SOF+RBV 24 Week group, subjects with cirrhosis had considerably lower SVR12 rates 
(66.3%; 55 of 83) than subjects without cirrhosis (87.2%; 163 of 187), and subjects with prior 
treatment experience had considerably lower SVR12 rates (63.4%; 45 of 71) than 
treatment-naive subjects (86.3%; 176 of 204).
HCV RNA levels (log10 IU/mL) declined rapidly, with similar decreases in HCV RNA observed 
in both treatment groups. Consistent with the rapid and sustained decline in HCV RNA, 91.7% 
of subjects in the SOF/VEL 12 Week group and 88.2% of subjects in the SOF+RBV 24 Week 
group had HCV RNA < LLOQ at Week 4. Time to virologic suppression did not impact 
virologic outcomes in the SOF/VEL 12 Week group: SVR12 rates were 96.0% and 95.7% 
among those subjects with HCV RNA < LLOQ and those with HCV RNA ≥LLOQ at Week 4, 
respectively.
Virologic Resistance
Pretreatment NS5A and NS5B NI RAVs were present in 16% and 4% of subjects, respectively, 
in the SOF/VEL 12 Week group. There was a numerically lower SVR12 rate in 
SOF/VEL -treated subjects with baseline NS5A RAVs compared with subjects without NS5A 
RAVs (88% vs 97%, respectively). All subjects with NS5B NI RAVs in the SOF/VEL 12 Week 
group achieved SVR12.
A total of 10 subjects in the SOF/VEL 12 Week group relapsed, and 1 subject was reinfected. All 
10 subjects had the NS5A RAV Y93H detected at relapse time points. No SOF/VEL -treated 
subjects had NS5B NI RAVs emerge at relapse. The NS5B NI RAVs (N142T, L159F, or 
V321A) emerged in 7 of 39 subjects in the SOF+RBV 24 Week group who had virologic failure.
Safety Results
Overall, treatment with SOF/VEL for 12 weeks or SOF+RBV for 24 weeks was generally safe 
and well tolerated. A lower percentage of subjects in the SOF/VEL 12 Week group experienced 
any AE (88.4%; 245 of 277) compared with the SOF+RBV 24 Week group (94.5%; 260 of 275). 


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Most AEs were Grade 1 (mild) or Grade 2 (moderate) in severity. Grade 3 (severe) AEs were 
reported for 4.3% (12 subjects) in the SOF/VEL 12 Week group and 7.3% (20 subjects) in the 
SOF+RBV 24 Week group. Grade 4 (life-threatening) AEs were reported for no subjects in the 
SOF/VEL 12 Week group and 1.1% (3 subjects) in the SOF+RBV 24 Week group (death due to 
natural causes in 1 subject, cerebrovascular accident in 1 subject, and multiple gunshot wounds 
in 1 subject).
Of the most common AEs (ie, AEs reported in ≥10% of subjects in either treatment group), a 
lower percentage of subjects in the SOF/VEL 12 Week group compared with the SOF+RBV 
24 Week group experienced fatigue (25.6% vs 38.2%), insomnia (11.2% vs 26.9%), nausea 
(16.6% vs 21.1%), irritability (8.3% vs 14.5%), cough (5.1% vs 12.7%), pruritus (2.9% vs 
12.7%), and dyspepsia (3.2% vs 10.9%).
Serious adverse events were reported for 2.2% (6 subjects) in the SOF/VEL 12 Week group and 
5.5% (15 subjects) in the SOF+RBV 24 Week group. No SAE was reported in > 1 subject, and 
no SOV/VEL-treated subject had a treatment-related SAE. Three subject deaths were reported 
during the study (1 treatment-emergent death due to natural causes, 1 treatment-emergent death 
due to multiple gunshot wounds, and 1 nontreatment-emergent death due to an unknown cause); 
all 3 subjects were in the SOF+RBV 24 Week group. A total of 9 subjects (in the SOF+RBV 
24 Week group) prematurely discontinued study drugs due to an AE. The most common AE 
resulting in discontinuation of study drug in the SOF+RBV 24 Week group was insomnia (1.1%, 
3 subjects).
Most subjects had at least 1 laboratory abnormality reported, with the majority being Grade 1 
(36.3%; 200 of 551 subjects) or Grade 2 (29.6%; 163 of 551 subjects) in severity. A lower 
percentage of subjects had Grade 3 laboratory abnormalities in the SOF/VEL 12 Week group 
(5.8%, 16 of 276) compared with the SOF+RBV 24 Week group (14.2%, 39 of 275). This 
difference was accounted for primarily by the expected decreases in hemoglobin observed during 
treatment with RBV. Grade 4 laboratory abnormalities were similarly low in the SOF/VEL
12 Week group (1.4%, 4 of 276) compared with the SOF+RBV 24 Week group (2.9%, 8 of 275).
The only Grade 3 or 4 hematology laboratory abnormality in the SOF/VEL 12 Week group 
occurring in more than 1 subject was decreased lymphocytes (1.1%, 3 of 276 subjects). 
One subject had normal lymphocytes throughout treatment and a Grade 3 decrease at the 
posttreatment Week 4 visit. The other 2 subjects had Grade 2 or 3 decreased lymphocytes at 
baseline that transiently decreased by 1 grade during treatment.
The most common Grade 3 or 4 chemistry laboratory abnormalities in both treatment groups 
were increased lipase, increased serum glucose (hyperglycemia), and increased creatine kinase. 
Grade 3 or 4 increases in lipase were reported for 9 subjects (3.3%) in the SOF/VEL 12 Week 
group and 5 subjects (1.8%) in the SOF+RBV 24 Week group. All of the Grade 3 or 4 increases 
in lipase were asymptomatic, with no cases of clinical pancreatitis. Grade 3 increases in serum 
glucose (hyperglycemia) were reported for 4 subjects (1.4%) in the SOF/VEL 12 Week group 
and 5 subjects (1.8%) in the SOF+RBV 24 Week group. All subjects with Grade 3 increased 
serum glucose had either a medical history of diabetes or HbA1c ≥6.0% at screening. Grade 3 
or 4 increases in creatine kinase were reported for 2 subjects (0.7%) in the SOF/VEL 12 Week 


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group and 4 subjects (1.5%) in the SOF+RBV 24 Week group. All of the Grade 3 or 4 creatine 
kinase elevations were transient and asymptomatic; the majority were associated with exercise. 
Grade 3 or 4 increases in total bilirubin (hyperbilirubinemia) were observed only in the 
SOF+RBV 24 Week group (Grade 3: 2 subjects, 0.7%; Grade 4: 1 subject, 0.4%). The timing 
and magnitude of the increases in total bilirubin were consistent with RBV-induced hemolysis.
No notable changes in vital signs (systolic blood pressure, diastolic blood pressure, and pulse) 
were reported during the study.
Conclusions 
The conclusions from this interim analysis were as follows:

The study met its predefined primary efficacy endpoint: subjects with genotype 3 HCV 
infection in the SOF/VEL 12 Week group achieved an SVR12 rate of 95.3% that was 
statistically noninferior to the SVR12 rate of 80.4% achieved by subjects with genotype 3 
HCV infection in the SOF+RBV 24 Week group.
— The superiority of treatment with SOF/VEL for 12 weeks over SOF+RBV for 24 weeks 
for SVR12 was also demonstrated (p < 0.001).

Across the 2 treatment groups, the SVR12 rates consistently favored the SOF/VEL 12 Week
group over the SOF+RBV 24 Week group. 
— For subjects with cirrhosis, the SVR12 rates (SOF/VEL 12 Weeks vs SOF+RBV 
24 Weeks) were 91.3% and 66.3%, respectively.
— For treatment-experienced subjects, the SVR12 rates (SOF/VEL 12 Weeks vs SOF+RBV 
24 Weeks) were 90.1% and 63.4%, respectively.

Among the 16% of SOF/VEL -treated subjects with baseline NS5A RAVs, the SVR12 rate 
was numerically lower (88%) compared with subjects without baseline NS5A RAVs (SVR12 
rate of 97%).

SOF/VEL was generally well tolerated and, compared with SOF+RBV, lacked toxicities 
associated with RBV. No treatment-emergent deaths, Grade 4 AEs, treatment-related SAEs, 
discontinuations due to AEs, or clinically relevant laboratory abnormalities were observed in 
SOF/VEL -treated subjects.
1.2.2.1.4.
Study GS-US-342-1137 (ASTRAL-4)
Study Design
This ongoing, Phase 3, randomized, open-label, multicenter study is assessing the antiviral 
efficacy, safety, and tolerability of SOF/VEL ±RBV for 12 weeks and SOF/VEL for 24 weeks in 
subjects with chronic HCV infection and Child-Pugh-Turcotte (CPT) class B cirrhosis. The study 
was conducted in the US.


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Subjects with genotype 1 to 6 HCV infection with CPT class B cirrhosis were randomized 
(1:1:1) to SOF/VEL for 12 weeks (SOF/VEL 12 Week group), SOF/VEL +RBV for 12 weeks 
(SOF/VEL +RBV 12 Week group), or SOF/VEL for 24 weeks (SOF/VEL 24 Week group). 
Randomization was stratified by HCV genotype (1, 2, 3, 4, 5, 6, and indeterminate).
Disposition
A total of 267 subjects were included in the Safety and Full Analysis Sets (90 subjects in the 
SOF/VEL 12 Week group, 87 subjects in the SOF/VEL +RBV 12 Week group, and 90 subjects 
in the SOF/VEL 24 Week group).
Of the 90 subjects in the SOF/VEL 12 Week group, 89 subjects (98.9%) completed study drug
and 1 subject (1.1%) discontinued due to an AE.
Of the 87 subjects in the SOF/VEL +RBV 12 Week group, 82 subjects (94.3%) completed study 
drug; 4 subjects (4.6%) discontinued due to AEs and 1 subject (1.1%) discontinued due to 
virologic failure (pharmacokinetic [PK] data for this subject indicated noncompliance with study 
drugs).
Of the 90 subjects in the SOF/VEL 24 Week group, 84 subjects (93.3%) completed study drug; 
4 subjects (4.4%) discontinued due to AEs, 1 subject (1.1%) discontinued due to virologic 
failure, and 1 subject (1.1%) discontinued due to noncompliance with study drug.
Demographics and Baseline Characteristics
Overall, demographics and baseline disease characteristics were balanced across the treatment 
groups.Of the 267 subjects randomized and treated, 207 subjects (77.5%) had genotype 1 HCV 
infection, 12 subjects (4.5%) had genotype 2 HCV infection, 39 subjects (14.6%) had genotype 3 
HCV infection, 8 subjects (3.0%) had genotype 4 HCV infection, and 1 subject (0.4%) in the 
SOF/VEL 24 Week group had genotype 6 HCV infection. The majority of subjects were male 
(69.7%), and 42.3% of subjects had a BMI 30 kg/m2. Most subjects (55.1%) had prior 
treatment experience and the majority of subjects had HCV RNA ≥800,000 IU/mL (55.8%).
Efficacy Results
The SVR12 rates were as follows:

SOF/VEL 12 Week group: 83.3% (95% CI: 74.0% to 90.4%) of subjects (75 of 90) achieved 
SVR12

SOF/VEL +RBV 12 Week group: 94.3% (95% CI: 87.1% to 98.1%) of subjects (82 of 87) 
achieved SVR12

SOF/VEL 24 Week group: 85.6% (95% CI: 76.6% to 92.1%) of subjects (77 of 90) achieved 
SVR12


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All 3 treatment groups met their primary efficacy endpoints with SVR12 rates that were 
statistically superior compared with the assumed spontaneous rate of 1%. The p-value 
was < 0.001 for the comparison with the SVR12 for each treatment group. 
Among subjects with genotype 1 HCV infection, the SVR12 rate was higher for those in the 
SOF/VEL +RBV 12 Week group (95.6%, 65 of 68) compared with the SOF/VEL 12 Week 
group (88.2%, 60 of 68) or the SOF/VEL 24 Week group (91.5%, 65 of 71). Similarly, among 
subjects with genotype 3 HCV infection, the SVR12 rate was higher for those in the SOF/VEL
+RBV 12 Week group (84.6%, 11 of 13) compared with the SOF/VEL 12 Week group (50.0%, 
7 of 14) or the SOF/VEL 24 Week group (50.0%, 6 of 12).
All subjects with genotype 2, 4, or 6 HCV infection achieved SVR12 across all treatment groups 
with the exception of 1 subject with genotype 2 HCV infection in the SOF/VEL 24 Week group 
who died 39 days after completing 28 days of treatment.
Most virologic failures were due to relapse. One subject with genotype 3 HCV infection in the 
SOF/VEL +RBV 12 Week group had on-treatment breakthrough with PK data showing 
undetectable plasma drug levels consistent with non-adherence to study drug and 1 subject with 
genotype 3 HCV infection in the SOF/VEL 24 Week group had on-treatment breakthrough.
There was 1 subject (1.5%) with genotype 1 HCV infection with virologic failure in the 
SOF/VEL +RBV 12 Week group compared with 5 subjects (7.4%) in the SOF/VEL 12 Week 
group and 3 subjects (4.2%) in the SOF/VEL 24 Week group. Among subjects with genotype 3 
HCV infection, the lowest rate of virologic failure was observed in the SOF/VEL +RBV 
12 Week group with 2 failures (15.4%) compared with 6 (42.9%) in the SOF/VEL 12 Week 
group and 5 (41.7%) in the SOF/VEL 24 Week group. 
There were no virologic failures in subjects with genotype 2, 4, or 6 HCV infection in any of the 
treatment groups.
Treatment with SOF/VEL +RBV for 12 weeks resulted in high SVR12 rates irrespective of 
genotype, prior treatment history, baseline HCV RNA, and presence of pretreatment NS5A or 
NS5B RAVs. Furthermore, there was no impact of demographic factors such as age, sex, BMI, 
or IL28B genotype on treatment outcome in the SOF/VEL +RBV 12 Week group.
Overall, 108 subjects (47.2%) had an improvement in CPT score (range: 1−5 points) while 
99 subjects (43.2%) had no change. A minority of subjects (9.6%, 22 subjects) experienced an 
increase (worsening) in CPT score from baseline to posttreatment Week 12. A higher percentage 
of subjects receiving SOF/VEL for 24 weeks (54.7%) compared with subjects receiving 
SOF/VEL ±RBV for 12 weeks (40.7%−46.6%) had improvements in CPT score from baseline to 
posttreatment Week 12; this difference likely reflects the longer time of observation with HCV 
RNA suppression. The improvements in CPT score were largely due to improvements in 
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Overall, the majority of subjects who achieved SVR12 also had a decrease (improvement) 
(55.5%, 127 of 229 subjects) in MELD score between baseline and posttreatment Week 12 
(range: 1−11 points). Among subjects who had MELD score < 15 at baseline and achieved 
SVR12, 197 of 203 subjects (97.0%) remained < 15 at posttreatment Week 12. A total of 
16 subjects (61.5%) with baseline MELD score ≥15 who achieved SVR12 improved to < 15. 
Improvements in MELD score were largely due to improvements in total bilirubin.
Virologic Resistance
Pretreatment NS5A RAVs were observed in 26% to 29% of subjects across the treatment groups. 
The presence of pretreatment NS5A RAVs did not impact treatment outcome in the SOF/VEL
+RBV 12 Week group. Slightly lower SVR rates were observed in subjects with genotype 1 
HCV infection with NS5A RAVs treated with SOF/VEL for 12 or 24 weeks compared to 
subjects without pretreatment NS5A RAVs. No virologic failures were observed in subjects with 
genotype 2, 4, or 6 HCV infection. The small numbers of subjects with genotype 3 HCV 
infection with pretreatment NS5A RAVs precluded meaningful subgroup analysis. The presence 
of pretreatment NS5B RAVs did not impact treatment outcome in any treatment group.
The majority of subjects had NS5A RAVs present at virologic failure with Y93H being the most 
common variant. NS5B NI RAVs were less common and typically observed at low levels. Of the 
9 subjects with genotype 1 HCV infection with virologic failure, 6 had NS5A RAVs at failure 
(5 treatment emergent and 1 maintained from pretreatment). Two genotype 1 HCV-infected 
subjects had L159F and S282T NS5B NI RAVs present at failure; both of these subjects had 
multiple NS5A RAVs at pretreatment that reduce susceptibility to VEL. All 13 subjects with 
genotype 3 HCV infection with virologic failure had Y93H at failure (10 were treatment 
emergent). Three genotype 3 HCV-infected subjects had low levels of NS5B NI RAVs emerge at 
virologic failure.
Safety Results
Overall, treatment with SOF/VEL ±RBV for 12 weeks or SOF/VEL for 24 weeks was generally 
safe and well tolerated. Adverse events were consistent with the expected clinical sequelae in the 
setting of decompensated cirrhosis and, in addition, with the known toxicities of RBV in the 
SOF/VEL +RBV 12 Week group.
A smaller percentage of subjects in the SOF/VEL 12 Week and SOF/VEL 24 Week groups 
experienced any AE (81.1% in each group) compared with the SOF/VEL +RBV 12 Week group 
(90.8%). The higher frequency of AEs observed in the SOF/VEL +RBV 12 Week group was 
primarily due to AEs consistent with RBV-associated toxicity. No treatment-related Grade 3 AEs 
were reported in > 1 subject in any group or overall. 
Most AEs were Grade 1 (mild) or Grade 2 (moderate) in severity. Overall, the most commonly 
reported Grade 3 or 4 AEs were hepatic encephalopathy and sepsis (5 subjects each), which are 
consistent with the natural history of disease progression in a population with decompensated 
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Serious adverse events (SAEs) occurred in 17.6% of subjects in similar proportions across 
treatment groups, and only 1 subject (0.4%) experienced SAEs considered related to SOF/VEL. 
The most commonly reported SAEs were hepatic encephalopathy and sepsis (5 subjects each). 
Nine deaths occurred during the study, 2 of which were treatment emergent, and none of which 
was assessed as related to study drugs. One subject in the SOF/VEL 24 Week group underwent a 
liver transplantation on posttreatment Day 8 after completing 35 days of treatment.
Nine subjects discontinued all study drugs due to an AE (SOF/VEL 12 Week group: 1.1%, 
1 subject; SOF/VEL +RBV 12 Week group: 4.6%, 4 subjects; SOF/VEL 24 Week group: 4.4%, 
4 subjects). No AE leading to discontinuation of study drugs was reported in > 1 subject. A total 
of 31.0% (27 of 87) of subjects had modified or interrupted RBV dosing due to AEs, and 10.3% 
(9 of 87) of subjects permanently discontinued RBV due to AEs while continuing SOF/VEL.
The majority of subjects had at least 1 Grade 3 or 4 laboratory abnormality (42.7% and 12.4%, 
respectively) with the highest rates observed in the SOF/VEL +RBV group (Grade 3: 43.7%; 
Grade 4 18.4%) due to a higher rate of hematologic abnormalities. The most commonly observed 
Grade 3 or 4 hematology laboratory abnormalities were decreased lymphocytes, hemoglobin, 
and platelet counts, all of which are a known effect of RBV therapy or expected in a subject 
population with decompensated liver disease. 
The most commonly observed Grade 3 or 4 chemistry laboratory abnormalities were increased 
glucose and increased total bilirubin. All of the Grade 3 or 4 increased glucose abnormalities 
occurred in subjects with a history of diabetes mellitus or had elevated glucose at baseline or 
continuing through the posttreatment period. The majority of subjects with Grade 3 or 4 
increased total bilirubin (71.7%, 22 of 31 subjects) were in the SOF/VEL +RBV 12 Week group, 
primarily in a pattern that was consistent with RBV-induced hemolysis. 
No notable changes in vital signs (systolic blood pressure, diastolic blood pressure, and pulse) 
were reported during the study. No trends in electrocardiogram findings suggestive of 
cardiotoxicity were observed.
Conclusions 
The conclusions from this interim analysis were as follows:

Treatment with SOF/VEL ±RBV for 12 or 24 weeks in subjects with decompensated 
cirrhosis resulted in high SVR12 rates:
— In the SOF/VEL 12 Week group, the SVR12 rate was 83.3% (75 of 90 subjects).
— In the SOF/VEL +RBV 12 Week group, the SVR12 rate was 94.3% (82 of 87 subjects).
— In the SOF/VEL 24 Week group, the SVR12 rate was 87.8% (79 of 90 subjects).


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
The SVR12 rates were highest in subjects treated with SOF/VEL +RBV for 12 weeks with 
few virologic failures:
— In subjects with genotype 1 HCV infection, the virologic failure rate was 1.5% (1 of 
68 subjects).
— In subjects with genotype 3 HCV infection, the virologic failure rate was 15.4% (2 of 
13 subjects), of which 1 subject had on-treatment breakthrough with PK data showing 
undetectable plasma drug levels consistent with non-adherence to study drug.

Overall, there were no virologic failures in subjects with genotype 2, 4, or 6 HCV infection.

The SVR12 rates between the SOF/VEL 12- and 24-week treatment durations were similar 
across all genotypes.

The presence of pretreatment NS5A and NS5B RAVs did not impact treatment outcome with 
SOF/VEL +RBV for 12 weeks.

Approximately half of subjects who achieved SVR12 experienced an early improvement in 
CPT and MELD scores, primarily related to improvements in synthetic function (albumin) 
and decreases in bilirubin.

SOF/VEL was generally well tolerated in these subjects with decompensated liver disease, as 
evidenced by low rates of study treatment discontinuation and the majority of Grade 3 and 4 
AEs, SAEs, and laboratory abnormalities being consistent with clinical sequelae of advanced 
liver disease and RBV toxicity.
1.2.2.1.5.
Study GS-US-342-1202 (ASTRAL-5)
Study Design
This ongoing, Phase 3, open-label, multicenter study is assessing the antiviral efficacy, safety, 
and tolerability of SOF/VEL for 12 weeks in subjects with chronic HCV infection and HIV-1 
coinfection. This study is being conducted in the US, New Zealand, and Australia.
Approximately 100 subjects with genotype 1 to 6 HCV infection with HIV-1 coinfection on a 
stable regiment of HIV antiretroviral therapy (ARV) are all scheduled to receive SOF/VEL for 
12 weeks.  The primary outcome is the proportion of subjects who achieve SVR12.
1.2.2.1.6.
Study GS-US-342-1553
Study Design
This ongoing, open-label, multicenter study is assessing the antiviral efficacy, safety, and 
tolerability of SOF/VEL ±RBV for 24 weeks in subjects with chronic HCV infection who have 
participated in prior Gilead sponsored HCV treatment studies. This study is being conducted in 
the US, New Zealand, and Australia.


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Approximately 150 subjects with and without cirrhosis with genotype 1 to 6 HCV infection who 
did not achieve SVR12 in previous Gilead sponsored HCV treatment studies will all receive 
SOF/VEL + RBV for 24 weeks). The primary outcome is the proportion of subjects who achieve 
SVR12.
1.2.2.1.7.
Study GS-US-342-1446
Study Design
This ongoing, open-label, multicenter study is assessing the antiviral efficacy, safety, and 
tolerability of SOF/VEL for 12 weeks in subjects who received placebo in 
study GS-US-342-1138 (ASTRAL 1). This study is being conducted in the US, Canada, Europe, 
and Asia.
Approximately 100 subjects with genotype 1, 2, 4, 5, and 6 HCV infection who received placebo 
in ASTRAL 1 will all receive SOF/VEL 12 weeks. The primary outcome is the proportion of 
subjects who achieve SVR12.
1.2.2.2.
Clinical Pharmacology Studies
1.2.2.2.1.
Study GS-US-281-1058
GS-US-281-1058 is an open-label, Phase 1, multiple-dose drug-drug interaction (DDI) study in 
healthy female subjects of childbearing age evaluating the effect of VEL on the 
pharmacokinetics of a representative hormonal oral contraceptive medication, 
norgestimate/ethinyl estradiol (NGM/EE, OC). Following screening, eligible subjects were 
enrolled in a lead-in period (Part A) of 28 days during which they completed dosing with the 
hormonal oral contraceptive (OC) prior to baseline assessments and initiation of Cycle 1 
(Part B). Subjects with a documented history of taking OC for at least 1 menstrual cycle could be 
enrolled directly into Cycle 1. The PK, safety, and tolerability of OC and OC + VEL were 
assessed in Part B of the study, which consisted of 2 cycles: subjects received OC alone during 
Cycle 1, and OC plus VEL 100 mg once daily during days 8-14 of Cycle 2. Fifteen subjects were 
enrolled, and 13 completed the study. Two subjects were discontinued from the study prior to 
initiation of Cycle 2 (OC+VEL) for laboratory abnormalities. 
Table 1-2 presents the steady-state PK parameters and statistical comparisons of NGM 
metabolites norelgestromin (NGMN) and norgestrel (NG) and EE following administration alone 
or in combination with VEL. Steady-state VEL PK parameters were also assessed. Norgestimate 
was not quantifiable for all subjects at most time points. Similar systemic exposure of NGMN 
and NG were achieved following NGM/EE administration with VEL relative to administration of 
NGM/EE alone. A modest increase in EE Cmax was observed when administered with VEL with 
no change in overall exposure (AUC) or Ctau. The magnitude of increase in EE Cmax when 
administered with VEL is similar to that observed with the concomitant administration of other 
drugs such as voriconazole and etravirine, which did not warrant dose adjustment {Andrews et al 
2008}, {Janssen Pharmaceuticals Inc. 2013}. VEL exposures were consistent with historical data 
(Studies GS-US-281-0115, GS-US-342-0104).


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Table 1-2.
NGMN, NG, EE, and VEL Plasma PK Parameters Following 
Administration of NGM/EE alone or with VEL
PK Parameter
Mean (%CV)
GLSM Ratio 
(90% CI) NGM/EE + VEL vs. 
NGM/EE
NGM/EE Alone 
(N = 15)
NGM/EE + VEL 
(N = 13)
Norelgestromin
AUCtau (pg•h/mL)
17,700 (16.7)
15,700 (11.2)
0.90 (0.82, 0.98)
Cmax (pg/mL)
1650 (16.8)
1600 (13.7)
0.97 (0.88, 1.07)
Ctau (pg/mL)
454 (18.5)
416 (14.3)
0.92 (0.83, 1.03)
Norgestrel
AUCtau (pg•h/mL)
47,000 (34.4)
43,000 (32.4)
0.91 (0.73, 1.15)
Cmax (pg/mL)
2410 (30.6)
2330 (31.5)
0.96 (0.78, 1.19)
Ctau (pg/mL)
1760 (34.4)
1640 (35.7)
0.92 (0.73, 1.18)
Ethinyl Estradiol
AUCtau (pg•h/mL)
666 (30.7)
686 (27.3)a
1.04 (0.87, 1.24)
Cmax (pg/mL)
57.5 (27.3)
80.0 (28.4)a
1.39 (1.17, 1.66)
Ctau (pg/mL)
14.8 (39.3)
12.4 (43.9)a
0.83 (0.65, 1.06)
Velpatasvir
AUCtau (ng•h/mL)
--
4680 (35.1)
--
Cmax (ng/mL)
--
626 (22.0)
--
Ctau (ng/mL)
--
68.3 (47.6)
--
Note: preliminary data presented to 3 significant figures.
a
N = 12
Luteinizing hormone (LH), follicle stimulating hormone (FSH), and progesterone concentrations 
were similar in both treatment cycles, as presented in Table 1-3. Luteinizing hormone and 
progesterone median values were lower than those expected for ovulatory or luteal phases, 
respectively {Quest Diagnostics 2013b}, {Quest Diagnostics 2013a}, {Barditch-Crovo et al 
1999}. Follicle stimulating hormone was lower or within the expected range for the ovulatory 
phase {Quest Diagnostics 2013a}. These results are consistent with a possible decrease in serum 
LH and FSH by hormonal contraceptives and absence of ovulation, as assessed by very low 
progesterone values on cycle Day 21.
Table 1-3.
Summary of LH, FSH, and Progesterone Concentrations Following 
Administration of NGM/EE alone or with VEL
PD Analyte
Median (Q1, Q3)
OC Alone (N = 15)
OC + GS-5816 (N = 13)
LH (mIU/mL)
8.0 (2.9, 12.7)
9.3 (5.4, 14.4)
FSH (mIU/mL)
3.6 (2.0, 5.9)
2.6 (2.2, 5.1)
Progesterone (ng/mL)
0.24 (0.17, 0.39)
0.27 (0.18, 0.80)


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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04 April 2016
Based on these results, no loss in contraceptive efficacy is expected upon administration of 
combined oral contraceptives containing norgestimate/ethinyl estradiol with VEL. 
Study GS-US-334-0146 previously demonstrated that the use of SOF with contraceptives 
(e.g., norgestimate/ethinyl estradiol) is permitted. Accordingly, the use of hormonal 
contraceptives with VEL as a single agent or as part of SOF/VEL FDC is permitted. 
1.2.2.2.2.
Drug-Drug Interaction Studies with SOF/VEL and Gastric Acid Suppressants
GS-US-342-1346 and GS-US-342-1709 were open-label, Phase 1, single-dose drug-drug 
interaction studies in healthy volunteers evaluating the effect of gastric acid suppressants 
(H2RAs and PPIs) on the PK of SOF/VEL. A summary of results from these studies are 
presented in the table below.
Study GS-US-342-1346 demonstrated that simultaneous or staggered (12 hour) administration of 
SOF/VEL, administered under fasting conditions, with famotidine 40 mg resulted in no change 
to the AUC of SOF or VEL, suggesting that SOF/VEL can be administered simultaneously or 
staggered with H2RAs at doses comparable to famotidine 40 mg. Study GS-US-342-1346 also 
demonstrated that simultaneous or staggered (12 hour) administration of SOF/VEL, administered 
under fasting conditions, with omeprazole 20 mg resulted in a reduction in VEL AUC of 37% 
and 56%, respectively. The AUC of SOF also decreased 29% to 44%, respectively, though these 
effects are secondary to the impact of PPIs on VEL, as SOF does not demonstrated pH-
dependent solubility. Based on these data, the use of SOF/VEL under fasting conditions with 
PPIs is not recommended. 
Study GS-US-342-1709 evaluated the effect of omeprazole 20 mg or 40 mg on the PK of 
SOF/VEL when SOF/VEL is administered with food. Administration of SOF/VEL with food and 
omeprazole did not alter the overall exposure (AUC) of SOF or its metabolites, regardless of 
timing or dose of omeprazole. Administration of SOF/VEL with food and omeprazole resulted in 
a decrease in VEL exposure. The smallest decrease in VEL exposure (AUC: 26%, Cmax: 33%) 
was observed following administration of SOF/VEL with food 4 hours before omeprazole 
20 mg. A slightly greater decrease in VEL exposure (AUC: 38%, Cmax: 48%) was observed when 
SOF/VEL was administered with food 2 hours after omeprazole 20 mg. The largest decline in 
VEL exposure (AUC: 53%, Cmax: 56%) was observed following SOF/VEL administration with 
food 4 hours before omeprazole 40 mg.
Collectively, these studies indicate that PPIs can impact the PK of SOF/VEL. Administration of 
SOF/VEL with food reduces the effect of omeprazole on SOF/VEL PK. The overall exposure of 
SOF and its metabolites were not affected by omeprazole 20 mg when SOF/VEL was 
administered with food, and the reduction in VEL exposure was less when administered with 
food (26% to 38%) compared to fasted administration (37% to 56%). Staggering timing of 
omeprazole 20 mg and SOF/VEL administration also modestly impacted VEL exposure; VEL 
AUC was least impacted when administered 4 hours before omeprazole 20 mg (equivalent to 
20 hours after the previous omeprazole dose). 


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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04 April 2016
Study GS-US-342-1709 also demonstrates that the nature of VEL exposure decrease was not 
uniform across the study population. Largest decreases were observed in subjects with highest 
exposure at reference, and those with low exposure at reference were generally unaffected by 
administration with a PPI. These data suggests that gastric pH is a contributor to the natural 
variability of VEL, and the range of exposure for HCV-infected subjects on PPIs is expected to 
be within that observed in Phase 3 ASTRAL studies. Accordingly, PPI doses comparable with 
omeprazole 20 mg can be administered with SOF/VEL when SOF/VEL is administered with 
food.
Table 1-4.
Summary of Changes in SOF/VEL PK following administration with 
Representative H2RAs and PPIs 
Study
Dosing 
Scheme
SOF PK Parameters
GS-331007 PK Parameters
VEL PK Parameters
AUClast
AUCinf
Cmax
AUClast
AUCinf
Cmax
AUClast
AUCinf
Cmax
GS-US-
342-1346 
(N=60)
SOF/VEL
(fasted) with 
simultaneous 
FAM 40 mg
↔
↔
↔
↔
↔
↔
↔
↔
↔
SOF/VEL
(fasted) with 
12 hours 
after FAM 
40 mg
↔
↔
↓23%
↔
↔
↔
↔
↔
↔
SOF/VEL
(fasted) with 
simultaneous 
OME 20 mg
↓29%
↓29%
↓34%
↔
↔
↔
↓37%
↓36%
↓37%
SOF/VEL
(fasted) 12 
hours after 
OME 20 mg 
↓44%
↓44%
↓45%
↔
↔
↔
↓56%
↓55%
↓57%
GS-US-
342-1709
(N=40)
SOF/VEL
(fed) 2 hours 
After OME
20 mg
↔
↔
↓16%
↔
↔
↔
↓38%
↓38%
↓48%
SOF/VEL
(fed)  4 hours 
Before OME
20 mg
↔
↔
↓21%
↔
↔
↔
↓26%
↓26%
↓33%
SOF/VEL
(fed) 4 hours 
Before OME
40 mg
↔
↔
↓30%
↔
↔
↔
↓53%
↓53%
↓56%
FAM = famotidine; OME = omeprazole
The 90% CIs of the %GLSM ratios were within (↔), or extended below (↓) the predetermined 
PK alteration boundary of 70%.


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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04 April 2016
1.2.2.2.3.
Study GS-US-342-1167 
Study GS-US-342-1167 evaluated safety, tolerability, and pharmacokinetics of SOF, its 
metabolites GS-566500 and GS-331007, and GS-5816 following administration of SOF/VEL
(400/100 mg) with Atripla® (ATR; efavirenz/emtricitabine/tenofovir disoproxil fumarate 
[EFV/FTC/TDF]), Eviplera® (emtricitabine/rilpivirine/tenofovir disoproxil fumarate 
[FTC/RPV/TDF]), Tivicay® (dolutegravir [DTG]), or 
elvitegravir/cobicistat/emtricitabine/tenofovir alafemamide fumarate (EVG/COBI/FTC/TAF).
Table 1-5 summarizes the differences in PK parameters of SOF, its metabolites GS-566500 and 
GS-331007, GS-5816, and evaluated ARVs (EFV, RPV, DTG, EVG, COBI, FTC, TAF, and 
TFV) when SOF/GS-5816 or the ARVs were administered alone compared with administration 
of SOF/GS-5816 + ARVs. 
Table 1-5.
GS-US-342-1167: Summary of Changes in PK Parameters of SOF, its 
Metabolites GS-566500 and GS-331007, GS-5816, and Evaluated 
ARVs (EFV, RPV, DTG, EVG, COBI, FTC, TAF, and TFV) (PK 
Analysis Sets)
Analyte
SOF/GS-5816+ARV / ARV
ARVs
SOF/GS-5816+ARV / SOF/GS-5816
ARV PK Parameters
SOF PK Parameters
GS-566500
PK Parameters
GS-331007
PK Parameters
GS-5816
PK Parameters
AUCtau Cmax
Ctau
AUCtau
Cmax
AUCtau
Cmax AUCtau Cmax Ctau
AUCtau Cmax
Ctau
EFV/FTC/TDF
EFV/
FTC/
TDF

38%





53% 47% 57%
  EFV



  FTC



  TFV
81%
77%
121%
FTC/RPV/TDF
FTC/
RPV/
TDF










  RPV



  FTC



  TFV
40%
44%
84%
DTG
DTG










DTG



EVG/COBI/FTC/TAF
EVG/
COBI/
FTC/
TAF
37%



48%
58% 50% 30% 60%
EVG



COBI


103%
FTC



TAF

20%
NC
TFV



NC = not calculable
Note:   90% CIs of the %GLSM ratios were within (↔), extended above (↑), or extended below (↓) the predetermined alteration 
boundaries of 70% to 143%.


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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04 April 2016
Effect of EFV/FTC/TDF, FTC/RPV/TDF, DTG (Dolutegravir), or EVG/COBI/FTC/TAF 
on Sofosbuvir, GS-566500, GS-331007, and GS-5816 Pharmacokinetics
No alteration in the overall exposure of SOF, GS-566500, and GS-331007 was observed 
following coadministration of SOF/GS-5816 + EFV/FTC/TDF, FTC/RPV/TDF, or DTG. Other 
than a small increase in SOF Cmax when administered with EFV/FTC/TDF, the 90% CIs for the 
%geometric least-squares mean (%GLSM) ratios for all primary PK parameters (AUCtau, Cmax, 
and Ctau [if measurable]) were within predetermined lack of PK alteration boundaries of 70% to 
143%, confirming a lack of an effect on the PK of SOF and metabolites by EFV/FTC/TDF, 
FTC/RPV/TDF, or DTG. An increase in SOF AUC (37%) and GS-331007 AUC (48%) and Ctau
(58%) were observed when administered with EVG/COBI/FTC/TAF. Of note, GS-331007 
exposure when administered with EVG/COBI/FTC/TAF was within the range of GS-331007 
exposures observed in the LDV/SOF Phase 3 studies, as well as similar to exposures seen in 
subjects with mild renal impairment where dosing of SOF is permitted without dose adjustment.
The PK of GS-5816 was not altered by FTC/RPV/TDF or DTG. A reduction (approximately 
50%) in GS-5816 systemic exposures was observed following administration of 
SOF/GS-5816 + EFV/FTC/TDF compared to SOF/GS-5816 alone. A modest increase 
(approximately 50%) in GS-5816 systemic exposures was observed following administration of 
SOF/GS-5816 + EVG/COBI/FTC/TAF compared to SOF/GS-5816 alone.
Effect of Sofosbuvir/VEL on Efavirenz, Rilpivirine, Dolutegravir, Elvitegravir, Cobicistat, 
Emtricitabine, Tenofovir, and Tenofovir Alafenamide Pharmacokinetics
The PK of EFV, RPV, DTG, EVG, and FTC were not altered following coadministration of 
EFV/FTC/TDF, FTC/RPV/TDF, DTG, or EVG/COBI/FTC/TAF with SOF/GS-5816. The 
90% CIs for the %GLSM ratios for EFV, RPV, DTG, EVG, and FTC AUCtau, Cmax, and Ctau
remained within the protocol-predefined lack of PK alteration boundaries of 70% to 143%. An 
increase in COBI Ctau (103%) was observed with no increase in AUCtau or Cmax following 
coadministration of EVG/COBI/FTC/TAF with SOF/GS-5816. A small decrease in TAF Cmax
(20%) was observed with no decrease in AUCtau following coadministration of 
EVG/COBI/FTC/TAF with SOF/GS-5816. 
The PK of TFV was not altered following coadministration of EVG/COBI/FTC/TAF with 
SOF/GS-5816. The 90% CIs for the %GLSM ratios for TFV AUCtau, Cmax, and Ctau remained 
within the protocol predefined lack of PK alteration boundaries of 70% to 143%. Modest 
increases in TFV AUCtau, Cmax, and Ctau of approximately 81%, 77%, and 121%, respectively, 
were observed following coadministration of EFV/FTC/TDF with SOF/GS-5816. Similarly, 
modest increases in TFV AUCtau, Cmax, and Ctau of approximately 40%, 44%, and 84%, 
respectively, were observed following coadministration of FTC/RPV/TDF with SOF/GS-5816. 
Similar absolute TFV plasma exposures were achieved following administration of 
SOF/GS-5816 + EFV/FTC/TDF and SOF/GS-5816 + FTC/RPV/TDF. Furthermore, TFV 
exposures were also comparable to those achieved upon coadministration of TDF with HIV 
protease inhibitor (PIs), which did not warrant dose adjustment {Hoetelmans et al 2007}, 
{Agarwala et al 2005}. Accordingly, administration of TDF as part of FTC/RPV/TDF or 
FTC/TDF does not warrant dose adjustment when administered with SOF/GS-5816.


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 37
04 April 2016
Based on the safety and PK data from this study in addition to safety, efficacy, and PK of the 
agents respectively, SOF/GS-5816 may be coadministered with FTC/RPV/TDF, DTG, 
FTC/TDF, or EVG/COBI/FTC/TAF without dose adjustment to any of the agents. SOF/GS-5816 
should not be administered with EFV/FTC/TDF or EFV as part of other ARV regimens.
1.2.2.2.4.
Study GS-US 342-1326 
Study GS-US-342-1326 evaluated safety, tolerability, and pharmacokinetics of SOF, its 
metabolites GS-566500 and GS-331007, and GS-5816 following administration of 
SOF/GS-5816 (400/100 mg) with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil 
fumarate (EVG/COBI/FTC/TDF; Stribild®), emtricitabine/tenofovir disoproxil fumarate 
(FTC/TDF; Truvada®) plus ritonavir (RTV)-boosted darunavir (DRV; Prezista®), atazanavir 
(ATV; Reyataz®), and lopinavir (LPV/RTV; Kaletra®), and raltegravir (RAL; Isentress®).
Table 1-6 summarizes the differences in preliminary PK parameters of SOF, its metabolites 
GS-566500 and GS-331007, GS-5816, and evaluated ARVs (EVG, COBI, DRV, ATV, LPV, 
RTV, RAL, FTC, and TFV) when SOF/GS-5816 or the ARVs were administered alone 
compared with administration of SOF/GS-5816 + ARVs. 
Table 1-6.
GS-US-342-1326: Preliminary Summary of Changes in PK 
Parameters of SOF, its Metabolites GS-566500 and GS-331007, 
GS-5816, and Evaluated ARVs (EVG, COBI, DRV, ATV, LPV, RTV, 
RAL, FTC, and TFV)
Analyte
SOF/GS-5816+ARV / 
ARV
ARVs
SOF/GS-5816+ARV / SOF/GS-5816
ARV PK Parameters
SOF PK 
Parameters
GS-566500
PK Parameters
GS-331007
PK Parameters
GS-5816
PK Parameters
AUCtau
Cmax
Ctau
AUCtau
Cmax
AUCtau
Cmax
AUCtau Cmax Ctau AUCtau Cmax
Ctau
EVG/COBI/FTC/TDF
EVG/
COBI/
FTC/
TDF




35%

45
%


37
%
EVG



COBI


71%
FTC



TFV
35%
36%
45%
DRV + RTV + FTC/TDF
DRV+ 
RTV+
FTC/
TDF
27%
39%






24%

DRV



RTV



FTC



TFV
38%
55%
51%


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 38
04 April 2016
Analyte
SOF/GS-5816+ARV / 
ARV
ARVs
SOF/GS-5816+ARV / SOF/GS-5816
ARV PK Parameters
SOF PK 
Parameters
GS-566500
PK Parameters
GS-331007
PK Parameters
GS-5816
PK Parameters
AUCtau
Cmax
Ctau
AUCtau
Cmax
AUCtau
Cmax
AUCtau Cmax Ctau AUCtau Cmax
Ctau
ATV + RTV + FTC/TDF
ATV+ 
RTV+
FTC/
TDF






42
%
142% 55% 301
%
ATV


39%
RTV


29%
FTC



TFV

55%
39%
LPV/RTV + FTC/TDF
LPV/ 
RTV+
FTC/
TDF
29%
41%






31% 62
%
LPV



RTV



FTC



TFV

42%

RAL + FTC/TDF
RAL+ 
FTC/
TDF










  RAL


21%
  FTC



  TFV
40%
46%
70%
NC = not calculable
Note:   90% CIs of the %GLSM ratios were within (↔), extended above (↑), or extended below (↓) the predetermined alteration 
boundaries of 70% to 143%.
Effect of EVG/COBI/FTC/TDF, DRV+RTV+FTC/TDF, ATV+RTV+FTC/TDF, 
LPV/RTV+FTC/TDF, or RAL+FTC/TDF on Sofosbuvir, GS-566500, GS-331007, and 
GS-5816 Preliminary Pharmacokinetics
No alteration in the exposure (AUCtau, Cmax, or Ctau) of SOF, GS-566500, GS-331007, or 
GS-5816 was observed following administration of SOF/GS-5816 with RAL+FTC/TDF. A small 
increase in GS-331007 overall exposure (~35%) was observed with no alteration in the overall 
exposure of SOF, GS-566500, or GS-5816 when administered with EVG/COBI/FTC/TDF. 
Administration of SOF/GS-5816 with DRV+RTV+FTC/TDF or LPV/RTV+FTC/TDF resulted 
in a modest decrease in the overall exposure of SOF (~27% and ~29%, respectively) with no 
alteration in the overall exposure of GS-566500, GS-331007, or GS-5816. Administration of 
SOF/GS-5816 with ATV+RTV+FTC/TDF resulted in an increase in GS-5816 AUCtau (~142%), 
Cmax (~55%), and Ctau (~301%) with no change in the overall exposure of SOF or its metabolites 
(GS-566500 and GS-331007). 


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 39
04 April 2016
Effect of Sofosbuvir/GS-5816 on Elvitegravir, Cobicistat, Darunavir, Atazanavir, 
Lopinavir, Ritonavir, Raltegravir, Emtricitabine, and Tenofovir Preliminary 
Pharmacokinetics
The overall exposure (AUCtau) and maximal exposure (Cmax) of EVG, COBI, DRV, ATV, LPV, 
RTV, RAL, and FTC were not altered when administered with SOF/GS-5816, as the 90% CIs for 
the %GLSM ratios for AUCtau were within the protocol-predefined lack of PK alteration 
boundaries of 70% to 143%. An increase in the Ctau of COBI (~71%), ATV (~39%), and RTV 
(~29%) when administered as part of ATV+RTV+FTC/TDF was observed following 
coadministration with SOF/GS-5816. A small decrease in the Ctau of RAL (~21%) was observed 
following coadministration with SOF/GS-5816 with no change in overall or maximal RAL 
exposure. 
Modest increases in TFV AUCtau (Range: 35-40%), Cmax (Range: 36-55%), and Ctau
(Range: 45-70%) were observed following administration of EVG/COBI/FTC/TDF, 
DRV+RTV+FTC/TDF, or RAL+FTC/TDF with SOF/GS-5816. A modest increase in TFV Cmax
(~55%) and Ctau (~39%) with no alteration in TFV AUCtau was observed following 
administration of ATV+RTV+FTC/TDF with SOF/GS-5816. A modest increase in TFV Cmax
(~42%) with no alteration in TFV AUCtau or Ctau was observed following administration of 
LPV/RTV+FTC/TDF with SOF/GS-5816.
Based on available safety and PK data from this study in addition to the safety, efficacy, and PK 
of these agents respectively, SOF/GS-5816 may be coadministered with EVG/COBI/FTC/TDF, 
DRV+RTV+FTC/TDF, ATV+RTV+FTC/TDF, LPV/RTV+FTC/TDF, or RAL+FTC/TDF 
without dose adjustment to any of the agents. 
1.3.
Ribavirin (RBV)
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of 
RNA and DNA viruses {Roche Laboratories Inc. 2010}, {Roche Products Limited 2010}. Ribavirin 
monotherapy has little or no effect on the replication of HCV in vivo but can result in 
normalization of serum ALT activity and improvement in liver histology. When combined with 
IFN or PEG therapy, RBV decreases substantially the relapse rate seen after cessation of IFN 
therapy {Poynard et al 1998}, {McHutchison et al 1998}.
Ribavirin is a known teratogen (FDA category X). Furthermore, RBV is known to accumulate 
intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, extreme care 
must be taken to avoid  pregnancy during RBV therapy and for up to 6 months following 
completion of treatment, and in the case of males, impregnating a female while on RBV and up 
to7 months following completion of therapy.
A comprehensive review of RBV is contained in the SmPC.


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 40
04 April 2016
1.4.
Rationale for This Study
This Phase 2 study is designed as a multicenter, randomized, open-label study evaluating 
SOF/VEL FDC for 12 weeks and SOF/VEL + RBV for 12 weeks in subjects with Chronic GT3 
HCV infection and compensated cirrhosis. Patients with genotype 3 HCV infection and cirrhosis 
have previously been studied as subgroups within 1 Phase 2 study (GS-US-342-0109) and 
2 Phase 3 studies (GS-US-342-1140 [ASTRAL-3] and GS-US-342-1137 [ASTRAL-4]) 
evaluating either SOF + VEL or SOF/VEL FDC. GS-US-342-0109 is described in detail in the 
investigators brochure.  Briefly, 27 and 26 patients with GT3 HCV infections without cirrhosis 
received SOF 400 mg + VEL 100 mg and SOF 400 mg + VEL 100mg + RBV, respectively, for 
12 weeks, while 26 and 26 patients with compensated cirrhosis received SOF 400 mg + VEL 
100mg and SOF 400 mg + VEL 100 mg + RBV, respectively, for 12 weeks.  All patients without 
cirrhosis achieved SVR12, regardless of the addition of RBV, suggesting the RBV provides no 
additional efficacy when given to such patients.  Among the patients with compensated cirrhosis, 
88.5% achieved SVR12 without RBV while 96.2% achieved SVR12 with the addition of RBV, 
suggesting that RBV provides additional efficacy when added to regimens of SOF + VEL FDC 
in patients with GT3 HCV infections and cirrhosis.  In ASTRAL-3 (described in 
Section 1.2.2.1.3), 277 patients with genotype 3 HCV were given SOF/VEL for 12 weeks, 80 
(29%) of whom had underlying cirrhosis.  The SVR12 rate for the cirrhotic patients was 91% 
compared to 97% for the non-cirrhotic patients.  In ASTRAL-4 (described in Section 1.2.2.1.4)
14, 13, and 12 patients with genotype 3 HCV and decompensated cirrhosis (CPT B) received 
12 weeks of SOF/VEL , 12 weeks of  SOF/VEL + RBV, and 24 weeks of SOF/VEL, 
respectively.  Of those patients, 7 (50%), 11 (85%), and 6 (50%) subjects achieved SVR12, 
suggesting that RBV provides additional efficacy on top of SOF/VEL when given to patients 
with GT3 HCV infections and decompensated cirrhosis.  
In this study, approximately 200 subjects with genotype 3 HCV and compensated cirrhosis will 
be randomized 1:1 into 2 treatment groups: SOF/VEL for 12 weeks and  SOF/VEL + RBV for 
12 weeks.  This study design will approximately double the number of patients with genotype 3 
HCV and compensated cirrhosis treated with a non-RBV SOF/VEL regimen in clinical trials to 
better characterize the efficacy and safety of SOF/VEL in this important subgroup.  Furthermore, 
though based on small numbers of patients with GT3 HCV infections and cirrhosis, both 
GS-US-342-0109 and ASTRAL-4 suggest that the regimen of SOF/VEL + RBV for 12 weeks is
potentially an important regimen in these patients.  This study design will also provide safety and 
efficacy data of the SOF/VEL + RBV regimen in patients with genotype 3 HCV and cirrhosis. 
In summary, this study will expand the knowledge of the safety and efficacy of SOF/VEL
± RBV in patients with genotype 3 HCV and cirrhosis, and will further characterize the use of 
SOF/VEL as a once-daily pangenotypic regimen for the treatment of chronic HCV infection. 
1.5.
Rationale for Dose Selection
Sofosbuvir 400 mg, once daily, when dosed in combination with RBV with or without PEG has 
demonstrated broad genotypic efficacy and favorable safety profile in over 1700  HCV-infected 
subjects across multiple patient populations in Phase 2 and 3 trials. This dose is the approved 


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marketed dose of sofosbuvir for the treatment of HCV-infection and as such, has been selected 
for co-formulation with VEL into a fixed-dose combination tablet.
VEL 100 mg has been administered in combination with SOF 400 mg for 12 weeks to 
237 HCV-infected subjects in Phase 2 studies. VEL 100 mg was selected for co-formulation with 
SOF and evaluation in this study based on the Phase 2 safety, PK and antiviral activity (studies 
GS-US-342-0102, GS-US-342-0109, and GS-US-337-0122 [Cohort 4]). The Phase 1 
study GS-US-281-0102 established the anti-HCV activity of VEL and indicated that the 
exposures achieved following administration of doses > 25 mg provide at least 80% of maximal 
antiviral response in all HCV genotypes. 
The favorable safety and efficacy profiles of SOF 400 mg and VEL 100 mg support further 
evaluation of this combination and doses in clinical development.
1.6.
Overall Risk/Benefit Assessment
This study will provide information on the safety and efficacy of SOF/VEL ± RBV, a potent 
HCV nucleotide inhibitor and a potent HCV NS5A inhibitor, in patients with GT3 HCV 
infections and cirrhosis. The potential benefits of SOF/VEL ± RBV over the current standard of 
care for the treatment of chronic GT3 HCV in patients with cirrhosis are:

Increasing the cure rate of GT3 HCV beyond that of currently approved therapies for patients 
with concomitant cirrhosis

Providing the first PEG and RBV-free treatment option for patients with GT3 HCV and 
cirrhosis

A once-daily, single tablet, single duration, pangenotypic therapy for HCV infection could 
simplify treatment algorithms and impact worldwide disease prevalence

A reduction in the AEs currently associated with the use of PEG and RBV

A short duration of therapy which should lead to better outcomes through improved 
adherence.
The safety profile of SOF in clinical studies includes over 1700 chronic HCV-infected subjects 
that have been administered 12 weeks of SOF and RBV+/-PEG-IFN.  No clinical safety issues 
specifically related to SOF have been identified to date. 
The safety profile of SOF + VEL 25mg or VEL 100mg administered for 8 or 12 weeks has been 
established in over 800 patients in Phase 2 studies. The safety profile of the proposed therapeutic 
regimen of SOF 400 mg and VEL 100 mg administered for 12 weeks has been established in 
237 subjects enrolled in Phase 2 studies. No clinical safety issues specifically related to VEL or 
SOF + VEL have been identified to date. No clinical safety issues specifically related to the 
NS5A inhibitor class including daclatasvir (DCV) and LDV have been identified to date {Afdhal 
et al 2014b}, {Afdhal et al 2014a}, {Kowdley et al 2014}.


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The safety profile of SOF/VEL has been studied in 4 Phase 3 trials (ASTRAL 1-4) in 
1302 patients.  Twelve weeks of SOF/VEL was generally well tolerated, and led to a similar 
incidence of AEs and SAEs compared to placebo in patients with GT 1, 2, 4, 5, or 6 HCV. When 
12 weeks of SOF/VEL was compared to SOF + RBV for 12 or 24 weeks in patients with GT2 or 
3 HCV, therapy with SOF/VEL was again well tolerated with few differences in AEs or SAEs, 
minus the avoidance of RBV associated toxicities. Patients who received SOF/VEL for either 12
or 24 weeks with decompensated cirrhosis experienced AEs and SAEs typical for patients with 
decompensated cirrhosis in no pattern that could be attributed to study drug.  Patients with 
decompensated cirrhosis who received SOF/VEL + RBV for 12 weeks also experienced AEs and 
SAEs consistent with underlying liver disease as well as toxicities expected with RBV treatment.
In summary, SOF/VEL ± RBV has the potential to increase SVR12 rates of GT3 HCV infections 
among patients with cirrhosis. If high rates of SVR can be obtained with a short, PEG-free ± 
RBV regimen, the anticipated improvements in safety and tolerability would offer a favourable 
risk-benefit determination for patients with chronic GT3 HCV infection and cirrhosis.
1.7.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2. 
OBJECTIVES 
The primaty objectives of this study are: 
Final 
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• 
To evaluate the efficacy of study treatment with SofosbuvirNelpatasvir (SOFNEL) FDC 
and SOFNEL FDC and Ribavirin (RBV) for 12 weeks as measured by the propotiion of 
subjects with sustained viralogic response 12 weeks after cessation of treatment regimen 
(SVR12) 
• 
To evaluate the safety and tolerability of each treatment regimen 
The secondaty objectives of this study are: 
• 
To detemline the prop01tion of subjects who attain SVR at 4 weeks after cessation of each 
treatment regimen (SVR4) 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
each treatment regimen 
• 
To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of study treatment regimen 
The explorat01y objective of this study is: 
• 
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3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is a multicenter, randomized, open-label study that will evaluate the safety, tolerability and 
antiviral efficacy of SOF/VEL FDC with and without RBV for 12 weeks in subjects with chronic 
genotype 3 HCV infection and compensated cirrhosis with or without HIV co-infection.
Approximately 200 subjects with chronic genotype 3 HCV infection and compensated cirrhosis 
will be randomized (1:1) to either:

Group 1 (n = 100): SOF/VEL once daily for 12 weeks
OR

Group 2 (n = 100): SOF/VEL + RBV for 12 weeks 
Randomization will be stratified by prior treatment experience (treatment naïve/treatment-
experienced).
3.2.
Visit Schedule
All subjects will complete screening, on-treatment, and post-treatment assessments. 
Screening assessments will be completed within 28 days of the Day 1 visit. The screening 
window can be extended to 42 days for subjects requiring liver biopsy, additional HCV 
genotyping or for extenuating circumstances. 
All subjects will complete the following study visits: Screening, Baseline/Day 1, on-treatment 
visits at the end of Weeks 2, 4, 8 and 12. All subjects will complete the post-treatment Week 4 
visit.  Subjects with HCV RNA < LLOQ at the post-treatment Week 4 visit will complete the 
post-treatment Week 12 visit. Subjects with HCV RNA ≥LLOQ at post-treatment Week 12 visit 
will be asked to return for a confirmatory visit.  
The assessments performed at each visit are described in Section 6 and shown in Appendix 2.
3.3.
Virologic Response
3.3.1.
HCV Virologic Response-Based Treatment Stopping Criteria
The following on-treatment HCV virologic response-based treatment stopping criteria will be 
utilized:

Confirmed HCV RNA ≥ LLOQ after 2 consecutive HCV RNA < LLOQ

Confirmed > 1 log10 increase from nadir

HCV RNA ≥ LLOQ through 12 weeks of treatment


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Confirmation should be performed as soon as possible and must occur no later than 2 weeks after 
an initial observation indicating virologic failure. 
If HCV viral relapse is detected at post-treatment Week 4 or 12 visits, subjects will be asked to 
return for a confirmatory visit.
3.3.2.
HIV Virologic Rebound Criteria
Subjects who have at least two consecutive post-baseline visit plasma HIV-1 RNA levels 
≥400 copies/mL (at least two weeks apart) will be considered to have HIV virologic rebound. 
Following an initial HIV-1 RNA result of ≥ 400 copies/mL, subjects will continue to take their 
current ARV regimen and be asked to return to the clinic after 2 weeks for a scheduled or 
unscheduled blood draw for confirmation of HIV virologic rebound. If HIV virologic rebound is 
confirmed at the scheduled or unscheduled visit, the blood samples from this visit will be used 
for HIV-1 genotype/phenotype testing. If no resistance to the subject’s current ARV regimen is 
detected, the subject may continue on current ARV regimen.  If resistance to the subject’s 
current ARV regimen is detected, then it is strongly recommended that whenever possible, the 
subject be switched to an alternative approved regimen, as outlined in Section 4.2 of this 
protocol.   
HCV study drug should be continued unless safety events warrant the discontinuation of the 
study drug, as outlined is Section 3.5 of the protocol, or if a subject must be switched to an 
unapproved HIV regimen based upon acquired resistance.
Please refer to Figure 3-1 for the management of subjects who meet the criteria for HIV virologic 
rebound.


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Figure 3-1.
HIV Virologic Rebound Schema
a
HCV study drug should be continued unless safety events warrant the discontinuation of these study drugs, as outlined in
Section 3.5 of the protocol
b
If virologic rebound is not confirmed, the subject should remain on their current ARV regimen.
c
If virologic rebound is confirmed, the HIV-1 genotype and phenotype (reverse transcriptase and protease) will be analyzed.
d
Based on the results of the genotype and phenotype assays, the subject may remain on their ARV regimen at the discretion 
of the Investigator (e.g. virologic rebound due to non-adherence). If the genotype and/or phenotype assay fails to provide 
results, a new ARV regimen may be configured at the discretion of the Investigator in consultation with the Medical 
Monitor.
e
A new ARV regimen should be configured or the ARV regimen held for the duration of SOF/VEL dosing at the 
Investigator’s discretion in consultation with the Medical Monitor. If a new ARV regimen is required, it is strongly 
recommended to use an alternative regimen that is approved in this protocol.  If an unapproved ARV regimen is prescribed, 
then SOF/VEL ± RBV must be discontinued after consultation with the medical monitor.
HIV-1 RNA ≥ 400 copies/mL
Continue current ARV regimen and return for 
scheduled/unscheduled visit (at least 2 weeks apart) 
HIV-1 RNA and potential genotype/phenotype 
HIV-1 genotype/phenotype
Unconfirmed 
virologic rebound: 
remain on current 
regimenb
Confirmed virologic reboundc
If no resistance to the subject’s current 
ARV regimen is detected, may 
continue on current ARV regimend
Study Period
(On-Treatment and Posttreatment)
If resistance to the subject’s current 
ARV regimen is detected, discontinue 
and construct a new ARV regimen
e


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3.4.
Stopping Rules for Individual Subjects
Subjects who meet any of the following criteria should be discontinued from the study and 
complete an Early Termination Visit and return for Posttreatment Follow-up visits:

Elevation of ALT and/or AST that is greater than the ULN and > 5x baseline or nadir 
confirmed by immediate repeat testing unless laboratory results are assessed by both the 
investigator and Gilead Medical Monitor as having an explanation other than drug induced 
liver injury and it is deemed in the best interest of the subject to continue HCV treatment

Confirmed elevation of ALT >15 x ULN (unrelated to any interventional procedures)

Confirmed total bilirubin >10 x ULN (unrelated to any interventional procedures)

Confirmed total bilirubin >3x baseline or 3x nadir (unrelated to any interventional 
procedures)

Any Grade 3 or greater rash associated with constitutional symptoms

Any non-laboratory Grade 4 events assessed as related to administration of SOF/VEL

Worsening of disease state as evidenced by progressing hepatic decompensation and/or 
progression of Child-Pugh Score (CPT) to ≥ 10
The Gilead Medical Monitor should be consulted prior to discontinuation of SOF/VEL and /or 
RBV unless the investigator believes that immediate action is warranted to ensure the continued 
safety of the subject. 
Any questions regarding toxicity management should be directed to Gilead Medical Monitor.
3.5.
Discontinuations
If the subject meets the Virologic Response-Based Stopping Criteria (Section 3.3.1), they should 
complete an Early Termination Visit as soon as possible after SOF/VEL is discontinued and 
complete post-treatment visits up to 30 days after the last dose of SOF/VEL and/or 60 days after 
the last dose of RBV to assess for safety.
If the subject meets the Stopping Rules for Individual Subjects (Section 3.4) or other criteria for 
discontinuation of study treatment (Section 3.7), prior to completion of SOF/VEL dosing period, 
the subject should complete an Early Termination Visit as soon as possible after SOF/VEL is 
discontinued and complete the post-treatment assessments as described in Section 6.3 and in 
Study Procedures Appendix 2. 
Subjects discontinuing treatment prior to completion of dosing period for reasons other than 
those described in Sections 3.3, 3.4 and 3.7 should complete an Early Termination Visit as soon 


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as possible after SOFNEL is discontinued. The subject should also complete the post-treatment 
assessments as described in Section 6.3 and in Study Procedures Appendix 2. 
3.6. 
Assessments for Premature Discontinuation from Study 
If a subject discontinues SOFNEL dosing (for example, as a result of an adverse event [AE]), 
every attempt should be made to keep the subject in the study and continue to perf01m the 
required study-related post-treatment assessments and procedures (see Section 6.3). If this is not 
possible or acceptable to the subject or investigator, the subject may be withdrawn from the 
study. 
3.7. 
Criteria for Discontinuation of Study Treatment 
When medically feasible, the Medical Monitor must be consulted prior to subject 
discontinuation. 
Study dmg must be discontinued in the following instances: 
• 
Intercunent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree 
• 
Unacceptable toxicity, as defined in the toxicity management section 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 
• 
Subject requests to discontinue for any reason; it is imp01tant to dete1mine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy , or other reason 
• 
Subject non-compliance 
• 
Pregnancy of female subject. Subjects randomized to Group 2 who have female pminers 
who become pregnant must immediately contact the Principal Investigator in order to discuss 
the risks and benefits of continuing treatment with RBV. It is pennissible to stop RBV but 
continue SOFNEL in subjects that have pregnant female pa1tners. 
• 
Discontinuation of the study at the request of Gilead, regulat01y agency or an IRBIIEC 
3.8. 
Biomarker Testing 
3.8.1. 
Biomarker Samples for Optional Future Research 
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3.8.2. 
Biomarker Samples for Optional Pharmacogenomic Research 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 200 chronic HCV Genotype 3 infected subjects will be randomized 1:1 into 
2 treatment groups in this study. Patients will be stratified by treatment experience (treatment 
naïve versus treatment experienced). 
In order to manage the total study enrollment, Gilead Sciences, Inc., at its discretion, may 
suspend screening and/or enrollment at any site or study-wide at any time.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1. Willing and able to provide written informed consent
2. Male or female age ≥ 18 years 
3. Chronic HCV infection (≥ 6 months) as documented by prior medical history or liver biopsy
4. Genotype 3 HCV at Screening as determined by the central laboratory. Any non-definitive 
HCV genotype results will exclude the subject from participation.
5. HCV RNA ≥104 IU/mL at Screening
6. Confirmation of cirrhosis by any of the following methods:
a.
Liver biopsy showing cirrhosis (eg., Metavir score=4 or Ishak score ≥ 5)
b. Fibroscan results > 12.5 kPa
c.
Fibrotest result >0.75 AND an AST platelet ratio index (APRI) >2 during Screening
d. Liver imaging within 6 months of Baseline/Day 1 to exclude hepatocellular carcinoma 
(HCC)
7. Subjects must have a determination of treatment experience (treatmenet naïve v. treatment 
experienced). Treatment naïve is defined as having never been exposed to an approved or 
experimental HCV-specific direct acting antiviral agents or prior treatment of HCV with 
interferon or ribavirin.  All other patients will be considered treatment experienced.
8. If treatment experienced, the subject’s medical records must include details of prior treatment 
regimen(s).  Any prior use of SOF or other nucleotide analogue HCV NS5B inhibitors should 
be documented. Previous use of an NS5A inhibitor is not allowed.


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9. A negative serum pregnancy test is required for female subjects (unless permanently sterile 
or greater than two years post-menopausal).
10. 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.
11. Lactating females must agree to discontinue nursing before the first dose of study drug is 
administered.
12. Subject must be able to comply with the dosing instructions for study drug administration 
and be able to complete the study schedule of assessments.
Subjects with HIV coinfection may be eligible, provided they satisfy these additional inclusion 
criteria:
13. Completed at least 3 months of any prior HIV ARV therapy and maintained HIV RNA 
<50 copies/mL (or <LLOQ if the local laboratory assay’s LLOQ is 50≥ copies/mL) and CD4 
T-cell count > 100 cells/mm3 prior to Screening. Subjects with an isolated or unconfirmed HIV 
RNA >50 copies/mL (or >LLOQ if the local laboratory assay’s LLOQ is 50≥copies/mL) are not 
excluded
14.  No history of HIV-associated opportunistic infections within 6 months of Screening. (see 
Appendix 6)
15.  On a stable, protocol-approved, ARV regimen for ≥ 8 weeks prior to Screening and is 
expected to continue the current ARV regimen through the end of study. HIV ARV agents 
allowed in this study are the following and should be administered per the prescribing 
information in the package insert:
— cobicistat/elvitegravir/emtricitabine/tenofovir disoproxil fumarate (Stribild)
OR
— emtricitabine/tenofovir disoproxil fumarate, emtricitabine/tenofovir alafenamide, or
abacavir/lamivudine plus:
o
ritonavir boosted atazanvir;  or
o
ritonavir boosted  darunavir; or
o
ritonavir boosted lopinavir; or
o
raltegravir; or
o
rilpivirine 


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OR
cobicistat/elvitegravir/emtircitabine/tenofovir alafenamide (Genvoya®)
a) Single tablet regimens containing emtricitabine/tenofovir disoproxil fumarate 
(Truvada®) plus rilpivirine (Eviplera®) or emtricitabine/tenofovir alafenamide plus 
rilpivirine) respectively are permitted.
b) Alternative combinations of the above listed medications may be allowed after 
discussion and approval by the Gilead Medical Monitor. Subjects taking ARV 
regimens not on the above list are excluded from this study.
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 any of the following:
a.
Clinically-significant illness (other than HCV or HIV) or any other major medical 
disorder that may interfere with subject treatment, assessment or compliance with the 
protocol; subjects currently under evaluation for a potentially clinically-significant illness 
(other than HCV/HIV) are also excluded.
b. Gastrointestinal disorder or postoperative condition that could interfere with the 
absorption of the study drug. 
c.
Difficulty with blood collection and/or poor venous access for the purposes of 
phlebotomy.
d. Solid organ or bone marrow transplantation.
e.
Significant pulmonary disease, significant cardiac disease, or porphyria.
f.
Clinically significant hemoglobinopathy (e.g., sickle cell disease, thalassemia).
g. Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of 
their psychiatric illness within the last 5 years. Subjects with psychiatric illness (without 
the prior mentioned conditions) that is well-controlled on a stable treatment regimen for 
at least 12 months prior to enrollment or has not required medication in the last 
12 months may be included. 
h. Malignancy within the 5 years prior to screening, with the exception of specific cancers 
that have been cured by surgical resection (basal cell skin cancer, etc). Subjects under 
evaluation for possible malignancy are not eligible.


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i.
Active, serious infection (other than HIV or HCV) requiring parental antibiotics, 
antivirals or antifungals within 30 days prior to baseline.
2. Child-Pugh-Turcotte (CPT) Score >7 at Screening
3. Current, uncontrolled ascites, variceal hemorrhage, hepatic encephalopathy, hepatorenal 
syndrome, hepatopulmonary syndrome, or other signs of decompensated cirrhosis
4. Screening ECG with clinically significant abnormalities
5. Subjects with the following laboratory parameters at screening: 

HIV-1 RNA >50 copies/mL 

CD4 T-cell count <100 cells/mm3

ALT > 10 the upper limit of normal  (ULN)

AST > 10 ULN

Direct bilirubin > 1.5 ULN
o
For subjects receiving ritonavir boosted atazanavir regimen, a direct bilirubin > 1.5 x 
ULN will be allowed if < 25% of the total bilirubin

Platelets < 50,000/L

HbA1c > 8.5%

Creatinine clearance (CLcr) < 60 mL /min as calculated by the Cockcroft-Gault equation 
{Cockcroft et al 1976}

Hemoglobin < 10 g/dL

Albumin < 3 g/dL

INR > 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR

HIV-2 positive test

Presence of HBV surface antigen
6. Prior exposure to VEL or any HCV NS5A inhibitor.
7. Pregnant or nursing female or male with pregnant female partner. 


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8. Females who may wish to become pregnant and/or plan to undergo egg harvesting during the 
course of the study and up to 6 months of the last dose of study drug 
9. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alfa-1 antitrypsin deficiency, cholangitis).
10. Active infection with hepatitis B virus (HBV).
11. Infection with HIV 2
12. Clinically-relevant alcohol or drug abuse within 12 months of screening, as determined by 
the investigator. A positive drug screen will exclude subjects unless it can be explained by a 
prescribed medication; the diagnosis and prescription must be approved by the investigator.
13. Use of any prohibited concomitant medications as described in Section 5.5
14. Chronic use of systemically administered immunosuppressive agents (e.g., prednisone 
equivalent > 10 mg/day).
15. Known hypersensitivity to VEL, SOF (and metabolites), or RBV.
16. The presence of contraindications to RBV.
17. Participation in a clinical study with an investigational drug or biologic within 3 months prior 
to Baseline/Day 1.
18. Treatment for HCV infection with experimental or approved regimens within 3 months of 
Baseline/Day 1.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, and Study Drug Supply
An Interactive Web Response System (IWRS) will be employed to manage subject 
randomization, treatment assignment, and study drug re-supply. Randomization will be stratified 
by prior treatment experience. Treatment naïve is defined as having never been exposed to an 
approved or experimental HCV-specific direct acting antiviral agents or prior treatment of HCV 
with interferon or ribavirin. All other patients will be considered treatment experienced. If 
treatment experienced, the subject’s medical records must include details of prior treatment 
regimen (See Section 6.2.1).
5.2.
Description and Handling of SOF/VEL FDC
5.2.1.
Formulation
The SOF/VEL (400/100 mg) tablets are pink, diamond-shaped, film-coated tablets, debossed 
with “GSI” on one side and “7916” on the other side. In addition to the active ingredients, the 
SOF/VEL tablets contain copovidone, microcrystalline cellulose, croscarmellose sodium, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron 
oxide red.
5.2.2.
Packaging and Labeling
SOF/VEL (400/100 mg) tablets are packaged in white, high density polyethylene (HDPE) 
bottles. Each bottle contains 28 tablets and polyester packing material. Each bottle is enclosed 
with a white, continuous thread, child-resistant screw cap with an induction-sealed, 
aluminum-faced liner.
SOF/VEL bottles to be distributed to centers in participating countries shall be labeled to meet 
all applicable requirements of the United States Food and Drug Administration (FDA), EU 
Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal Products), 
and/or other local regulations.
5.2.3.
Storage and Handling
SOF/VEL tablets should be stored at controlled room temperature until required for 
administration. Controlled room temperature is defined as 25C (77 F); excursions are permitted 
between 15C and 30C (59F to 86F).
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 


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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 tablets.
Sufficient quantities of SOF/VEL to complete the entire study will be shipped to the investigator 
or qualified designee from the Gilead Supply Management Team (or its designee).
5.3.
Dosage and Administration of SOF/VEL FDC
SOF/VEL tablet is to be administered once daily with or without food. Each subject must be 
given instructions to maintain approximately the same daily dosing interval between study drug 
doses.
For missed dose(s) of study medication, subjects should be instructed to take the missed dose of 
study medication as soon as possible during the same day.  Subjects should be cautioned never to 
double the next dose with a missed dose of study drug under any circumstances.
5.4.
Description and Handling of Ribavirin (RBV)
5.4.1.
Formulation
RBV tablets, 200 mg, are blue, capsule-shaped, film-coated tablets debossed with “3RP” on one 
side and “200” on the other side. In addition to the active ingredient, RBV tablets contain the 
following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose 
sodium, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, 
FD&C blue #2. 
The RBV tablets being supplied by Gilead Sciences are a US marketed formulation of RBV.
5.4.2.
Packaging and Labeling
The RBV tablets are packaged in white, HDPE bottles. Each bottle contains 168 tablets and 
rayon coil packing material and is enclosed with a white, continuous thread, child-resistant screw 
cap with an induction-sealed, aluminum-faced liner. 
All RBV bottles to be distributed to centers in the participating countries and shall be labeled to 
meet all applicable requirements of the US Food and Drug Administration (FDA), EU Guideline 
to Good Manufacturing Practices- Annex 13 (Investigational Medicinal Products), and/or other 
local regulations as applicable.
RBV tablets (200 mg) will be supplied by Gilead Sciences for all Group 2 subjects.
5.4.3.
Storage and Handling
RBV tablets should be stored at 25 °C (77 °F); excursions are permitted between 15 and 30 °C 
(59 and 86 °F).


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All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling RBV.
5.4.4.
Dosage and Administration 
Subjects in Group 1 will take SOF/VEL once daily with or without food.  
Subjects in Group 2 will take SOF/VEL once daily and RBV 1000–1200 mg taken in a divided 
daily dose (1000 mg for subjects weighing < 75 kg and 1200 mg for subjects weighing ≥75 kg). 
Subjects who are to receive total daily doses of 1000 mg will take 3 × 200 mg tablets in the 
morning and 2 × 200 mg tablets in the evening (or 2 x 200 mg tablets in the morning and 
3 x 200 mg tablets in the evening). For those who are to receive 1200 mg of RBV, subjects 
should take 3 × 200 mg tablets twice daily. RBV should be taken with food. 
Body Weight kg (lbs.)
RBV Daily Dose
RBV Number of tablets
< 75 kg
1000mg
3 X 200mg tablets A.M.
2 X 200mg tablets P.M.
≥75 kg
1200mg
3 X 200mg tablets A.M.
3 X 200mg tablets P.M
All subjects should be instructed to maintain approximately the same daily dosing interval 
between study drug doses. To aid compliance, it is suggested that SOF/VEL is administered with 
either the morning or evening dose of RBV with food.
For missed dose(s) of SOF/VEL, subjects should be instructed to take the missed dose of study 
medication as soon as possible during the same day.  Subjects should be cautioned never to 
double the next dose of SOF/VEL with a missed dose under any circumstances.  
For missed dose(s) of RBV, subjects should be instructed to take the missed dose(s) of study 
drug as soon as possible, unless more than 6 hours has elapsed since the scheduled time of the 
missed dose. In this case, the subject should be instructed to wait and take the next dose at the 
regularly scheduled time. No more than the daily dose of RBV (1000 mg or 1200 mg) should be 
taken on any calendar day. Subjects should be cautioned never to double the next dose with a 
missed dose of study drug under any circumstances. 
No food restrictions apply to SOF/VEL. However as RBV must be taken with food hence it is 
suggested that when SOF/VEL is taken with RBV, both drugs should be taken together and with 
food for optimal adherence.


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Dose modifications due to anemia or other reasons, may be made at the discretion of the 
Investigator.
5.5.
Prior and Concomitant Medications
Concomitant medications taken within 30 days of Screening, up to and including the date of the 
visit four weeks after discontinuation of study drug, need to be recorded in the source documents 
and eCRFs. All concomitant medications should be recorded in the source documents (including 
all blood products).
The following medications are prohibited from 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)

Chronic 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 (inducers of drug 
transporters i.e. P-gp) with study drug may result in pharmacokinetic interactions resulting in 
increases or decreases in exposure of study drug or these medication. The use of such agents is 
prohibited from 21 days prior to Baseline/Day 1 through the end of study drug dosing. The use of 
amiodarone is prohibited from 60 days prior to Baseline/Day 1 through the end of study drug 
dosing.
Examples of representative medications which are prohibited or are to be used with caution are 
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Table 5-1.
List of Disallowed /Use with Caution Medications
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Anticonvulsantsb
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Antimycobacterialsb
Rifabutin, Rifapentine, Rifampin
Cardiac Medicationsc
Amiodaronef
Diltiazem, Verapamil, Dronedarone, 
Quinidine, Ranolazine, Bosentan, 
Olmesartan, Valsartan, Digoxind
Herbal/Natural 
Supplementsb
St. John’s Wort, Echinacea. Milk thistle 
(ie, silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorse
Rosuvastatin (≤10 mg/day),
Other
Modafinil b, Sulfasalazinec, Methotrexatec
a
Proton pump inhibitor (PPI dose comparable with omeprazole (20 mg) can be administered with SOF/VEL when SOF/VEL
is administered with food.  H2-receptor anagonist must not exceed a dose of 40 mg famotidine or equivalent and can be 
taken simultaneously with SOF/VEL and/or staggered by 12 hours.  Antacids that directly neutralize stomach acid (i.e. 
Tums, Maalox) may not be taken within 4 hours (before or after ) SOF/GS-5816 administration.
b
May result in a decrease in the concentration of study drugs.
c
May result in an increase in the concentration of study drugs and/or concomitant medications
d
Monitor for signs and sympotoms of digoxin toxicity.
e
Use with SOF/VEL may result in an increase in the concentration of HMG-CoA Reductase Inhibitors. Monitor for signs and 
symptoms of muscle weakness or myopathy, including rhabdomyolysis
f
May result in symptomatic bradycardia.  Mechanism is not currently known.  The use of amiodarone is prohibited from 
60 days prior to Baseline/Day 1 through the end of treatment.
Medications for disease conditions excluded from the protocol (eg, active cancer, 
transplantation) are not listed under this Concomitant Medication section and are disallowed in 
the study.
Subjects may not take any approved HCV medications during their participation in the study 
period.
Should subjects have a need to initiate treatment with any excluded concomitant medication, the 
Medical Monitor must be consulted prior to initiation of the new medication. In instances where 
an excluded medication is initiated prior to discussion with the Sponsor, the Investigator must 
notify Gilead as soon as he/she is aware of the use of the excluded medication.
5.6.
Acceptable HIV Antiretroviral Regimens
Acceptable HIV antiretroviral medications allowed in this study include the following and 
should be administered per the prescribing information in the package insert:


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
cobicistat/elvitegravir/emtricitabine/tenofovir disoproxil fumarate (Stribild)
OR

emtricitabine/tenofovir disoproxil fumarate, emtricitabine/tenofovir alafenamide, or
abacavir/lamivudine plus:
— ritonavir boosted atazanvir; or
— ritonavir boosted darunavir; or
— ritonavir boosted lopinavir; or
— raltegravir; or 
— rilpivirine
OR
— cobicistat/elvitegravir/emtircitabine/tenofovir alafenamide (Genvoya®)
Single tablet regimens containing emtricitabine/tenofovir disoproxil fumarate (Truvada®) plus 
rilpivirine (Eviplera®) or emtricitabine/tenofovir alafenamide plus rilpivirine) respectively are 
permitted. 
Alternative combinations of the above listed medications may be allowed on a case by case basis 
with approval from the Gilead Medical Monitor. ARV regimens not on the above list are 
excluded from this study at enrollment. ARVs not on the approved list may be allowed in the 
cases of HIV virologic breakthrough during the study period if approved by the Medical 
Monitor. HIV medications will not be supplied by Gilead.
5.7.
Study Drug Adherence and Drug Accountability
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug (SOF/VEL FDC) ± RBV. This includes acknowledgement of receipt of each shipment of 
study drugs (quantity and condition). All used and unused study drugs dispensed to subjects must 
be returned to the site.
SOF/VEL FDC ± RBV accountability records will be provided to each study site:

Record the date received and quantity of study drug bottles

Record the date, subject number, subject initials, the study drug bottle number dispensed

Record the date, quantity of used and unused study drug returned, along with the initials of 
the person recording the information.


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
At the Baseline/Day 1 visit, subjects will be dispensed 2 bottles of SOF/VEL so that they 
have sufficient tablets to cover the 3 day time window around the Week 4 and Week 8 visit. 
Subjects must be instructed to bring back the study drug in the original container at every 
post Day 1 study visit through the end of study treatment. The extra bottle dispensed at 
Baseline/Day 1 visit must be brought back to each on-treatment visit for accountability 
purposes and will be re-dispensed to the subject except at Week 12 or EOT visit.

Subjects will be dispensed bottles of RBV based on their weight-based dose of RBV at the 
Baseline/Day 1 visit, as applicable.  Subjects should bring back the study drug in the original 
container at every post Day 1 study visit through the end of study treatment.  Any extra 
bottles dispensed should be brought back to each on-treatment visit for accountability 
purposes and will be re-dispensed to the subject except at Week 12 or EOT visit.
5.8.
Study Drug Return or Disposal
Refer to Section 10.1.7 for information on return and disposal of study drugs.


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6. 
STUDY PROCEDURES 
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The study procedures to be conducted for each subject emolled in the study are presented in 
tabula!' fonn in Appendix 2 and described in the text that follows. All eligible subjects will 
complete Screening, Baseline/Day 1, On-Treatment visits at the end of Weeks 2, 4, 8 and 12 and 
post-treatment Visits at Weeks 4 and 12, as appropriate. Subjects with HCV RNA ~LLOQ at 
post-treatment Week 4 visit will complete a confumat01y visit within 2 weeks of the Week 4 
post-treatment visit. Subjects with HCV RNA ~LLOQ at post-treatment week 12 visit will be 
asked to return for confumat01y visit within 2 weeks of the Week 12 post-treatment visit. Viral 
breakthrough or relapse must be confi1med. 
lnf01mation on the specific laborat01y parameters to be measured and clinical assessment to be 
perf01med are provided in Section 6.5. 
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 
This is an open-label study. An Interactive Web Response System (IWRS) will be employed to 
manage subject enrollment, treatment assigmnent (Group 1 or Group 2), and study dmg 
dispensing and re-supply. Randomization will be stratified by prior treatment experience 
(treatment naive/treatment -experienced). 
6.2. 
Screening Assessments 
6.2.1. 
Screening Visit (Day 28 to Day 0) 
Subjects will be screened within 28 days of the Baseline/Day 1 visit. The screening window can 
be extended to 42 days for subjects requiring liver biopsy, additional HCV genotype testing or 
for extenuating circumstances. 
The following will be perf01med and documented at screening: 
• 
Obtain written inf01med consent 
PD 
• 
Determine inclusion and exclusion eligibility 
• 
Appropriate diagnostic imaging (CT or Ultrasound) must be perf01med within 6 months of 
Baseline/Day 1 to exclude the presence of hepatocellular carcinoma 
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
Obtain medical history, including
Hepatitis C history
Liver biopsy results (if applicable)
Determine cirrhosis status as defined in Section 2
Exclusion of hepatocellular carcinoma (HCC). Appropriate diagnostic imaging (CT or 
Ultrasound) should be performed or confirmed to have been performed within 6 months
of Screening to exclude the presence HCC.
Determine treatment experience status as defined in Section 4.2
■
If treatment experience, record the duration(s) and type(s) of the prior treatment 
administered.
■
If treatment experienced, record whether or not any past treatment regimens 
contained SOF or other nucleotide analogue HCV NS5B inhibitors

Complete physical examination including, vital signs (resting blood pressure, pulse, 
respiratory rate and temperature), body weight, and height

Obtain details of concomitant medications 

Perform 12-lead ECG

Calculate CPT score

Obtain blood samples for tests as listed in Section 6.7.1:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Determination of HCV viral genotype and subtype
— HCV antibody, HIV, and HBV antibody
— HbA1c
— IL28B


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— Serum β-hCG pregnancy test for females of childbearing potential only
— HIV-1 RNA will only be collected and analyzed for co-infected subjects

Obtain urine sample for:
— Urinalysis
— Urine drug screen

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form.

Retests of Screening labs are permitted only if there is reason to believe the retest value will 
be within accepted parameters, for example, if the initial exclusionary value was either due to 
a sample processing error or due to an extenuating circumstance such as intercurrent illness.

Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to 
the clinic for the Baseline/Day 1 Visit assessments and enrollment into the study
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events case report form (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.
6.3.
Treatment Assessments
6.3.1.
Baseline/Day 1 Visit
The following baseline tests and procedures must be completed prior to enrollment and
dosing/dispensation of study drug:

Confirm eligibility (Reference Sections 4.2 & 4.3)

Perform complete physical examination, including body weight

Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature)

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counseling

Obtain blood samples for:
— Hematology
— Chemistry


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Coagulation tests 
HCVRNA 
Viral sequencing 
HIV-1 RNA will only be collected and analyzed for co-infected subjects 
Final 
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• 
Obtain blood sample for Pharmacogenomics testing (for subjects who have consented) 
• 
PPD 
• 
Obtain urine samples for the following procedures: 
Urinalysis 
Pregnancy test for females of child bearing potential only 
• 
Study Drug Administration 
Dispense study drug as directed by the IWRS 
Instruct the subject on the packaging, storage and administration of the study drugs 
Observe the subject taking the first dose of study drug and record the time of first dose 
and whether it was taken with or without food. 
6.3.2. 
Week 2 (±3 days) 
The following procedures/assessments are to be completed at the end of Week 2. 
• 
Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature) 
• 
Assessment of AEs and concomitant medications 
• 
Obtain blood samples for: 
Hematology 
Chemistry 
HCVRNA 
Viral sequencing 
PK sample 
HIV-1 RNA will only be collected and analyzed for co-infected subjects 
• 
Assess adherence with study drug dosing regimen including pill count 
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6.3.3.
Weeks 4 and 8 (3 days)
The following procedures/assessments are to be completed at the end of Weeks 4 and 8:

Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature)

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counseling

Obtain blood samples for:
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing
— PK sample
— HIV-1 RNA will only be collected and analyzed for co-infected subjects

Obtain urine sample for pregnancy test (for females of child bearing potential only)

Assess adherence with study drug dosing regimen including pill count

Dispense study drugs as directed by the IWRS
6.3.4.
Week 12 or Early Termination (3 days)
The following procedures/assessments are to be completed at the end of Week 12 or ET:

Perform complete physical examination, including weight

Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature)

Calculate CPT score

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Obtain blood samples for:
— Hematology
— Chemistry


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Coagulation tests 
HCVRNA 
Viral sequencing 
PK sample 
HIV-1 RNA will only be collected and analyzed for co-infected subjects 
• 
I PD 
• 
Obtain urine samples for 
Urinalysis 
Pregnancy test for females of child bearing potential only 
Final 
Amendment 1 
• 
Assess adherence with study drug dosing regimen including pill count. Study drug should be 
returned at this visit 
6.3.5. 
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. At all unscheduled visits initiated for the purpose 
of confirming HCV or HIV virologic failure, a sample for HCV RNA Sequencing I Phenotyping, 
or a sample for HIV RNA Genotyping/Phenotyping, respectively, must be collected. 
The Sponsor (e.g. Medical Monitor and Clinical Trial Manager) and CRO must be informed, as 
soon as possible, when a subject comes offtreatment due to an AE. 
6.4. 
Posttreatment Assessments 
The post-treatment Week 4 and 12 visits should be timed from the date oflast administration of 
study drug. All subjects must complete the post-treatment Week 4 visit. All subjects who achieve 
SVR4 will attend the Week 12 visit. The end of study will occur at the post-treatment Week 4 
visit in the case of subjects who do not achieve SVR4, and the post-treatment Week 12 visit in 
the case of patients who do achieve SVR4. 
6.4.1. 
Post-treatment Week 4 (±5 days) 
The following procedures/assessments are to be completed for all subjects, 4 weeks after taking 
the last dose of study drug: 
• 
Perform complete physical examination 
• 
Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature) 
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
Assessment of AEs and concomitant medications

Pregnancy Prevention Counseling

Obtain blood samples for:
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing
— HIV-1 RNA will only be collected and analyzed for co-infected subjects

Obtain urine sample for pregnancy test (for females of child bearing potential only)
6.4.2.
Post-treatment Week 12 (± 5 days)
The following procedures/assessments are to be completed for all subjects who achieve SVR4, 
12 weeks after taking the last dose of study drug:

Perform complete physical examination

Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature)

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Obtain blood samples for:
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing
— HIV-1 RNA will only be collected and analyzed for co-infected subjects

Obtain urine sample for pregnancy test (for females of child bearing potential only)


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6.5.
Confirmatory Visit
Subjects with HCV RNA ≥LLOQ at either post-treatment Week 4 or 12 visits will be asked to 
return for confirmatory visit within 2 weeks. A sample for viral HCV RNA 
sequencing/phenotyping will be collected.
6.6.
End of Study
Discontinuation from study drug dosing and discontinuation from the overall study, including the 
Post-treatment period, will be collected as two separate events.
The end of study will occur at the post-treatment Week 4 visit in the case of subjects who do not 
achieve SVR4, and the post-treatment Week 12 visit in the case of patients who do achieve 
SVR4.
6.7.
Procedures and Specifications
6.7.1.
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: international normalized ratio (INR), Prothrombin time (PT), Activated partial 
thromboplastin time (APTT).
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Creatine Kinase (CK) , Creatinine, Total Bilirubin (reflex to 
Direct Bilirubin), Glucose, Lipase, Potassium, Sodium, Uric Acid, Fibrotest®/APRI calculation 
and Direct Bilirubin at Screening only.
Virological Tests: Serologies for HCV and HBV, Serology and/or antigen testing for HIV, 
including reflex testing, as necessary. HCV RNA will be measured using the COBAS®
AmpliPrep®/COBAS® TaqMan® HCV Quantitative Test, v2. HCV genotype and subtype will be 
determined using the Siemens VERSANT® HCV genotype INNO-LiPA 2.0 Assay. HIV RNA 
will be measured using the AmpliPrep/COBAS® TaqMan® HIV-1 Test, v2.0. If HIV-1 virologic 
rebound is confirmed, HIV-1 genotype/phenotype will be determined using the PhenoSense
Integrase HIV, GeneSeqIntegrase HIV, PhenoSenseHIV, GenoSure MG, GeneSeqHIV, 
and PhenoSense GT.  Gilead reserves the right to use alternate assays for HCV RNA, HIV 
RNA, HCV genotype, and HIV-1 genotype/phenotype should the above assays become 
unavailable or the results are indefinitive.
IL28B genotype will be determined by polymerase chain reaction (PCR) amplification of the 
SNP, rs12979860, with sequence specific forward and reverse primers and allele specific 
fluorescently labeled TaqMan® MGB probes. Gilead reserves the rights to use an alternate assay 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum β-hCG or Urine β-hCG (if positive, requires immediate confirmation 
with Serum β-hCG)


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Additional Tests: Urine Drug screen (for Amphetamines, Cocaine, Methadone, Opiates) and 
Hemoglobin A1c (HbA1c), CD4 T-lymphocyte Absolute Count and %
Urinalysis: Appearance, Blood, Color, Glucose, Leukocyte esterase, pH, Protein, Urobilinogen. 
Reflex to microscopic urinalysis if dipstick result is abnormal. At each visit this is tested, it will 
be recorded whether female subjects of childbearing potential are currently menstruating. 
6.7.2.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history, including prior HCV treatment history 
if available will be collected on all subjects during screening.
6.7.3.
Complete Physical Examination
A complete physical examination must include source documentation of general appearance, and 
the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, mouth and tongue; 
chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, nails; 
musculoskeletal; neurological. 
6.7.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
6.7.5.
Creatinine Clearance
Creatinine clearance will be calculated at all visits where blood is drawn.  Creatinine clearance is 
calculated by the Cockcroft-Gault equation {Cockcroft et al 1976} using actual body weight 
(BW).
Male:
CLcr (mL/min) = [140 - age (years)] BW(kg)
72 Scr
Female:
CLcr (mL/min) = [140 - age (years)] BW(kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)


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6.7.6. 
12-Lead ECGs 
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Subjects will be required to rest in a supine position for~ 5 minutes prior to making a recording. 
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abnormalities. On treatment ECGs should be compared to the subject's 
baseline as part of routine safety monitoring. 
6.7.7. 
HCV Viral RNA Sequencing I Phenotyping Sample (Archive) 
Plasma samples will be collected at Baseline/Day 1 and each subsequent visit for HCV viral 
sequence analysis. At any unscheduled visit initiated for the purpose of confirming HCV 
virologic breakthrough, a HCV viral sequence/phenotype plasma sample must also be collected. 
Unused samples may be archived. 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. 
6.7.8. 
HIV Viral RNA Genotyping/Phenotyping Sample (Archive) 
Plasma samples will be collected at Baseline/Day 1 and each subsequent visit for HIV viral 
sequence analysis. At any unscheduled visit initiated for the purpose of confirming HIV 
virologic failure, an HIV genotype/phenotype plasma sample must also be collected. Unused 
samples may be archived. 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. 
6.7.9. 
Single Phannacokinetic (PK) Sample 
Single PK blood samples will be collected for all subjects at each on-treatment visit and archived 
for PK analysis of SOF (and metabolites), and VEL. 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. 
6.7.10. 
Phannacogenomics Testing 
An additional and distinct informed consent document will be provided to allow the Sponsor to 
obtain and test a subject's blood sample taken on Baseline/Day 1 for pharmacogenomics 
discovery research. If not obtained at Baseline/Day 1, the sam2le may be drawn at any time 
during the study. PD 
L-----------------------------------------------------------~ 
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6.7.11. 
Sample Storage 
PD 
6.7.12. 
Pregnancy Testing 
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All females of childbearing potential will have urine pregnancy testing evety 4 weeks during the 
dosing period and 30 days after last dose of SOFNEL, 6 months after the last dose ofRBV, or 
last visit of the study, whichever comes last. 
If a positive urine pregnancy test is reported, an immediate confinnation with Semm ~-hCG is 
required. 
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7.
TOXICITY MANAGEMENT
7.1.
Dose Modification Due to Toxicity
7.2.
Group 1:  Subjects administered SOF/VEL
There is no option for dose reduction or modification of SOF/VEL
7.3.
Group 2:  Subjects administered SOF/VEL+ RBV
Dose modification for subjects administered SOF/VEL+RBV should be performed according to 
the prescribing information.
Dose reduction of SOF/VEL is not permitted.
Table 7-1.
Ribavirin Dose Modification Guideline for Coadministration with 
SOVALDI
Laboratory Values
Reduce Ribavirin Dose to 
600 mg/daya If:
Discontinue Ribavirin If:b
Hemoglobin in patients with no 
cardiac disease
<10 g/dL
<8.5 g/dL
Hemoglobin in patients with history 
of stable cardiac disease
≥2 g/dL decrease in hemoglobin 
during any 4 week treatment period 
<12 g/dL despite 4 weeks at reduced 
dose
a
The daily dose of ribavirin is administered orally in two divided doses with food. 
b
Once ribavirin has been withheld due to either a laboratory abnormality or clinical manifestation, an attempt may be made to 
restart ribavirin at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that 
ribavirin be increased to the original assigned dose (1000 mg to 1200 mg daily).
If RBV is permanently discontinued, SOF should also be discontinued.
7.3.1.
Subject Stopping Rules
See Section 3.4 for individual subject stopping rules.. 
7.4.
Subject Stopping Rules
See Section 3.4 for individual subject stopping rules.
7.5.
Special Situations Reports
7.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  


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Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  


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8.
ADVERSE EVENTS MANAGEMENT
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
8.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.5.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
8.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity


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
A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is 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.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to SOF/VEL interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 8.1.1 and 8.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 3.4.
8.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the 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 study drug.


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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)
8.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale 
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs associated 
with laboratory abnormalities, the event should be graded on the basis of the clinical severity in 
the context of the underlying conditions; this may or may not be in agreement with the grading 
of the laboratory abnormality.
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead 
Requirements for collection prior to study drug initiation:

After informed consent, but prior to initiation of study medication, the following types of 
events should be reported on the case report form (eCRF): all SAEs and adverse events 
related to protocol-mandated procedures.
Adverse Events

Following initiation of study medication, all AEs, regardless of cause or relationship, 
pregnancy and other special situation reports, until 30 days after last administration of study 
drug must be collected/ reported 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 post-treatment follow-up period, must be reported to 
the eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This 
also includes any SAEs resulting from protocol-associated procedures performed after 
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
Any SAEs and deaths that occur after the post-treatment follow-up visit but within 30 days of 
the last dose of study drug, regardless of causality, should also be reported.

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 report the event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:
Gilead DSPH
Email: Safety_FC@gilead.com
Fax:
+1 650-522-5477

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.
8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 


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worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
8.5.
Toxicity Management 
8.5.1.
Instructions for Reporting Special Situations
8.5.1.1.
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 post study drug follow-up 
period, to the Gilead DSPH using the pregnancy report form within 24 hours of becoming aware 
of the pregnancy.
Refer to Section 8.3 and 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 
Sections 8.1.1 and 8.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH. Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477


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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 DSPH using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead DSPH, fax number 
+1 650 522-5477 or email Safety_FC@gilead.com.
Clinical staff should also report any pregnancies to the Ribavirin Pregnancy Registry at 
1-800-593-2214 (see also https://www.ribairinpregnancyregistry.com) Refer to Appendix 5 for 
Pregnancy Precautions, Definition for Female of Childbearing Potential, and Contraceptive 
Requirements.
8.5.1.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study drug 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 8.3 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.


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Analysis Objectives and Endpoints 
9.1.1. 
Analysis Objectives 
The prima1y objectives of this study are as follows: 
Final 
Amendment 1 
• 
To evaluate the efficacy of study treatment with SOFNEL FDC and SOFNEL FDC and 
Ribavirin (RBV) for 12 weeks as measmed by the proportion of subjects with sustained 
viralogic response 12 weeks after cessation of treatment regimen (SVR12) 
• 
To evaluate the safety and tolerability of each treatment regimen 
The secondmy objectives of this study are: 
• 
To determine the prop01tion of subjects who attain SVR at 4 weeks after cessation of each 
treatment regimen (SVR4) 
• 
To evaluate the kinetics of circulating HCV RNA dming treatment and after cessation of 
each treatment regimen 
• 
To evaluate the emergence of viral resistance to SOP and VEL dming treatment and after 
cessation of treatment 
The explorat01y objective of this study is: 
• 
PD 
9.1.2. 
Primary Endpoints 
The prima1y efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after cessation of study 
treatment regimen) in the Full Analysis Set (F AS). 
The prima1y safety endpoint is any AE that led to pe1manent discontinuation of study dmg. 
9.1.3. 
Secondary Endpoints 
The secondmy efficacy endpoints include the prop01tion of subjects who attain sustained 
virologic response at 4 weeks after cessation of the study treatment regimen (SVR4); the 
prop01tion of subjects who have HCV RNA < LLOQ by visit while on study treatment; absolute 
and change from baseline/Day 1 in HCV RNA through Week 12; and the prop01tion of subjects 
with virologic failme. 
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9.1.4.
Other Endpoints of Interest
Additional efficacy evaluations may include ALT normalization.
9.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using SASsoftware (SAS Institute, Cary, North Carolina, USA).
The study drug in this study is SOF/VEL or SOF/VEL +RBV. Last dose of study drug refers to 
the last dose of any of the study drugs in a treatment group and will be used in the definition of 
treatment-emergent AEs and laboratory abnormalities as well as the efficacy endpoints of SVR 
at various post-treatment time points.
9.2.1.
Analysis Sets
9.2.1.1.
All Randomized 
All Randomized Analysis Set includes all subjects who were randomized in the study.
9.2.1.2.
Efficacy
The primary analysis set for efficacy analysis will be the FAS which include all randomized
subjects who received at least 1 dose of study drug. 
9.2.1.3.
Safety
The primary analysis set for safety analyses will be the Safety Analysis Set which includes all 
subjects who took at least 1 dose of study drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose of the
study drug through the last dose date of the study drug plus 30 days.
9.2.1.4.
Pharmacokinetics
The Pharmacokinetic (PK) Analysis Set includes all subjects who took at least 1 dose of study 
drug and have at least 1 nonmissing postdose concentration value for the corresponding analyte 
in plasma.  The analytes of interest may include SOF (and its metabolites GS-566500 and 
GS-331007), VEL, and RBV if applicable.  The PK analysis set will be used for analyses of 
general PK.
9.3.
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. 


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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).
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject took at least 1 dose of study medication, the subject will be included in a 
summary of AEs according to the treatment received; otherwise, if the subject is not dosed 
then they will be excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the pre-dose value and the change from pre-dose values.
Values for missing safety laboratory data will not be imputed; however, a missing Baseline/Day 
1 result will be replaced with a screening result, if available. If no pretreatment laboratory value 
is available, the Baseline/Day 1 value will be assumed to be normal (i.e., no grade [Grade 0]) for 
the summary of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing Baseline/Day 1 result
will be replaced with a screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for 
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).
HIV RNA in this study will be measured using the AmpliPrep/COBAS® TaqMan® HIV-1 Test, 
v2.0. The LLOQ of the assay is 20 cp/mL.
When the calculated HIV RNA value is within the linear range of the assay, then the result will 
be report as the “<< numeric value>> cp/mL”. When HIV RNA is not detected, the result is 


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rep01ied as "No HIV-1 RNA detected". When the calculated HIV RNA cp/mL is less than 
LLOQ of the assay, the result is repotied as "<20 cp/mL HIV-1 RNA Detected". 
For numerical HIV RNA data analysis, values retumed as "<20 cp/mL HIV-1 RNA Detected" or 
"No HIV-1 RNA detected" will be set to the LLOQ minus 1 (ie, 19 HIV RNA cp/mL). If 
methods based on the assumption that the data are nonnally distributed are not adequate, 
analyses may be perf01med on transf01med data (eg, log10 scale) or nonpal'ametric analysis 
methods may be used, as appropriate. 
9.4. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be summarized using standard descriptive 
methods 
Demographic summaries will include age, sex, self-identified race and ethnicity. 
Baseline characteristic data will include body mass index, absence or presence of cinhosis, 
baseline HCV RNA level (log10 IU/mL), HCV genotype, IL28B genotype, HIV co-infection and 
additional endpoints as necessaty. 
9.5. 
Efficacy Analysis 
9.5.1. 
Primary Analysis 
The primaty efficacy endpoint for this study will be the propotiion of subjects with SVR12 as 
defined as HCV RNA < LLOQ 12 weeks after cessation of study treatment regimen in the F AS 
population. Point estimate and 95% confidence interval (using the Clopper-Peru·son method) of 
SVR12 will be computed for each treatment group. 
9.5.2. 
Secondary Analyses 
The propotiion of subjects with HCV RNA below LLOQ over time (including SVR endpoints) 
will be presented in tabular and graphical fotm. 
Descriptive summru·ies and listings will be provided for additional efficacy evaluations including 
serum HCV RNA actual values and change from baseline through Week 12, the proportion of 
subjects who experience virologic failure and AL T nonnalization. 
PD 
Details on efficacy analyses will be described in the statistical analysis plan. 
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9.6.
Safety Analysis
Safety will be evaluated by assessment of clinical laboratory tests (including HIV-1 RNA and 
CD4 T-cell count for HCV/HIV co-infection subjects), physical examinations, vital signs 
measurements and AEs will be documented at various time points during the study.
All safety data collected on or after the first dose of study drug administration up to 30 days after 
the last dose of study drugs will be summarized.
9.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug data will be generated from the study drug 
administration page of the CRF. Exposure data will be summarized by treatment group. 
9.6.2.
Adverse Events
Clinical and laboratory adverse events (AEs) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
AE will be defined as any AE with an onset date on or after the study drugs start date and no 
later than 30 days after permanent discontinuation of the study drugs; or any AE leading to 
premature discontinuation of the study drugs.
Summaries (number and percentage of subjects) of treatment-emergent AEs (by SOC and PT) 
will be provided for:

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 any study drug

All AEs leading to premature discontinuation from SOF/VEL
All AEs collected during the study will be presented in data listings.


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9.6.3.
Laboratory Evaluations
Selected laboratory data (including HIV RNA and CD4 T-cell count for HCV/HIV co-infection 
subjects) will be summarized (n, mean, SD, median, Q1, Q3, minimum, and maximum) by 
treatment group and by study visit along with corresponding change from Baseline/Day 1.
Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme in 
Appendix 3 of this protocol. Incidence of treatment-emergent laboratory abnormalities, defined 
as values that increase at least one toxicity grade from Baseline/Day 1 at any time post baseline 
up to and including the date of last dose of study drug plus 30 days will be summarized by 
treatment group. 
Values for missing safety laboratory data will not be imputed; however, a missing Day 1 result 
will be replaced with a screening result, if available. If no pre-treatment laboratory value is 
available, the Baseline/Day 1 value will be assumed to be normal (i.e., no grade [Grade 0]) for 
the summary of graded laboratory abnormalities. If Baseline/Day 1 data are missing, then any 
post-baseline graded abnormality (ie, at least Grade 1) will be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
9.6.4.
Other Safety Evaluations
Individual data and change from baseline for vital signs measurements will be listed by subject 
and summarized by treatment group and overall by descriptive statistical summaries (n, mean, 
SD, median, Q1, Q3, minimum, and maximum). 
9.6.5.
HIV RNA Analysis
Subjects with HCV/HIV co-infection RNA < 50 copies/mL at Baseline/Day 1 will be 
summarized by visit to assess the proportion of subjects that maintain HIV-1 RNA 
< 50 copies/mL while on HCV treatment.
Details on HIV-1 RNA related safety analyses will be described in the statistical analysis plan.
9.7.
Pharmacokinetic Analysis
Concentrations of SOF (and its metabolites GS-566500 and GS-331007) and VEL (GS-5816) in 
plasma may be determined using validated bioanalytical assays and listed.
9.8.
Sample Size
Approximately 200 cirrhotic subjects with chronic genotype 3 HCV infection will be enrolled in 
this study. This sample size is based on the number of subjects who meet the eligibility criteria 
who could practically be enrolled.  With a sample size of 100 for each treatment, a two-sided 
95% exact confidence interval will extend at most 21% in length for each treatment.


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, South Africa, 
Washington DC, Seoul and Brazil), 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 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.
10.1.2.
Institutional Review Board (IRB)/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.
10.1.3.
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 
and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IEC or local 


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requirements. The consent form will inform subjects about pharmacogenomic testing and sample 
retention, and their right to receive clinically relevant pharmacogenomic analysis results.
10.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IEC or laboratory. Laboratory specimens 
must be labeled in such a way as to protect subject identity while allowing the results to be 
recorded to the proper subject. Refer to specific laboratory instructions 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 information received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRF, the study drugs, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
10.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IEC
and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);


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
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 study drug, 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.
Biological samples at the conclusion of this study may be retained in storage by the Sponsor for 
a period of up to 15 years for purposes of this study
10.1.6.
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. The 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 


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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 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 (e.g. 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 10.1.5.
10.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused study drugs 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 study drug disposal 
procedures and provide appropriate instruction for destruction of unused study drugs. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, 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 study drug is destroyed on site, the investigator must maintain accurate records for all study 
drug destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the study drug. 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.
10.1.8.
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.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IEC in 
accordance with local requirements and receive documented IEC approval before modifications 
can be implemented.
10.2.2.
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 10.1.4).
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.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings.  If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.


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10.3.2.
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.
10.3.3.
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.
10.3.4.
Study Discontinuation
The sponsor reserves the right to terminate the study at any time. Should this be necessary, both 
the sponsor and the investigator will arrange discontinuation procedures and notify the 
appropriate regulatory authority (ies), IRBs, and IECs. In terminating the study, Gilead and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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11.
REFERENCES
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and 
sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 
2014a;370 (16):1483-93.
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for 
untreated HCV genotype 1 infection. N Engl J Med 2014b;370 (20):1889-98.
Agarwala S, Eley T, Villegas C, Wang EH, Grasela D. Pharmacokinetic interaction between 
tenofovir and atazanavir coadministered with ritonavir in healthy subjects 
[poster]. 6th International Workshop on Clinical Pharmacology of HIV Therapy; 
2005 April 26-29; Quebec, Canada. 
Andrews E, Damle BD, Fang A, Foster G, Crownover P, LaBadie R, et al. Pharmacokinetics and 
tolerability of voriconazole and a combination oral contraceptive co-administered 
in healthy female subjects. Br J Clin Pharmacol 2008;65 (4):531-9.
Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA. A sustained virologic 
response reduces risk of all-cause mortality in patients with hepatitis C. Clin 
Gastroenterol Hepatol 2011;9 (6):509-16 e1.
Barditch-Crovo P, Trapnell CB, Ette E, Zacur HA, Coresh J, Rocco LE, et al. The effects of 
rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a 
combination oral contraceptive. Clin Pharmacol Ther 1999;65 (4):428-38.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Curry MP, O'Leary JG, Bzowej N, Muir AJ, Korenblat KM, Fenkel JM, et al. Sofosbuvir and 
Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med 
2015.
Denniston MM, Jiles RB, Drobeniuc J, Klevens RM, Ward JW, McQuillan GM, et al. Chronic 
Hepatitis C Virus Infection in the United States, National Health and Nutrition 
Examination Survey 2003 to 2010. Ann Intern Med 2014;160:293-300.
Feld JJ, Jacobson IM, Hezode C, Asselah T, Ruane PJ, Gruener N, et al. Sofosbuvir and 
Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med 2015.
Foster GR, Pianko S, Brown A, Forton D, Nahass RG, George J, et al. Efficacy of Sofosbuvir 
Plus Ribavirin With or Without Peginterferon-Alfa in Patients With Hepatitis C 
Virus Genotype 3 Infection and Treatment-Experienced Patients With Cirrhosis 
and Hepatitis C Virus Genotype 2 Infection. Gastroenterology 2015;149 (6):1462-
70.


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Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing Information.  
Foster City, CA. December 2013:
Hoetelmans RM, Marien K, De Pauw M, Hill A, Peeters M, Sekar V, et al. Pharmacokinetic 
interaction between TMC114/ritonavir and tenofovir disoproxil fumarate in 
healthy volunteers. Br J Clin Pharmacol 2007;64 (5):655-61.
Janssen Pharmaceuticals Inc. INTELENCE® (etravirine) tablets for oral use. US Prescribing 
Information. 2008 Titusville NJ. Revised February 2013.
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and 
sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 
2014;370 (20):1879-88.
Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing burden of 
mortality from viral hepatitis in the United States between 1999 and 2007. Ann 
Intern Med 2012;156 (4):271-8.
Mahajan R, Xing J, Liu SJ, Ly KN, Moorman AC, Rupp L, et al. Mortality Among Persons in 
Care With Hepatitis C Virus Infection: The Chronic Hepatitis Cohort Study 
(CHeCS), 2006-2010. Clin Infect Dis 2014.
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon 
alfa-2b alone or in combination with ribavirin as initial treatment for chronic 
hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998;339 
(21):1485-92.
Nelson DR, Cooper JN, Lalezari JP, Lawitz E, Pockros PJ, Gitlin N, et al. All-oral 12-week 
treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus 
genotype 3 infection: ALLY-3 phase III study. Hepatology 2015;61 (4):1127-35.
Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of 
interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon 
alpha2b plus placebo for 48 weeks for treatment of chronic infection with 
hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). 
Lancet 1998;352 (9138):1426-32.
Quest Diagnostics. FSH and LH Reference Ranges.  2013a:
Quest Diagnostics. Progesterone, LC/MS/MS Reference Ranges.  2013b:
Roche Laboratories Inc. COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. 
Nutley, NJ. Revised: January 2010.


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Roche Products Limited. Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
Characteristics. Welwyn Garden City, United Kingdom. Revised: March 2010.
World Health Organization (WHO). Hepatitis C Fact sheet N°164. Available at: 
http://www.who.int/mediacentre/factsheets/fs164/en/#. Accessed: 20 March.  
2014.


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12.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 4.
Child-Pugh-Turcotte Classification of the severity of cirrhosis
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 6.
Opportunistic Infections


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404, USA 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Multicenter, Randomized, Open-Label Study to Evaluate the Efficacy and Safety of 
Sofosbuvir/Velpatasvir Fixed Dose Combination (FDC) and SofosbuvirNelpatasvir FDC and 
Ribavirin in Subjects with Chronic Genotype 3 HCV Infection and Cirrhosis 
GS-US-342-2097, Amendment 1, 04 April2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PO 
Brian McNabb, MD 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I vvill 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 97 
04 April 2016 


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Appendix 2.
Study Procedures Table
Screen
Baseline/Day 1b
On-treatment Week
Post-treatment Week
2
4
8
12/ET
4
12
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
X
X
Height
X
Weight
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
12-Lead ECG
X
CPT score
X
X
Adverse Events and 
Concomitant Medications
X
X
X
X
X
X
X
X
Pregnancy Prevention 
Counseling
X
X
X
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
Study Drug Dispensinga
X
X
X
Laboratory Assessments
Hematology, Chemistry g
X
X
X
X
X
X
X
X
Coagulation Tests
X
X
X
Urinalysis
X
X
X
HCV RNAc
X
X
X
X
X
X
X
Xf


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Screen
Baseline/Day 1b
On-treatment Week
Post-treatment Week
2
4
8
12/ET
4
12
HIV-1 RNAh
X
X
X
X
X
X
X
X
Viral Sequencingc  
X
X
X
X
X
X
Xf
Single PK
X
X
X
X
Serum β-hCG or Urine 
Pregnancy Testd
X
X
X
X
X
X
X
Urine Drug Screen
X
HCV Genotyping, IL28B 
X
HCV, HIV, HBV Serology
X
HbA1c, Fibrotest®
X
Archive Samplee
X
X
Pharmacogenomic Samplee
X
a
The IWRS will provide direction on the specifics of each subject’s study drug dispensing
b
Baseline/Day 1 assessments must be performed prior to dosing
c
Viral sequencing samples for virologic sequencing required at baseline and after any visit where a previously undetectable HCV RNA becomes detectable 
d
Serum β-hCG pregnancy test performed at screening and for confirmation of positive urine pregnancy test.
e
Only for subjects who have provided consent for this sample and testing. The  Week 12 / Early Termination visit will be the last opportunity for this to be collected.
f
Only for subjects with HCV RNA ≥LLOQ at post-treatment week 12 visit will be asked to return after for a confirmatory visit where additional samples are collected.
g
CrCl will be calculated at all visits where a blood sample is drawn
h
HIV-1 RNA will only be collected and analyzed for co-infected subjects


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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
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


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 101
04 April 2016
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0% 
#
An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects.  Please follow the Gilead convention of grading 
any result within the LLN and ULN a 0.  


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 102
04 April 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant  <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 t o <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant  <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 103
04 April 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL                          
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL              
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL                      
1.51 to < 1.74 mmolL
< 6.1 mg/dL                           
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*) 
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 104
04 April 2016
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


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 105
04 April 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 106
04 April 2016
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 FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 107
04 April 2016
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to < 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 108
04 April 2016
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(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


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 109
04 April 2016
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


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 110
04 April 2016
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70% to 80%
FEV1 or peak flow 50% to 69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak flow 
25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in affected 
eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in affected 
eye(s)


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


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


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


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


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


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


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


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


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


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Appendix 4.
Child-Pugh-Turcotte Classification of the severity of cirrhosis
POINTS*
1
2
3
Encephalopathy
None
Grade 1-2
(or precipitant-induced)
Grade3-4
(or chronic)
Ascites
None
Mild/Moderate
(diuretic-responsive)
Severe
(diuretic-refractory)
Bilirubin (mg/dL)
< 2
2-3
> 3
Albumin (g/dL)
> 3.5
2.8-3.5
< 2.8
PT (sec 
prolonged)
or INR
< 4
< 1.7
4-6
1.7-2.3
> 6
> 2.3
*
CPT score is obtained by adding the score for each parameter
CPT class: A = 5-6 points
B = 7-9 points
C = 10-15 points
a
U.S. Department of Veterans Affairs. Child -Pugh-Turcotte Classification of the severity of cirrhosis. 
Available at http://www hepatitis.va.gov/provider/tools/child-pugh-calculator.asp, Accessed May 29, 2012.


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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Background
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects have 
been demonstrated in all animal species tested. Pregnancy must be excluded before the start of 
treatment with study drugs and prevented thereafter by reliable contraceptive methods. 
Pregnancy tests will be performed regularly throughout this study. Furthermore, RBV is known 
to accumulate intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, 
extreme care must be taken to avoid pregnancy during RBV therapy and for up to 6 months 
following completion of treatment (7 months for males). Please refer to the latest version of the 
product insert for additional information. 
2) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following menarche until becoming post-menopausal, unless permanently sterile or with 
medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.  
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
3) Study Drug Effect on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of SOF have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception.  Non-clinical toxicity studies of 
SOF have demonstrated no adverse effect on fertility or embryo-fetal development.
Data from clinical pharmacokinetic interaction studies of VEL have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception.  Non-clinical toxicity studies of 
GS-5816 have demonstrated no adverse effect on fertility or embryo-fetal development.
However, the risks of treatment with SOF/VEL during pregnancy in humans have not been 
evaluated.  Please refer to the latest version of the Investigator’s Brochure for additional
information.


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4) Contraception Requirements for Female Subjects of Childbearing Potential
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 Baseline/Day 1 visit prior to first dose of study drug.  
Pregnancy testing will occur at regular intervals throughout the duration of the trial.  In the event 
of a delayed menstrual period (over one month between menstruations), a pregnancy test must be 
performed to rule out pregnancy.  This is even true for women of childbearing potential with 
infrequent or irregular periods.  They must also agree to one of the following from Screening 
until 30 days after the last dose of SOF/VEL or 6 months after the last dose of RBV, whichever 
occurs last.

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below, in 
addition to a male partner who correctly used a condom from the date of Screening until 
30 days after the last dose of SOF/VEL or 6 months after the last dose of RBV, whichever 
occurs last.
— Intrauterine device (IUD) 
— Intrauterine hormone-releasing system (IUS) 
— Tubal sterilization
— Essure micro-insert system 
— Vasectomy in the male partner 
— Barrier methods 
■
Female barriers: Diaphragm with spermicide or Cervical cap with spermicide
— Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel or etonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring


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Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 125
04 April 2016
Female subjects must also refrain from egg donation and in vitro fertilization during study 
treatment and until at least 30 days after the last dose of SOF/VEL or 6 months after the last dose 
of RBV, whichever occurs last.
5) 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 treatment or 7 months after the last dose 
or RBV, whichever comes last, 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 or 7 months after last dose of RBV, whichever comes last.
Male subjects must also refrain from sperm donation during treatment and until at least 30 days 
after the last dose of SOF/VEL or 7 months after the last dose of RBV, whichever comes last.
6) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
7) 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, if they become pregnant within 30 days of last dose of SOF/VEL , or if they become 
pregnant within 6 months of the last dose of RBV. 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 within 30 days of the last dose of SOF/VEL or 7 months after the last 
dose of RBV, whichever occurs last, must report the information to the investigator.
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in
Section 8.5.1.1


SOF/VEL FDC
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Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 126
04 April 2016
Appendix 6.
Opportunistic Infections
Non-inclusive list of opportunistic infections base on AIDS-Indicator Conditions from CDC 
Classification System for HIV Infection Clinical Category C:  
1. Bacterial pneumonia, recurrent (two or more episodes in 12 months)
2. Candidiasis of the bronchi, trachea, or lungs
3. Candidiasis, esophageal
4. Cervical carcinoma, invasive, confirmed by biopsy
5. Coccidioidomycosis, disseminated or extrapulmonary
6. Cryptococcosis, extrapulmonary
7. Cryptosporidiosis, chronic intestinal (>1 month in duration)
8. Cytomegalovirus disease (other than liver, spleen, or nodes)
9. Encephalopathy, HIV-related
10. Herpes simplex: chronic ulcers (>1 month in duration), or bronchitis, pneumonitis, or 
esophagitis
11. Histoplasmosis, disseminated or extrapulmonary
12. Isosporiasis, chronic intestinal (>1-month in duration)
13. Kaposi sarcoma
14. Lymphoma, Burkitt, immunoblastic, or primary central nervous system
15. Mycobacterium avium complex (MAC) or Mycobacterium kansasii, disseminated or 
extrapulmonary
16. Mycobacterium tuberculosis, pulmonary or extrapulmonary 
17. Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
18. Pneumocystis jiroveci (formerly carinii) pneumonia (PCP)
19. Progressive multifocal leukoencephalopathy (PML)
20. Salmonella septicemia, recurrent (nontyphoid)
21. Toxoplasmosis of brain
22. Wasting syndrome caused by HIV (involuntary weight loss >10% of baseline body weight) 
associated with either chronic diarrhea (two or more loose stools per day for ≥1 month) or 
chronic weakness and documented fever for ≥1 month

Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Study Director 
or Medical Monitor: 
Protocol Version/Date: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Multicenter, Randomized, Open-Label Study to Evaluate 
the Efficacy and Safety of SofosbuvirN elpatasvir Fixed Dose 
Combination (FDC) and SofosbuvirN elpatasvir FDC and Ribavirin 
in Subjects with Cln·onic Genotype 3 HCV Infection and Cinhosis 
Gilead Sciences, Inc. 
This is a non-IND study 
2016-000417-73 
Not Available 
Hepatitis C Virus Infection 
GS-US-342-2097 
Name: 
Brian McNabb, MD 
Telephone: 
PPD 
Fax: 
PPD 
Cell Phone: PPD 
Original: 
16 March 2016 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document, pruiicularly unpublished data, is the prope1iy or 
lmder control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The info1mation is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocoL 
Yon will not disclose any of the infmmation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain info1med consent from those 
persons to whom the dmg may be administered. 


SOF/VEL FDC
Protocol GS-US-342-2097
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Gilead Sciences, Inc. 
Original
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................10
1.
INTRODUCTION ..............................................................................................................................................13
1.1.
Background ............................................................................................................................................13
1.2.
Sofosbuvir/Velpatasvir Fixed Dose Combination..................................................................................14
1.2.1.
General Information .............................................................................................................14
1.2.2.
Additional Clinical Experience ............................................................................................15
1.3.
Ribavirin (RBV).....................................................................................................................................39
1.4.
Rationale for This Study ........................................................................................................................40
1.5.
Rationale for Dose Selection..................................................................................................................40
1.6.
Overall Risk/Benefit Assessment...........................................................................................................41
1.7.
Compliance ............................................................................................................................................42
2.
OBJECTIVES.....................................................................................................................................................43
3.
STUDY DESIGN................................................................................................................................................44
3.1.
Treatment Plan and Regimen .................................................................................................................44
3.2.
Visit Schedule ........................................................................................................................................44
3.3.
Virologic Response ................................................................................................................................44
3.3.1.
HCV Virologic Response-Based Treatment Stopping Criteria ............................................44
3.3.2.
HIV Virologic Rebound Criteria..........................................................................................45
3.4.
Stopping Rules for Individual Subjects..................................................................................................47
3.5.
Discontinuations.....................................................................................................................................47
3.6.
Assessments for Premature Discontinuation from Study.......................................................................48
3.7.
Criteria for Discontinuation of Study Treatment....................................................................................48
3.8.
Biomarker Testing..................................................................................................................................48
3.8.1.
Biomarker Samples for Optional Future Research...............................................................48
3.8.2.
Biomarker Samples for Optional Pharmacogenomic Research............................................49
4.
SUBJECT POPULATION..................................................................................................................................50
4.1.
Number of Subjects and Subject Selection ............................................................................................50
4.2.
Inclusion Criteria....................................................................................................................................50
4.3.
Exclusion Criteria...................................................................................................................................52
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................55
5.1.
Randomization, and Study Drug Supply................................................................................................55
5.2.
Description and Handling of SOF/VEL FDC ........................................................................................55
5.2.1.
Formulation..........................................................................................................................55
5.2.2.
Packaging and Labeling .......................................................................................................55
5.2.3.
Storage and Handling...........................................................................................................55
5.3.
Dosage and Administration of SOF/VEL FDC......................................................................................56
5.4.
Description and Handling of Ribavirin (RBV) ......................................................................................56
5.4.1.
Formulation..........................................................................................................................56
5.4.2.
Packaging and Labeling .......................................................................................................56


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5.4.3.
Storage and Handling...........................................................................................................56
5.4.4.
Dosage and Administration..................................................................................................57
5.5.
Prior and Concomitant Medications.......................................................................................................58
5.6.
Acceptable HIV Antiretroviral Regimens..............................................................................................59
5.7.
Study Drug Adherence and Drug Accountability...................................................................................60
5.8.
Study Drug Return or Disposal ..............................................................................................................61
6.
STUDY PROCEDURES ....................................................................................................................................62
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................62
6.2.
Screening Assessments ..........................................................................................................................62
6.2.1.
Screening Visit (Day 28 to Day 0) .......................................................................................62
6.3.
Treatment Assessments..........................................................................................................................64
6.3.1.
Baseline/Day 1 Visit.............................................................................................................64
6.3.2.
Week 2 (±3 days) .................................................................................................................65
6.3.3.
Weeks 4 and 8 (3 days) .....................................................................................................66
6.3.4.
Week 12 or Early Termination (3 days)............................................................................66
6.3.5.
Unscheduled Visit ................................................................................................................67
6.4.
Posttreatment Assessments ....................................................................................................................67
6.4.1.
Post-treatment Week 4 (±5 days) .........................................................................................67
6.4.2.
Post-treatment Week 12 (± 5 days) ......................................................................................68
6.5.
Confirmatory Visit .................................................................................................................................69
6.6.
End of Study...........................................................................................................................................69
6.7.
Procedures and Specifications................................................................................................................69
6.7.1.
Clinical Laboratory Analytes ...............................................................................................69
6.7.2.
Medical History....................................................................................................................70
6.7.3.
Complete Physical Examination...........................................................................................70
6.7.4.
Vital Signs............................................................................................................................70
6.7.5.
Creatinine Clearance ............................................................................................................70
6.7.6.
12-Lead ECGs......................................................................................................................71
6.7.7.
HCV Viral RNA Sequencing / Phenotyping Sample (Archive)...........................................71
6.7.8.
HIV Viral RNA Genotyping/Phenotyping Sample (Archive)..............................................71
6.7.9.
Single Pharmacokinetic (PK) Sample ..................................................................................71
6.7.10.
Pharmacogenomics Testing..................................................................................................71
6.7.11.
Sample Storage.....................................................................................................................72
6.7.12.
Pregnancy Testing................................................................................................................72
7.
TOXICITY MANAGEMENT............................................................................................................................73
7.1.
Dose Modification Due to Toxicity........................................................................................................73
7.2.
Group 1:  Subjects administered SOF/VEL ...........................................................................................73
7.3.
Group 2:  Subjects administered SOF/VEL+ RBV................................................................................73
7.3.1.
Subject Stopping Rules ........................................................................................................73
7.4.
Subject Stopping Rules ..........................................................................................................................73
7.5.
Special Situations Reports......................................................................................................................73
7.5.1.
Definitions of Special Situations..........................................................................................73
8.
ADVERSE EVENTS MANAGEMENT ............................................................................................................75
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................75
8.1.1.
Adverse Events.....................................................................................................................75
8.1.2.
Serious Adverse Events........................................................................................................75
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................76
8.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................76
8.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................76
8.2.2.
Assessment of Severity ........................................................................................................77


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8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................77
8.4.
Gilead Reporting Requirements.............................................................................................................78
8.5.
Toxicity Management ............................................................................................................................79
8.5.1.
Instructions for Reporting Special Situations.......................................................................79
9.
STATISTICAL CONSIDERATIONS................................................................................................................81
9.1.
Analysis Objectives and Endpoints........................................................................................................81
9.1.1.
Analysis Objectives..............................................................................................................81
9.1.2.
Primary Endpoints................................................................................................................81
9.1.3.
Secondary Endpoints............................................................................................................81
9.1.4.
Other Endpoints of Interest ..................................................................................................82
9.2.
Analysis Conventions.............................................................................................................................82
9.2.1.
Analysis Sets ........................................................................................................................82
9.3.
Data Handling Conventions ...................................................................................................................82
9.4.
Demographic Data and Baseline Characteristics ...................................................................................84
9.5.
Efficacy Analysis ...................................................................................................................................84
9.5.1.
Primary Analysis..................................................................................................................84
9.5.2.
Secondary Analyses .............................................................................................................84
9.6.
Safety Analysis.......................................................................................................................................85
9.6.1.
Extent of Exposure...............................................................................................................85
9.6.2.
Adverse Events.....................................................................................................................85
9.6.3.
Laboratory Evaluations ........................................................................................................86
9.6.4.
Other Safety Evaluations......................................................................................................86
9.6.5.
HIV RNA Analysis ..............................................................................................................86
9.7.
Pharmacokinetic Analysis......................................................................................................................86
9.8.
Sample Size............................................................................................................................................86
10.
RESPONSIBILITIES..........................................................................................................................................87
10.1.
Investigator Responsibilities ..................................................................................................................87
10.1.1.
Good Clinical Practice..........................................................................................................87
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................87
10.1.3.
Informed Consent.................................................................................................................87
10.1.4.
Confidentiality......................................................................................................................88
10.1.5.
Study Files and Retention of Records ..................................................................................88
10.1.6.
Case Report Forms...............................................................................................................89
10.1.7.
Investigational Medicinal Product Accountability and Return.............................................90
10.1.8.
Inspections............................................................................................................................90
10.1.9.
Protocol Compliance............................................................................................................90
10.2.
Sponsor Responsibilities ........................................................................................................................91
10.2.1.
Protocol Modifications.........................................................................................................91
10.2.2.
Study Report and Publications .............................................................................................91
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................91
10.3.1.
Payment Reporting...............................................................................................................91
10.3.2.
Access to Information for Monitoring..................................................................................92
10.3.3.
Access to Information for Auditing or Inspections ..............................................................92
10.3.4.
Study Discontinuation..........................................................................................................92
11.
REFERENCES ...................................................................................................................................................93
12.
APPENDICES ....................................................................................................................................................96
Appendix 1.
Investigator Signature Page....................................................................................................97


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Appendix 2.
Study Procedures Table..........................................................................................................98
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............100
Appendix 4.
Child-Pugh-Turcotte Classification of the severity of cirrhosis ...........................................123
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................124
Appendix 6.
Opportunistic Infections .......................................................................................................127
LIST OF IN-TEXT TABLES
Table 1-1.
GS-US-342-1138: SVR12 Overall and by HCV Genotypes ..................................................16
Table 1-2.
NGMN, NG, EE, and VEL Plasma PK Parameters Following Administration of 
NGM/EE alone or with VEL..................................................................................................32
Table 1-3.
Summary of LH, FSH, and Progesterone Concentrations Following Administration 
of NGM/EE alone or with VEL..............................................................................................32
Table 1-4.
Summary of Changes in SOF/VEL PK following administration with 
Representative H2RAs and PPIs ............................................................................................34
Table 1-5.
GS-US-342-1167: Summary of Changes in PK Parameters of SOF, its Metabolites 
GS-566500 and GS-331007, GS-5816, and Evaluated ARVs (EFV, RPV, DTG, 
EVG, COBI, FTC, TAF, and TFV) (PK Analysis Sets).........................................................35
Table 1-6.
GS-US-342-1326: Preliminary Summary of Changes in PK Parameters of SOF, its 
Metabolites GS-566500 and GS-331007, GS-5816, and Evaluated ARVs (EVG, 
COBI, DRV, ATV, LPV, RTV, RAL, FTC, and TFV)..........................................................37
Table 5-1.
List of Disallowed /Use with Caution Medications................................................................59
Table 7-1.
Ribavirin Dose Modification Guideline for Coadministration with SOVALDI.....................73
LIST OF IN-TEXT FIGURES
Figure 3-1.
HIV Virologic Rebound Schema............................................................................................46


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Multicenter, Randomized, Open-Label Study to Evaluate 
the Efficacy and Safety of Sofosbuvir/Velpatasvir Fixed Dose 
Combination (FDC) and Sofosbuvir/Velpatasvir FDC and Ribavirin 
in Subjects with Chronic Genotype 3 HCV Infection and Cirrhosis
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
This is a non-IND study
2016-000417-73
Not Available
Study Centers:
Approximately 30 centers in Spain
Number of Subjects 
Planned:
Approximately 200 subjects with chronic genotype 3 HCV infection 
and compensated cirrhosis
Target Population:
Male and non-pregnant/non-lactating female subjects with chronic 
genotype 3 HCV infection and compensated cirrhosis, ages 18 years 
or older with and without HIV-1 coinfection. 
Duration of 
Treatment:
Following randomization, enrolled subjects will receive assigned 
study treatment for 12 weeks
Objectives:
The primary objectives of this study are:

To evaluate the efficacy of study treatment with 
Sofosbuvir(SOF)/Velpatasvir(VEL, GS-5816) FDC and
SOF/VEL FDC and Ribavirin (RBV) for 12 weeks as measured 
by the proportion of subjects with sustained virologic response 
12 weeks after cessation of treatment regimen (SVR12) 

To evaluate the safety and tolerability of each treatment regimen 
The secondary objectives of this study are: 

To determine the proportion of subjects who attain SVR at 
4 weeks after cessation of each treatment regimen (SVR4)

To evaluate the kinetics of circulating HCV RNA during 
treatment and after cessation of each treatment regimen

To evaluate the emergence of viral resistance to SOF and VEL
during treatment and after cessation of treatment


SOFNELFDC 
Protocol GS-US-342-2097 
Gilead Sciences, Inc. 
Study Design: 
Substudy 
Diagnosis and Main 
Eligibility Criteria: 
Study Procedmes/ 
Frequency: 
CONFIDENTIAL 
The explorat01y objective of this study is: 
• 
PD 
Final 
Original 
Approximately 200 subjects with chronic genotype 3 HCV infection 
and compensated cinhosis will be randomized (1:1) to either: 
1. Group 1 (n = 100): 
SOFNEL once daily for 12 weeks 
or 
2. Group 2 (n = 100): 
SOFNEL + RBV for 12 weeks 
Randomization will be stratified by prior treatment experience 
(treatment naive/treatment -experienced). 
Phannacogenomics (PG) Substudy 
In consenting pruiicipants, a blood sample will be drawn at baseline 
or dming the study for phmmacogenomics resem·ch. 
Chronic genotype 3 HCV infected, male and non-pregnant/ 
non-lactating female subjects with compensated cinhosis, ages 
18 years or older. 
HIV -1 co infected patients at·e eligible to pa1ticipate. They must meet 
the HIV specific eligibility criteria. 
Refer to Sections 4.2 and 4.3 of the protocol for detailed Inclusion 
and Exclusion Criteria 
Screening assessments will be completed within 28 days of the 
Baseline/Day 1 visit. The screening window can be extended to 
42 days for subjects requiring liver biopsy, additional HCV genotype 
testing, or for extenuating circumstances. 
All subjects will complete the following study visits: Screening, 
Baseline/Day 1, on-treatment visits at the end of Weeks 2, 4, 8, and 
12, and posttreatment Week 4. Patients who achieve SVR4 will also 
be required to attend a posttreatment Week 12 visit. 
Screening assessments will include physical examination, medical 
hist01y, height, weight, vital signs, 12-lead ECG, adverse events 
related to screening procedmes, concomitant medications, safety 
laborat01y tests (including hematology, chemistty, and coagulation), 
Page 7 
16 March 2016 


SOFNELFDC 
Protocol GS-US-342-2097 
Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
CONFIDENTIAL 
Final 
Original 
HCV RNA, HIV-1 RNA, CD4 T-cell count and percent, serology 
(HIV, HCV, HBV), hemoglobin Ale (HbAlc), assessment of the 
presence or absence of cinhosis, screening for hepatocellular 
carcinoma (HCC), senun ~-hCG (females of child bearing potential 
only), IL28B genotyping, urinalysis and urine dmg screen. Subjects 
with HIV co-infection will also have the following laboratoty tests: 
HIV -1 RNA, CD4 T -cell cmmt and percent. 
On-treatment assessments include adverse events (AEs ), concomitant 
medications, study medication pill count, physical examination, 
weight, vital signs, safety laboratoty tests, HCV RNA, 
phannacokinetic samples, and urine pregnancy tests (females of child 
bearing potential only). Subjects with HIV co-infection will also have 
the following laboratmy tests: HIV-1 RNA, CD4 T-cell count and 
percent. 
Post-treatment assessments include AEs, concomitant medications, 
vital signs, safety laboratoty tests, HCV RNA, and mine pregnancy 
tests (females of child bearing potential only). Subjects with HIV 
co-infection will also have the following laboratoty tests: HIV-1 
RNA, CD4 T -cell count and percent. 
Samples for HCV RNA sequencing I phenotyping will be collected at 
Baseline and eve1y visit thereafter. Subects' with HIV co-infection 
will also have samples for HIV RNA genotyping/phenotyping 
collected at Baseline/Day 1 and at Weeks 2, 4, 8, 12, ET and 
Posttreatment Week 4. Samples will be collected during on-treatment 
visits for pharmacokinetic (PK) analysis of study dmgs. 
For subjects who provide their additional and specific consent, an 
appropriate blood sample will be collected at the Baseline/Day 1 visit 
for PG (this sample may be drawn after Baseline/Day 1 ifnecessmy). 
For subjects who provide their additional and specific consent, 
PPD 
SOF /VEL fixed dose combination (FDC) is manufactured as a 
400/100mg FDC tablet for oral administration. All subjects will take 
1 tablet daily with or without food. 
Subjects in Group 2 will take RBV with food at a total daily oral dose 
of 1000 or 1200 mg (1000 mg for subjects weighing < 75 kg and 
1200 mg for subjects weighing 2. 75 kg) in a divided daily dose. 
Page8 
16 March 2016 


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Criteria for 
Evaluation:
Safety:
AEs and laboratory tests will be collected throughout the study
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV RNA 
performed using COBAS® AmpliPrep®/COBAS® TaqMan® HCV 
Quantitative Test, v2.0
Pharmacokinetics:
A single PK blood sample will be collected at each on-treatment visit 
for all subjects. 
The PK of SOF (and metabolites), VEL and RBV may be assessed.
Statistical Methods:
The primary efficacy endpoint for the study is SVR12 in all 
randomized and treated subjects. 
In the primary efficacy analysis, point estimate and 95% confidence 
interval of SVR12 will be computed for each treatment group.
Secondary efficacy endpoints include SVR4 and the proportion of 
subjects with virologic failure.
All continuous endpoints (except for safety endpoints) will be 
summarized using an 8-number summary (n, mean, standard 
deviation, median, Q1, Q3, minimum, maximum) by treatment group 
and stratification within group (as appropriate). All categorical 
endpoints will be summarized by number and percentage of subjects 
who meet the endpoint definition.
Safety endpoints will be analyzed by the number and percent of 
subjects with events or abnormalities for categorical values or 
8-number summary (n, mean, standard deviation, median, Q1, Q3, 
minimum, maximum) for continuous data by treatment group.
With a sample size of 100 for each treatment, a two-sided 95% exact 
confidence interval will extend at most 21% in length for each 
treatment.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil counts
APRI
AST: platelet ratio index
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the curve
AUCtau
area under the plasma concentration versus time curve over the dosing interval (tau)
ß-hCG
ß-human chorionic gonadotropin
BLQ
below the lower limit of quantification
BMI
body mass index
CD4
cluster of differentiation 4
CI
confidence interval
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
CK
creatine kinase
CPT
Child-Pugh-Turcotte Classification
CRF
case report form(s)
CRO
Contract (or clinical) research organization 
CSA
colony stimulating agents
DAA
direct acting antiviral
DCV
daclatasvir (HCV NS5A Inhibitor)
DDI
drug-drug interaction
DSPH
Drug Safety and Public Health
EC
Ethics committee
ECG
electrocardiogram
EDC
electronic data capture
eCRF
Electronic case report form(s)
ESA
Erythropoiesis-stimulating agents 
ET
early termination
EU
European Union
EudraCT
European clinical trials database
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
fixed dose combination


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FSH
follicle stimulating hormone
GCP
Good Clinical Practice (Guidelines)
GM-CSF
Granulocyte macrophage colony stimulating factor
GSI
Gilead Sciences, Inc.
GT
genotype (viral)
H2RA
Histamine-2 receptor antagonist
Hb
Hemoglobin
HBV
Hepatitis B virus
HbA1C
Hemoglobin A1C
HCC
Hepatocellular carcinoma
hCG
human chorionic gonadotropin
HDPE
high-density polyethylene
HCV
Hepatitis C virus
HIV
Human Immunodeficiency Virus
HLGT
high-level group term
HLT
high-level term
IB
investigator’s brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IFN
interferon
IL28B
interleukin-28B gene
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
INR
international normalized ratio of prothrombin time
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
LAM
lactational amenorrhea method
LDV
ledipasvir
LFT
liver function test
LH
luteinizing hormone
LLN
lower limit of the normal range
LLOQ
lower limit of quantification
LLT
lower-level term
LT
liver transplantation
MELD
Model for End Stage Liver Disease
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute


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mL
milliliter
mmHg
millimeters mercury
MCV
mean cellular volume
NDA
New Drug Application
ng
nanogram
ng•h/mL
nanograms times hours per milliliter
NG
norgestrel
NGM
norgestimate
NGM/EE
norgestimate/ethinyl estradiol
NGMN
norelgestromin
NS (3/4A/5A/5B)
Non-structural protein
OC
oral contraceptive
PCR
Polymerase chain reaction
Peg-IFN
Pegylated-Interferon-
pg
pictogram
pg•h/mL
picograms times hours per milliliter
P-gp
P-glycoprotein
PK
pharmacokinetic
PPI
Proton pump inhibitor
PT
Preferred term or prothrombin time
RBV
ribavirin
RNA
ribonucleic acid
SADR
serious adverse drug reaction
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
Standard deviation
SOC
System Organ Class
SOF
Sovaldi® or Sofosbuvir, formerly GS-7977
SOF/VEL
SOF/VEL fixed dose combination
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained virologic response
tmax
The time (observed time point) of Cmax
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant (λz)
ULN
upper limit of the normal range
US
United States
VA
Veterans Affairs
VEL
Velpatasvir, formerly GS-5816
WBC
White blood cell count


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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) infection is a global health challenge with estimates ranging up to 
150 million individuals infected worldwide {World Health Organization (WHO) 2014}. In the 
United States (US), approximately 2.7 million people have chronic HCV infection {Denniston et 
al 2014} and HCV infection causes over 15,000 deaths each year {Ly et al 2012}, although 
under-reporting of HCV infection on death certificates may contribute to as much as a 5-fold 
underestimation of the actual number of deaths {Mahajan et al 2014}. Successful treatment of 
chronic HCV infection reduces the need for liver transplantation, the incidence of HCC, and 
overall mortality {Backus et al 2011}. Thus, the public health benefit of safe and effective HCV 
treatment regimens is high.
The development of sofosbuvir (Sovaldi®, SOF), a nucleotide analog HCV NS5B polymerase 
inhibitor, represents a major advance in the treatment of HCV as SOF-based regimens are shorter 
in duration, better tolerated, and result in higher SVR rates than prior therapies. SOF is currently 
approved in the US for the treatment of genotype (GT) 1, 2, 3 and 4 HCV infection and in the 
European Union for GT1-6 with different regimens and durations dependent on the HCV 
genotype and the presence or absence of cirrhosis {Gilead Sciences Inc 2013}.The next wave of 
therapies for the treatment of HCV includes combinations of direct acting antivirals (DAAs) 
including SOF in Peg-IFN and RBV free regimens. The first of these treatments, a fixed dose 
combination (FDC) of SOF and the HCV nonstructural protein 5A (NS5A) inhibitor ledipasvir 
(LDV), has been approved in the US and Europe. The Phase 3 studies GS-US-337-0102 (ION 1), 
GS-US-337-0109 (ION 2), and GS-US-337-0108 (ION 3) demonstrated that treatment with 
LDV/SOF with or without RBV for 8, 12 or 24 weeks resulted in high SVR12 rates in subjects 
with GT1 HCV infection {Afdhal et al 2014b}, {Afdhal et al 2014a}, {Kowdley et al 2014}.
LDV/SOF with RBV is currently approved as a 24 week regimen for the treatment of genotype 3 
HCV infection in Europe, but is not approved for GT3 HCV infections in the US.
Despite the recent advances of DAA based therapy for HCV, there remains room for 
improvement in therapy for certain subgroups of patients based on genotype, previous HCV 
treatment experience, and the presence or absence of cirrhosis.  For example, while there are 
good treatment options available for patients with GT3 HCV infections without cirrhosis 
(12 weeks of SOF plus daclatasvir has been shown to lead to SVR12 rates as high as 98% in 
patients with GT 3 HCV infections) {Nelson et al 2015}, this regimen has not been as effective
in patients with concomitant cirrhosis, where SVR12 rates are around 60%.  Treatment options 
for patients with GT 3 HCV infections and cirrhosis are limited to longer regimens (24 weeks) 
that include the use of ribavirin or 12 week regimens that require the use of ribavirin and 
pegylated interferon {Gilead Sciences Inc 2013}. Considering these subgroups is critical as over 
half of all HCV infections are non-GT1: estimates from 2 recent meta-analyses indicate GT3 
HCV is the next most common after GT1 accounting for 22-30% of HCV infections. The 
availability of a well-tolerated, all oral, ribavirin-free, pegylated interferon-free, short duration 
therapy that is effective in all HCV genotypes, including patients with GT3 HCV and cirrhosis


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would be a major advance for the treatment of HCV infection globally.  Moreover, a 
pangenotypic regimen that does not require HCV genotyping, response guided therapy, or 
intensive safety monitoring due to use of Peg-IFN or RBV would allow a greater number of 
patients to be treated in regions where HCV genotyping or careful safety monitoring of treated 
patients is not part of routine medical care for HCV infection.
1.2.
Sofosbuvir/Velpatasvir Fixed Dose Combination
SOF/ velpatasvir (VEL) fixed-dose combination (SOF/VEL FDC) combines two HCV specific 
DAAs into a single tablet for the treatment of chronic HCV infection.
SOF is a nucleotide analog HCV NS5B polymerase inhibitor currently approved in the US and 
other regions for the treatment of HCV infection as described in Section 1.1. VEL (formerly 
known as GS-5816) is a HCV NS5A inhibitor that has demonstrated activity against HCV in 
phase 1, phase 2, and phase 3 studies.  VEL showed activity against genotypes 1, 2, 3 and 4 HCV 
in a phase 1, 3 day, monotherapy study. Phase 2 studies of SOF + VEL administered as single 
agents have demonstrated that the combination of SOF 400 mg and VEL 100 mg administered 
for 12 weeks is well tolerated and results in high SVR rates across a broad range of HCV 
genotypes. In the Phase 2 study GS-US-342-0109 all patients with GT3 HCV infections without 
cirrhosis achieved SVR12, regardless of the addition of RBV. Patients with compensated 
cirrhosis achieved higher SVR12 rates with the addition of RBV, suggesting that RBV provides 
additional efficacy when added to regimens of SOF + VEL in these patients. The SOF/VEL FDC 
(400/100 mg) is a co-formulation of SOF 400 mg and VEL 100 mg has been shown to be 
effective in the treatment of GT1-6 HCV in four Phase 3 trials (ASTRAL 1-4), including patients 
with GT3 HCV infections and cirrhosis.{Feld et al 2015, Foster et al 2015} {Curry et al 2015}.
The ASTRAL studies and several ongoing phase 3 trials are described in detail in 
Section 1.2.2.1.
The development of SOF/VEL may have a major impact on the global prevalence and burden of 
HCV as it may represent a simple, well tolerated, highly efficacious, pangenotypic treatment for 
all HCV infected patients.
1.2.1.
General Information
Please refer to the SOF/VEL FDC Investigator’s Brochure (IB) for additional information on 
SOF/VEL, and the individual components, including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience


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1.2.2.
Additional Clinical Experience
1.2.2.1.
Sofosbuvir/Velpatasvir Phase 3 Studies
Four Phase 3 studies have been completed evaluating the efficacy and safety of SOF/VEL in 
subjects with genotype 1-6 HCV infection. Three studies enrolled subjects without cirrhosis or 
with compensated cirrhosis, GS-US-342-1138 (ASTRAL-1), GS-US-342-1139 (ASTRAL-2) 
and GS-US-342-1140 (ASTRAL-3); and one study enrolled subjects with decompensated 
cirrhosis GS-US-342-1137 (ASTRAL-4). Three Phase 3 trials enrolling patients with HIV-1 
coinfection (GS-US-342-1202 [ASTRAL-5]), patients who failed to achieve SVR12 in previous 
Gilead sponsored HCV treatment studies (GS-US-342-1553), and patients who received placebo 
during ASTRAL-1 (GS-US-342-1446) are currently ongoing.  Summaries of results from the 
completed Phase 3 studies and descriptions of the ongoing Phase 3 studies are presented below.
1.2.2.1.1.
Study GS-US-342-1138 (ASTRAL-1)
Design
This ongoing Phase 3, randomized, double-blind, placebo-controlled, multicenter, international 
study is assessing the antiviral efficacy, safety, and tolerability of 12 weeks of SOF/VEL  
treatment compared with 12 weeks of  SOF/VEL placebo treatment in subjects with chronic 
genotype 1, 2, 4, 5, or 6 hepatitis C virus (HCV) infection. This study was conducted in Begium, 
Canada, France, Germany, Hong Kong, Italy, United Kingdom and United States.
Subjects with genotype 1, 2, 4, or 6 HCV infection were randomized in a 5:1 ratio to treatment 
with SOF/VEL for 12 weeks (SOF/VEL 12 Week group) or SOF/VEL placebo for 12 weeks 
(Placebo 12 Week group). Subjects with genotype 5 HCV infection were enrolled to the 
SOF/VEL 12 Week group. Randomization was stratified by HCV genotype (1, 2, 4, 6, and 
indeterminate) and the presence or absence of cirrhosis at screening.
Disposition
A total of 740 subjects were enrolled and treated; 624 subjects in the SOF/VEL 12 Week group 
and 116 subjects in the Placebo 12 Week group.
The majority of subjects (99.3%) completed study treatment. Five subjects (0.7%) prematurely 
discontinued study treatment; 2 subjects in the SOF/VEL group and 3 subjects in the placebo 
group. The reasons for premature discontinuation of study drug for subjects in the SOF/VEL
12 Week group were an AE (1 subject) and lost to follow-up (1 subject) and for subjects in the 
Placebo 12 Week group were AEs (2 subjects) and investigator discretion (1 subject).
Demographics and Baseline Characteristics
Demographics and baseline disease characteristics were generally balanced between the 
SOF/VEL 12 Week and Placebo 12 Week groups.


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In the SOF/VEL 12 Week group, the majority of subjects were male (59.9%), and 21.6% of 
subjects had a body mass index (BMI) 30 kg/m2, 19.4% had cirrhosis and most subjects 
(73.9%) had baseline HCV RNA ≥800,000 IU/mL. Of the 624 subjects who received SOF/VEL, 
328 subjects (52.6%) had genotype 1 HCV infection (210 subjects [33.7%] with HCV 
genotype 1a and 118 subjects [18.9%] with HCV genotype 1b), 104 subjects (16.7%) had 
genotype 2 HCV infection, 116 subjects (18.6%) had genotype 4 HCV infection, 35 subjects 
(5.6%) had genotype 5 HCV infection, and 41 subjects (6.6%) had genotype 6 HCV infection.
Efficacy Results 
The SOF/VEL  12 Week group met the primary endpoint of an SVR12 rate that was statistically 
superior relative to the prespecified performance goal of 85% (p < 0.001). The SVR12 rate was 
as follows:
SOF/VEL 12 Week group: 99.0% (95% CI: 97.9% to 99.6%) of subjects (618 of 624) achieved 
SVR12.
Table 1-1 presents the SVR12 results for the SOV/VEL FDC12 Week group overall and by HCV 
genotype. A total of 6 of 624 subjects (1.0%) who received SOF/VEL did not achieved SVR12. 
Two subjects had relapse determined at posttreatment week 4; one treatment-naïve subject with 
genotype 1a HCV infection without cirrhosis and one treatment experienced subject with 
genotype 1b infection and cirrhosis. Four additional subjects (3 with genotype 1 and 1 with 
genotype 5) did not achieve SVR12 (1 subject withdrew consent, 2 subjects had not returned for 
the posttreatment Week 12 visit, and 1 subject died prior to the posttreatment Week 4 visit). 
Table 1-1.
GS-US-342-1138: SVR12 Overall and by HCV Genotypes 
SOF/VEL
12 Weeks
Total
(All 
Genotypes)
(N = 624)
GT-1a
(N = 210)
GT-1b
(N = 118)
GT-1
Total
(N = 328)
GT-2
(N = 104)
GT-4
(N = 116)
GT-5
(N = 35)
GT-6
(N = 41)
SVR12
618/624 
(99.0%)
206/210 
(98.1%)
117/118 
(99.2%)
323/328 
(98.5%)
104/104 
(100.0%)
116/116 
(100.0%)
34/35 
(97.1%)
41/41 
(100.0%)
GT = genotype
The SVR4 results for subjects with genotype 1, 2, 4, 5, or 6 HCV infection were the same as the 
SVR12 results with the exception of 1 subject with genotype 1a HCV infection who achieved 
SVR4 but had not returned for his posttreatment Week 12 visit at the time of the interim analysis.
HCV RNA declined rapidly with similar decreases in HCV RNA observed across all HCV 
genotypes in the SOF/VEL 12 Week group. Consistent with the rapid and sustained decline in 
HCV RNA, > 88.5% of subjects in the SOF/VEL 12 Week group had HCV RNA LLOQ at 
Week 4. Time to virologic suppression was not associated with treatment outcome overall or in 
any genotype.


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Virologic Resistance
Deep sequence analyses indicated that subjects in the SOF/VEL 12 Week group had a diverse 
population of HCV with more than 30 subtypes across genotypes 1, 2, 4, 5, 6, and 7. 
Approximately 42% and 9% of subjects in the SOF/VEL 12 Week group had baseline NS5A 
resistance-associated variants (RAVs) and NS5B RAVs, respectively. Baseline NS5A or NS5B 
RAVs had no impact on SVR12, with high SVR12 across all subtypes/genotypes regardless of 
the presence of NS5A RAVs or NS5B RAVs. Two subjects had virologic failure and both had 
baseline NS5A RAVs. At virologic failure time points, both subjects developed additional NS5A 
RAVs (Y93N and Y93H) that conferred a high (> 700) fold shift in EC50 to VEL. No NS5B 
RAVs were detected at baseline or posttreatment in either subject with virologic failure.
Safety Results
Treatment with SOF/VEL was well tolerated. Subjects in the SOF/VEL 12 Week treatment 
group had similar type, incidence, and severity of AEs as subjects in the Placebo 12 Week group.
Grade 3 (severe) and Grade 4 (life-threatening) AEs were rare, 19 of 624 (2.9%) in the SOF/VEL
12 Week group and 1 of 116 (0.9%) in the Placebo 12 Week group. Two subjects (0.3%) in the 
SOF/VEL 12 Week group had Grade 4 AEs. One subject had a Grade 4 AE of malignant lung 
neoplasm and 1 subject had a Grade 4 AE of sudden death. Both events were assessed by the 
investigators as unrelated to study drugs.
SAEs were rare and occurred in 15 subjects (2.4%) in the SOF/VEL 12 Week group. All SAEs 
were assessed by the investigators as unrelated to study drugs. No placebo treated subjects had 
SAEs. No trends in SAE type or onset time were observed, and no SAE was reported in 
> 1 subject. No SAEs led to treatment discontinuation. One subject death was reported in the 
study. This subject completed 12 weeks of treatment with SOF/VEL and died in his sleep on 
posttreatment Day 8. The death was assessed as not related to study drug by the investigator. One 
subject (0.2%) in the SOF/VEL 12 Week group discontinued study treatment due to a Grade 3 
AE of anxiety and 2 subjects (1.7%) in the Placebo 12 Week group discontinued study treatment 
due to meeting the prespecified stopping criteria of elevated ALT and/or AST levels ≥5 nadir.
Most laboratory abnormalities were Grade 1 or 2 in severity. Subjects in the SOF/VEL 12 Week 
group had Grade 3 or 4 chemistry abnormalities of elevated AST (Grade 3; 1 subject [0.2%]), 
elevated creatine kinase (Grade 3; 2 subjects [0.3%], Grade 4; 2 subjects [0.3%]), hyperglycemia 
(Grade 3, 15 subjects [2.4%]), and elevated lipase (Grade 3; 14 subjects [2.2%], Grade 4, 
2 subjects [0.3%]). Among subjects in the SOF/VEL 12 Week, all Grade 3 or 4 creatinine kinase 
elevations were transient, all Grade 3 or 4 lipase elevations were asymptomatic and generally 
transient, and Grade 3 or 4 hyperglycemia occurred in subjects with a medical history of 
diabetes. The most frequently observed Grade 3 or 4 laboratory abnormalities observed in 
placebo treated subjects were elevated ALT (Grade 3; 6 subjects [5.2%] and Grade 4; 2 subjects 
[1.7%]) consistent with ongoing HCV infection.


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No notable changes from baseline in vital signs (systolic blood pressure, diastolic blood pressure, 
or pulse) were observed during the study. No trends in ECG findings suggestive of cardiotoxicity 
were observed.
Conclusions 
The conclusions from this interim analysis were as follows:

The study met its primary efficacy endpoint demonstrating that the SVR12 rate of 99.0% 
(95% CI: 97.9% to 99.6%) in genotype 1, 2, 4, 5, and 6 HCV-infected subjects treated for 
12 weeks with SOF/VEL was statistically superior to the prespecified SVR12 performance 
goal of 85% (p<0.001).

High SVR12 rates were achieved across all HCV genotypes and subgroups
— Among subjects with cirrhosis, the SVR rate was 99.2%
— Among subjects with prior treatment failure, the SVR rate was 99.5%
— Among subjects with baseline NS5A RAVs, the SVR12 rate was 99.2%

Treatment with SOF/VEL for 12 Weeks was generally well tolerated with a safety profile 
similar to that of placebo treatment. There was a low incidence of SAEs, discontinuations 
due to AEs and no clinically relevant laboratory abnormalities.
1.2.2.1.2.
Study GS-US-342-1139 (ASTRAL-2)
Study Design
This ongoing Phase 3, randomized, open-label, multicenter study is assessing the antiviral 
efficacy, safety, and tolerability of 12 weeks of SOF/VEL treatment compared with 12 weeks of 
SOF+RBV treatment in subjects with chronic genotype 2 HCV infection. The study was 
conducted in the United States (US).
Subjects with genotype 2 HCV infection were randomized (1:1) to treatment with SOF/VEL for 
12 weeks (SOF/VEL 12 Week group) or SOF+RBV for 12 weeks (SOF+RBV 12 Week group). 
Randomization was stratified by the presence or absence of cirrhosis at screening and prior 
treatment experience (treatment naive vs treatment experienced).
Disposition
A total of 266 subjects were randomized and treated; 134 in the SOF/VEL 12 Week group and 
132 in the SOF+RBV 12 Week group. The majority of subjects (99.2%) completed study 
treatment. Two subjects (0.8%), 1 in each treatment group, prematurely discontinued study 
treatment. One subject in the SOF/VEL 12 Week group discontinued study treatment on Day 1 
(after receiving 1 dose of study drug) due to AEs of disturbance in attention, headache, and 
anxiety. One subject in the SOF+RBV 12 Week group completed the Week 10 study visit, but 


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did not return for any subsequent study visits and was assumed to be lost to follow-up; the last 
confirmed dosing date was Day 71.
Demographics and Baseline Characteristics
Overall, demographics and baseline disease characteristics were balanced across both treatment 
groups. The majority of subjects were male (59.4%), and 32.7% of subjects had a BMI 
30 kg/m2. A total of 38 subjects (14.3%) had cirrhosis at screening. Overall, the majority of 
subjects had HCV RNA 800,000 IU/mL (79.7%). Overall, 14.7% (39 subjects) were treatment 
experienced.
Efficacy Results
The SOF/VEL 12 Week group met the primary endpoint of an SVR12 rate that was noninferior 
to the SVR12 rate in the SOF+RBV 12 Week group. The SVR12 rates were as follows:

SOF/VEL 12 Week group: 99.3% (95% CI: 95.9% to 100%) of subjects (133 of 134) 
achieved SVR12

SOF+RBV 12 Week group: 93.9% (95% CI: 88.4% to 97.3%) of subjects (124 of 132) 
achieved SVR12
The strata-adjusted difference (95% CI) in the proportions was 5.2% (0.2% to 10.3%). Since the 
lower bound of the 2-sided 95% CI for the difference between groups was greater than the 
prespecified noninferiority margin of −10%, the efficacy of SOF/VEL for 12 weeks was 
demonstrated to be statistically noninferior to SOF+RBV for 12 weeks. There was sufficient 
evidence to demonstrate the statistical superiority of treatment with SOF/VEL for 12 weeks over 
SOF+RBV for 12 weeks for SVR12 (p = 0.018; CMH test stratified by cirrhosis status and prior 
treatment experience).
In the SOF/VEL 12 Week group, 1 of 134 subjects (0.7%) did not achieve SVR12: the subject 
discontinued study treatment on Day 1 (after receiving 1 dose) due to AEs of difficulty 
concentrating, headache, and anxiety. The subject never achieved HCV RNA LLOQ. In the 
SOF+RBV 12 Week group, 8 of 132 subjects (6.1%) did not achieve SVR12. Of these, 
6 subjects relapsed and 2 were lost to follow-up. Four relapses occurred by the posttreatment 
Week 4 visit and 2 relapses occurred between the posttreatment Week 4 and 12 visits. The low 
number of virologic failures in the study precluded meaningful subgroup analysis of SVR.
The SVR4 results were similar to the SVR12 results with the exception of 3 subjects in 
SOF+RBV 12 Week group: 1 subject was lost to follow-up after posttreatment Week 4 and 
2 subjects relapsed between the posttreatment Week 4 and Week 12 visits.
HCV RNA levels (log10 IU/mL) declined rapidly with similar decreases in HCV RNA observed 
in both treatment groups. After 1 week of treatment, the mean change from baseline in HCV 
RNA levels was 4.51 log10 IU/mL in both treatment groups. The decreases in HCV RNA were 
maintained from Weeks 2 through 12. Consistent with the rapid and sustained decline in 


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HCV RNA, 90.2% of subjects in both treatment groups had HCV RNA LLOQ at Week 4. 
There was a lack of correlation of time to suppression with virologic outcome in the SOF/VEL
12 week group as all subjects who completed treatment achieved SVR regardless of the time to 
suppression.
Virologic Resistance
Deep sequencing analyses indicated that genotype 2a and 2b were the predominant HCV 
subtypes in subjects who were randomized and treated in this study. Approximately 60% and 
10% of subjects in the SOF/VEL 12 Week group had pretreatment NS5A and NS5B RAVs, 
respectively. The most prevalent NS5A RAV observed was L31M in 51% of subjects. Despite 
the presence of pretreatment NS5A and NS5B RAVs, no subjects in the SOF/VEL 12 Week 
group experienced virologic failure in this study. Two of the 6 subjects who relapsed in the 
SOF+RBV 12 Week group had low levels of the NS5B NI RAV L159F detectable at failure.
Safety Results
Overall, treatment with SOF/VEL or SOF+RBV for 12 weeks was generally safe and well 
tolerated. A smaller percentage of subjects in the SOF/VEL 12 Week group experienced any AE 
(68.7%, 92 of 134) compared with the SOF+RBV 12 Week group (76.5%, 101 of 132), 
including treatment-related AEs (SOF/VEL, 33.6%; SOF+RBV, 56.8%) and AEs leading to 
modification or interruption of any study drug (SOF/VEL, 0; SOF+RBV, 9.8%).
The most common AEs (ie, AEs reported in > 10% of subjects in either group) were reported by 
a smaller percentage of subjects in the SOF/VEL 12 Week group compared with the SOF+RBV 
12 Week group, including fatigue (14.9% vs 35.6%), headache (17.9% vs 22.0%), nausea 
(10.4% vs 14.4%), and insomnia (4.5% vs 13.6%). 
Most AEs were Grade 1 (mild) or Grade 2 (moderate) in severity. Grade 3 (severe) AEs were 
rare (SOF/VEL, 2.2%; SOF+RBV, 2.3%). No Grade 4 (life-threatening) AEs were reported. 
Anxiety was the only Grade 3 AE reported in > 1 subject in the SOF/VEL 12 Week group (n = 2, 
1.5%).
Serious adverse events (SAEs) were also rare (1.5%, 4 of 266 subjects [2 in each treatment 
group]). No SAE was reported in 1 subject. All SAEs were considered by the investigators to 
be not related to study drug. Two non-treatment-emergent deaths were reported during the study 
(metastatic lung cancer and cardiac arrest after treatment completion). No pregnancies were 
reported during the study. Only 1 subject permanently discontinued any study drug (SOF/VEL) 
due to AEs. After receiving 1 dose of SOF/VEL, the subject, who had a medical history of 
depression, insomnia and post-traumatic stress disorder, discontinued study treatment due to 
Grade 3 AEs of difficulty concentrating, headache, and anxiety that were assessed as related to 
study drugs by the investigator.
Most subjects had at least 1 laboratory abnormality reported, with the majority being Grade 1 
(104 of 266 subjects, 39.1%) or Grade 2 (70 of 266 subjects, 26.3%) in severity. A smaller 
percentage of subjects had Grade 3 laboratory abnormalities in the SOF/VEL 12 Week group 


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(7.5%, 10 subjects) compared with the SOF+RBV 12 Week group (13.6%, 18 subjects). This
difference was accounted for primarily by the expected decreases in hemoglobin observed with 
RBV therapy. No subjects in the SOF/VEL 12 Week group had a Grade 3 or 4 hematology 
laboratory abnormality. The only Grade 3 hematology laboratories abnormality in the SOF+RBV 
12 Week group were decreased hemoglobin (5.3%, 7 subjects) and increased lymphocytes 
(0.8%, 1 subject). The most common Grade 3 or 4 chemistry laboratory abnormalities in both 
treatment groups were increased serum glucose (hyperglycemia) and increased lipase. Grade 3 
increases in lipase were reported for 7 subjects (5.3%) in the SOF/VEL 12 Week group and 
2 subjects (1.5%) in the SOF+RBV 12 Week group. Grade 4 increases in lipase were reported for 
1 subject (0.8%) in each treatment group. All of the Grade 3 lipase elevations were transient and 
asymptomatic, with no cases of clinical pancreatitis. In the SOF/VEL 12 Week group, 1 subject 
each experienced a Grade 3 or 4 increase in creatine kinase following workout sessions. Grade 3 
hyperbilirubinemia was only observed in the SOF+RBV 12 Week group and was consistent with 
RBV-associated hemolysis. Grade 4 chemistry laboratory abnormalities were reported for lipase 
and creatine kinase.
No notable changes in vital signs (systolic blood pressure, diastolic blood pressure, and pulse) or 
ECGs were reported during the study.
Conclusions 
The conclusions from this interim analysis were as follows:

The study met its predefined primary efficacy endpoint, demonstrating that the SVR12 rate 
of 99.3% with SOF/VEL for 12 weeks was noninferior to the SVR12 rates of 93.9% with 
SOF+RBV for 12 weeks.

Treatment with SOF/VEL for 12 weeks led to a statistically superior SVR12 rate compared 
with SOF+RBV for 12 weeks (p = 0.018). 

No subjects treated with SOF/VEL experienced virologic failure, including subjects with 
cirrhosis (14%), prior treatment failure (14%), and baseline NS5A RAVs (60%).

SOF/VEL was generally well tolerated and, compared with SOF+RBV, lacked toxicities 
associated with RBV. No treatment-emergent deaths, Grade 4 AEs, treatment-related SAEs, 
or clinically relevant laboratory abnormalities were observed.
1.2.2.1.3.
Study GS-US-342-1140 (ASTRAL-3)
Study Design
This ongoing, Phase 3, randomized, open-label, multicenter study is assessing the antiviral 
efficacy, safety, and tolerability of 12 weeks of SOF/VEL treatment compared with 24 weeks of 
SOF+RBV treatment in subjects with chronic genotype 3 HCV infection. This study was 
conducted in Australia, Canada, France, Germany, Italy, New Zealand, United Kingdom and 
United States.


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Subjects with genotype 3 HCV infection were randomized (1:1) to treatment with SOF/VEL for 
12 weeks (SOF/VEL 12 Week group) or SOF+RBV for 24 weeks (SOF+RBV 24 Week group). 
Randomization was stratified by the presence or absence of cirrhosis at screening and prior 
treatment experience (treatment naive vs treatment-experienced).
Disposition
A total of 552 subjects were randomized and treated (277 subjects in the SOF/VEL 12 Week 
group and 275 subjects in the SOF+RBV24 Week group). A total of 21 subjects (7.6%) in the 
SOF+RBV 24 Week group discontinued treatment compared with 2 subjects (0.7%) in the 
SOF/VEL 12 Week group. The most common reason for discontinuation of treatment for 
subjects in the SOF+RBV 24 Week group was AEs (9 subjects, 3.3%).
Demographics and Baseline Characteristics
The majority of subjects were male (62.3%), and 20.3% of subjects had a BMI ≥30 kg/m2. 
Overall, the majority of subjects had HCV RNA ≥800,000 IU/mL (69.7%). A total of 
163 subjects (29.5%) had cirrhosis at screening. Overall, 25.7% (142 subjects) were treatment 
experienced.
Efficacy Results
The study met the primary efficacy endpoint. The SVR12 rate for the SOF/VEL 12 Week group 
was statistically noninferior to the SVR12 rate for the SOF+RBV 24 Week group. The SVR12 
rates were as follows:

SOF/VEL 12 Week group: 95.3% (95% CI: 92.1% to 97.5%) of subjects (264 of 277) 
achieved SVR12.

SOF+RBV 24 Week group: 80.4% (95% CI: 75.2% to 84.9%) of subjects (221 of 275) 
achieved SVR12.
The strata-adjusted difference (95% CI) in the proportions was 14.8% (9.6% to 20.0%). The 
superiority of treatment with SOF/VEL for 12 weeks over SOF+RBV for 24 weeks for SVR12 
was also demonstrated (p < 0.001; CMH test stratified by cirrhosis status and prior treatment 
experience).
In the SOF/VEL 12 Week group, 13 of 277 subjects (4.7%) did not achieve SVR12. Of these, 
no subjects had on-treatment virologic failure, 11 subjects relapsed, and 2 subjects were lost to 
follow-up. In the SOF+RBV 24 Week group, 54 of 275 subjects (19.6%) did not achieve SVR12. 
Of these, 1 subject had on-treatment virologic failure (nonresponse), 38 subjects relapsed, and 
15 subjects did not achieve SVR12 for reasons other than virologic failure. These 15 subjects 
included 6 subjects who were lost to follow-up or who did not attend a posttreatment Week 12 
visit, 4 subjects who withdrew from the study due to AEs, 2 subjects who withdrew consent from 
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achieve HCV RNA < LLOQ on treatment, and did not meet the protocol definition for virologic 
failure.
Most relapses occurred by the posttreatment Week 4 visit. In the SOF/VEL 12 Week group, 8 of 
11 relapses occurred by posttreatment Week 4, and 3 of 11 relapses occurred between 
posttreatment Weeks 4 and 12. 
Across the 2 treatment groups, the SVR12 rates consistently favored the SOF/VEL 12 Week 
group over the SOF+RBV 24 Week group. Within each treatment group, the SVR12 rates for 
most subgroups were generally consistent with those observed in the overall population. In the 
SOF/VEL 12 Week group, the SVR12 rates for subjects with and without cirrhosis were 91.3% 
(73 of 80) and 97.0% (191 of 197), respectively, and the SVR12 rates for treatment-naive and 
treatment-experienced subjects were 97.1% (200 of 206) and 90.1% (64 of 71), respectively. In 
the SOF+RBV 24 Week group, subjects with cirrhosis had considerably lower SVR12 rates 
(66.3%; 55 of 83) than subjects without cirrhosis (87.2%; 163 of 187), and subjects with prior 
treatment experience had considerably lower SVR12 rates (63.4%; 45 of 71) than 
treatment-naive subjects (86.3%; 176 of 204).
HCV RNA levels (log10 IU/mL) declined rapidly, with similar decreases in HCV RNA observed 
in both treatment groups. Consistent with the rapid and sustained decline in HCV RNA, 91.7% 
of subjects in the SOF/VEL 12 Week group and 88.2% of subjects in the SOF+RBV 24 Week 
group had HCV RNA < LLOQ at Week 4. Time to virologic suppression did not impact 
virologic outcomes in the SOF/VEL 12 Week group: SVR12 rates were 96.0% and 95.7% 
among those subjects with HCV RNA < LLOQ and those with HCV RNA ≥LLOQ at Week 4, 
respectively.
Virologic Resistance
Pretreatment NS5A and NS5B NI RAVs were present in 16% and 4% of subjects, respectively, 
in the SOF/VEL 12 Week group. There was a numerically lower SVR12 rate in 
SOF/VEL -treated subjects with baseline NS5A RAVs compared with subjects without NS5A 
RAVs (88% vs 97%, respectively). All subjects with NS5B NI RAVs in the SOF/VEL 12 Week 
group achieved SVR12.
A total of 10 subjects in the SOF/VEL 12 Week group relapsed, and 1 subject was reinfected. All 
10 subjects had the NS5A RAV Y93H detected at relapse time points. No SOF/VEL -treated 
subjects had NS5B NI RAVs emerge at relapse. The NS5B NI RAVs (N142T, L159F, or 
V321A) emerged in 7 of 39 subjects in the SOF+RBV 24 Week group who had virologic failure.
Safety Results
Overall, treatment with SOF/VEL for 12 weeks or SOF+RBV for 24 weeks was generally safe 
and well tolerated. A lower percentage of subjects in the SOF/VEL 12 Week group experienced 
any AE (88.4%; 245 of 277) compared with the SOF+RBV 24 Week group (94.5%; 260 of 275). 


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Most AEs were Grade 1 (mild) or Grade 2 (moderate) in severity. Grade 3 (severe) AEs were 
reported for 4.3% (12 subjects) in the SOF/VEL 12 Week group and 7.3% (20 subjects) in the 
SOF+RBV 24 Week group. Grade 4 (life-threatening) AEs were reported for no subjects in the 
SOF/VEL 12 Week group and 1.1% (3 subjects) in the SOF+RBV 24 Week group (death due to 
natural causes in 1 subject, cerebrovascular accident in 1 subject, and multiple gunshot wounds 
in 1 subject).
Of the most common AEs (ie, AEs reported in ≥10% of subjects in either treatment group), a 
lower percentage of subjects in the SOF/VEL 12 Week group compared with the SOF+RBV 
24 Week group experienced fatigue (25.6% vs 38.2%), insomnia (11.2% vs 26.9%), nausea 
(16.6% vs 21.1%), irritability (8.3% vs 14.5%), cough (5.1% vs 12.7%), pruritus (2.9% vs 
12.7%), and dyspepsia (3.2% vs 10.9%).
Serious adverse events were reported for 2.2% (6 subjects) in the SOF/VEL 12 Week group and 
5.5% (15 subjects) in the SOF+RBV 24 Week group. No SAE was reported in > 1 subject, and 
no SOV/VEL-treated subject had a treatment-related SAE. Three subject deaths were reported 
during the study (1 treatment-emergent death due to natural causes, 1 treatment-emergent death 
due to multiple gunshot wounds, and 1 nontreatment-emergent death due to an unknown cause); 
all 3 subjects were in the SOF+RBV 24 Week group. A total of 9 subjects (in the SOF+RBV 
24 Week group) prematurely discontinued study drugs due to an AE. The most common AE 
resulting in discontinuation of study drug in the SOF+RBV 24 Week group was insomnia (1.1%, 
3 subjects).
Most subjects had at least 1 laboratory abnormality reported, with the majority being Grade 1 
(36.3%; 200 of 551 subjects) or Grade 2 (29.6%; 163 of 551 subjects) in severity. A lower 
percentage of subjects had Grade 3 laboratory abnormalities in the SOF/VEL 12 Week group 
(5.8%, 16 of 276) compared with the SOF+RBV 24 Week group (14.2%, 39 of 275). This 
difference was accounted for primarily by the expected decreases in hemoglobin observed during 
treatment with RBV. Grade 4 laboratory abnormalities were similarly low in the SOF/VEL
12 Week group (1.4%, 4 of 276) compared with the SOF+RBV 24 Week group (2.9%, 8 of 275).
The only Grade 3 or 4 hematology laboratory abnormality in the SOF/VEL 12 Week group 
occurring in more than 1 subject was decreased lymphocytes (1.1%, 3 of 276 subjects). 
One subject had normal lymphocytes throughout treatment and a Grade 3 decrease at the 
posttreatment Week 4 visit. The other 2 subjects had Grade 2 or 3 decreased lymphocytes at 
baseline that transiently decreased by 1 grade during treatment.
The most common Grade 3 or 4 chemistry laboratory abnormalities in both treatment groups 
were increased lipase, increased serum glucose (hyperglycemia), and increased creatine kinase. 
Grade 3 or 4 increases in lipase were reported for 9 subjects (3.3%) in the SOF/VEL 12 Week 
group and 5 subjects (1.8%) in the SOF+RBV 24 Week group. All of the Grade 3 or 4 increases 
in lipase were asymptomatic, with no cases of clinical pancreatitis. Grade 3 increases in serum 
glucose (hyperglycemia) were reported for 4 subjects (1.4%) in the SOF/VEL 12 Week group 
and 5 subjects (1.8%) in the SOF+RBV 24 Week group. All subjects with Grade 3 increased 
serum glucose had either a medical history of diabetes or HbA1c ≥6.0% at screening. Grade 3 
or 4 increases in creatine kinase were reported for 2 subjects (0.7%) in the SOF/VEL 12 Week 


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group and 4 subjects (1.5%) in the SOF+RBV 24 Week group. All of the Grade 3 or 4 creatine 
kinase elevations were transient and asymptomatic; the majority were associated with exercise. 
Grade 3 or 4 increases in total bilirubin (hyperbilirubinemia) were observed only in the 
SOF+RBV 24 Week group (Grade 3: 2 subjects, 0.7%; Grade 4: 1 subject, 0.4%). The timing 
and magnitude of the increases in total bilirubin were consistent with RBV-induced hemolysis.
No notable changes in vital signs (systolic blood pressure, diastolic blood pressure, and pulse) 
were reported during the study.
Conclusions 
The conclusions from this interim analysis were as follows:

The study met its predefined primary efficacy endpoint: subjects with genotype 3 HCV 
infection in the SOF/VEL 12 Week group achieved an SVR12 rate of 95.3% that was 
statistically noninferior to the SVR12 rate of 80.4% achieved by subjects with genotype 3 
HCV infection in the SOF+RBV 24 Week group.
— The superiority of treatment with SOF/VEL for 12 weeks over SOF+RBV for 24 weeks 
for SVR12 was also demonstrated (p < 0.001).

Across the 2 treatment groups, the SVR12 rates consistently favored the SOF/VEL 12 Week
group over the SOF+RBV 24 Week group. 
— For subjects with cirrhosis, the SVR12 rates (SOF/VEL 12 Weeks vs SOF+RBV 
24 Weeks) were 91.3% and 66.3%, respectively.
— For treatment-experienced subjects, the SVR12 rates (SOF/VEL 12 Weeks vs SOF+RBV 
24 Weeks) were 90.1% and 63.4%, respectively.

Among the 16% of SOF/VEL -treated subjects with baseline NS5A RAVs, the SVR12 rate 
was numerically lower (88%) compared with subjects without baseline NS5A RAVs (SVR12 
rate of 97%).

SOF/VEL was generally well tolerated and, compared with SOF+RBV, lacked toxicities 
associated with RBV. No treatment-emergent deaths, Grade 4 AEs, treatment-related SAEs, 
discontinuations due to AEs, or clinically relevant laboratory abnormalities were observed in 
SOF/VEL -treated subjects.
1.2.2.1.4.
Study GS-US-342-1137 (ASTRAL-4)
Study Design
This ongoing, Phase 3, randomized, open-label, multicenter study is assessing the antiviral 
efficacy, safety, and tolerability of SOF/VEL ±RBV for 12 weeks and SOF/VEL for 24 weeks in 
subjects with chronic HCV infection and Child-Pugh-Turcotte (CPT) class B cirrhosis. The study 
was conducted in the US.


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Subjects with genotype 1 to 6 HCV infection with CPT class B cirrhosis were randomized 
(1:1:1) to SOF/VEL for 12 weeks (SOF/VEL 12 Week group), SOF/VEL +RBV for 12 weeks 
(SOF/VEL +RBV 12 Week group), or SOF/VEL for 24 weeks (SOF/VEL 24 Week group). 
Randomization was stratified by HCV genotype (1, 2, 3, 4, 5, 6, and indeterminate).
Disposition
A total of 267 subjects were included in the Safety and Full Analysis Sets (90 subjects in the 
SOF/VEL 12 Week group, 87 subjects in the SOF/VEL +RBV 12 Week group, and 90 subjects 
in the SOF/VEL 24 Week group).
Of the 90 subjects in the SOF/VEL 12 Week group, 89 subjects (98.9%) completed study drug
and 1 subject (1.1%) discontinued due to an AE.
Of the 87 subjects in the SOF/VEL +RBV 12 Week group, 82 subjects (94.3%) completed study 
drug; 4 subjects (4.6%) discontinued due to AEs and 1 subject (1.1%) discontinued due to 
virologic failure (pharmacokinetic [PK] data for this subject indicated noncompliance with study 
drugs).
Of the 90 subjects in the SOF/VEL 24 Week group, 84 subjects (93.3%) completed study drug; 
4 subjects (4.4%) discontinued due to AEs, 1 subject (1.1%) discontinued due to virologic 
failure, and 1 subject (1.1%) discontinued due to noncompliance with study drug.
Demographics and Baseline Characteristics
Overall, demographics and baseline disease characteristics were balanced across the treatment 
groups.Of the 267 subjects randomized and treated, 207 subjects (77.5%) had genotype 1 HCV 
infection, 12 subjects (4.5%) had genotype 2 HCV infection, 39 subjects (14.6%) had genotype 3 
HCV infection, 8 subjects (3.0%) had genotype 4 HCV infection, and 1 subject (0.4%) in the 
SOF/VEL 24 Week group had genotype 6 HCV infection. The majority of subjects were male 
(69.7%), and 42.3% of subjects had a BMI 30 kg/m2. Most subjects (55.1%) had prior 
treatment experience and the majority of subjects had HCV RNA ≥800,000 IU/mL (55.8%).
Efficacy Results
The SVR12 rates were as follows:

SOF/VEL 12 Week group: 83.3% (95% CI: 74.0% to 90.4%) of subjects (75 of 90) achieved 
SVR12

SOF/VEL +RBV 12 Week group: 94.3% (95% CI: 87.1% to 98.1%) of subjects (82 of 87) 
achieved SVR12

SOF/VEL 24 Week group: 85.6% (95% CI: 76.6% to 92.1%) of subjects (77 of 90) achieved 
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All 3 treatment groups met their primary efficacy endpoints with SVR12 rates that were 
statistically superior compared with the assumed spontaneous rate of 1%. The p-value 
was < 0.001 for the comparison with the SVR12 for each treatment group. 
Among subjects with genotype 1 HCV infection, the SVR12 rate was higher for those in the 
SOF/VEL +RBV 12 Week group (95.6%, 65 of 68) compared with the SOF/VEL 12 Week 
group (88.2%, 60 of 68) or the SOF/VEL 24 Week group (91.5%, 65 of 71). Similarly, among 
subjects with genotype 3 HCV infection, the SVR12 rate was higher for those in the SOF/VEL
+RBV 12 Week group (84.6%, 11 of 13) compared with the SOF/VEL 12 Week group (50.0%, 7 
of 14) or the SOF/VEL 24 Week group (50.0%, 6 of 12).
All subjects with genotype 2, 4, or 6 HCV infection achieved SVR12 across all treatment groups 
with the exception of 1 subject with genotype 2 HCV infection in the SOF/VEL 24 Week group 
who died 39 days after completing 28 days of treatment.
Most virologic failures were due to relapse. One subject with genotype 3 HCV infection in the 
SOF/VEL +RBV 12 Week group had on-treatment breakthrough with PK data showing 
undetectable plasma drug levels consistent with non-adherence to study drug and 1 subject with 
genotype 3 HCV infection in the SOF/VEL 24 Week group had on-treatment breakthrough.
There was 1 subject (1.5%) with genotype 1 HCV infection with virologic failure in the 
SOF/VEL +RBV 12 Week group compared with 5 subjects (7.4%) in the SOF/VEL 12 Week 
group and 3 subjects (4.2%) in the SOF/VEL 24 Week group. Among subjects with genotype 3 
HCV infection, the lowest rate of virologic failure was observed in the SOF/VEL +RBV 12 
Week group with 2 failures (15.4%) compared with 6 (42.9%) in the SOF/VEL 12 Week group 
and 5 (41.7%) in the SOF/VEL 24 Week group. 
There were no virologic failures in subjects with genotype 2, 4, or 6 HCV infection in any of the 
treatment groups.
Treatment with SOF/VEL +RBV for 12 weeks resulted in high SVR12 rates irrespective of 
genotype, prior treatment history, baseline HCV RNA, and presence of pretreatment NS5A or 
NS5B RAVs. Furthermore, there was no impact of demographic factors such as age, sex, BMI, 
or IL28B genotype on treatment outcome in the SOF/VEL +RBV 12 Week group.
Overall, 108 subjects (47.2%) had an improvement in CPT score (range: 1−5 points) while 
99 subjects (43.2%) had no change. A minority of subjects (9.6%, 22 subjects) experienced an 
increase (worsening) in CPT score from baseline to posttreatment Week 12. A higher percentage 
of subjects receiving SOF/VEL for 24 weeks (54.7%) compared with subjects receiving 
SOF/VEL ±RBV for 12 weeks (40.7%−46.6%) had improvements in CPT score from baseline to 
posttreatment Week 12; this difference likely reflects the longer time of observation with HCV 
RNA suppression. The improvements in CPT score were largely due to improvements in 
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Overall, the majority of subjects who achieved SVR12 also had a decrease (improvement) 
(55.5%, 127 of 229 subjects) in MELD score between baseline and posttreatment Week 12 
(range: 1−11 points). Among subjects who had MELD score < 15 at baseline and achieved 
SVR12, 197 of 203 subjects (97.0%) remained < 15 at posttreatment Week 12. A total of 
16 subjects (61.5%) with baseline MELD score ≥15 who achieved SVR12 improved to < 15. 
Improvements in MELD score were largely due to improvements in total bilirubin.
Virologic Resistance
Pretreatment NS5A RAVs were observed in 26% to 29% of subjects across the treatment groups. 
The presence of pretreatment NS5A RAVs did not impact treatment outcome in the SOF/VEL
+RBV 12 Week group. Slightly lower SVR rates were observed in subjects with genotype 1 
HCV infection with NS5A RAVs treated with SOF/VEL for 12 or 24 weeks compared to 
subjects without pretreatment NS5A RAVs. No virologic failures were observed in subjects with 
genotype 2, 4, or 6 HCV infection. The small numbers of subjects with genotype 3 HCV 
infection with pretreatment NS5A RAVs precluded meaningful subgroup analysis. The presence 
of pretreatment NS5B RAVs did not impact treatment outcome in any treatment group.
The majority of subjects had NS5A RAVs present at virologic failure with Y93H being the most 
common variant. NS5B NI RAVs were less common and typically observed at low levels. Of the 
9 subjects with genotype 1 HCV infection with virologic failure, 6 had NS5A RAVs at failure 
(5 treatment emergent and 1 maintained from pretreatment). Two genotype 1 HCV-infected 
subjects had L159F and S282T NS5B NI RAVs present at failure; both of these subjects had 
multiple NS5A RAVs at pretreatment that reduce susceptibility to VEL. All 13 subjects with 
genotype 3 HCV infection with virologic failure had Y93H at failure (10 were treatment 
emergent). Three genotype 3 HCV-infected subjects had low levels of NS5B NI RAVs emerge at 
virologic failure.
Safety Results
Overall, treatment with SOF/VEL ±RBV for 12 weeks or SOF/VEL for 24 weeks was generally 
safe and well tolerated. Adverse events were consistent with the expected clinical sequelae in the 
setting of decompensated cirrhosis and, in addition, with the known toxicities of RBV in the 
SOF/VEL +RBV 12 Week group.
A smaller percentage of subjects in the SOF/VEL 12 Week and SOF/VEL 24 Week groups 
experienced any AE (81.1% in each group) compared with the SOF/VEL +RBV 12 Week group 
(90.8%). The higher frequency of AEs observed in the SOF/VEL +RBV 12 Week group was 
primarily due to AEs consistent with RBV-associated toxicity. No treatment-related Grade 3 AEs 
were reported in > 1 subject in any group or overall. 
Most AEs were Grade 1 (mild) or Grade 2 (moderate) in severity. Overall, the most commonly 
reported Grade 3 or 4 AEs were hepatic encephalopathy and sepsis (5 subjects each), which are 
consistent with the natural history of disease progression in a population with decompensated 
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Serious adverse events (SAEs) occurred in 17.6% of subjects in similar proportions across 
treatment groups, and only 1 subject (0.4%) experienced SAEs considered related to SOF/VEL. 
The most commonly reported SAEs were hepatic encephalopathy and sepsis (5 subjects each). 
Nine deaths occurred during the study, 2 of which were treatment emergent, and none of which 
was assessed as related to study drugs. One subject in the SOF/VEL 24 Week group underwent a 
liver transplantation on posttreatment Day 8 after completing 35 days of treatment.
Nine subjects discontinued all study drugs due to an AE (SOF/VEL 12 Week group: 1.1%, 
1 subject; SOF/VEL +RBV 12 Week group: 4.6%, 4 subjects; SOF/VEL 24 Week group: 4.4%, 
4 subjects). No AE leading to discontinuation of study drugs was reported in > 1 subject. A total 
of 31.0% (27 of 87) of subjects had modified or interrupted RBV dosing due to AEs, and 10.3% 
(9 of 87) of subjects permanently discontinued RBV due to AEs while continuing SOF/VEL.
The majority of subjects had at least 1 Grade 3 or 4 laboratory abnormality (42.7% and 12.4%, 
respectively) with the highest rates observed in the SOF/VEL +RBV group (Grade 3: 43.7%; 
Grade 4 18.4%) due to a higher rate of hematologic abnormalities. The most commonly observed 
Grade 3 or 4 hematology laboratory abnormalities were decreased lymphocytes, hemoglobin, 
and platelet counts, all of which are a known effect of RBV therapy or expected in a subject 
population with decompensated liver disease. 
The most commonly observed Grade 3 or 4 chemistry laboratory abnormalities were increased 
glucose and increased total bilirubin. All of the Grade 3 or 4 increased glucose abnormalities 
occurred in subjects with a history of diabetes mellitus or had elevated glucose at baseline or 
continuing through the posttreatment period. The majority of subjects with Grade 3 or 4 
increased total bilirubin (71.7%, 22 of 31 subjects) were in the SOF/VEL +RBV 12 Week group, 
primarily in a pattern that was consistent with RBV-induced hemolysis. 
No notable changes in vital signs (systolic blood pressure, diastolic blood pressure, and pulse) 
were reported during the study. No trends in electrocardiogram findings suggestive of 
cardiotoxicity were observed.
Conclusions 
The conclusions from this interim analysis were as follows:

Treatment with SOF/VEL ±RBV for 12 or 24 weeks in subjects with decompensated 
cirrhosis resulted in high SVR12 rates:
— In the SOF/VEL 12 Week group, the SVR12 rate was 83.3% (75 of 90 subjects).
— In the SOF/VEL +RBV 12 Week group, the SVR12 rate was 94.3% (82 of 87 subjects).
— In the SOF/VEL 24 Week group, the SVR12 rate was 87.8% (79 of 90 subjects).


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
The SVR12 rates were highest in subjects treated with SOF/VEL +RBV for 12 weeks with 
few virologic failures:
— In subjects with genotype 1 HCV infection, the virologic failure rate was 1.5% (1 of 
68 subjects).
— In subjects with genotype 3 HCV infection, the virologic failure rate was 15.4% (2 of 
13 subjects), of which 1 subject had on-treatment breakthrough with PK data showing 
undetectable plasma drug levels consistent with non-adherence to study drug.

Overall, there were no virologic failures in subjects with genotype 2, 4, or 6 HCV infection.

The SVR12 rates between the SOF/VEL 12- and 24-week treatment durations were similar 
across all genotypes.

The presence of pretreatment NS5A and NS5B RAVs did not impact treatment outcome with 
SOF/VEL +RBV for 12 weeks.

Approximately half of subjects who achieved SVR12 experienced an early improvement in 
CPT and MELD scores, primarily related to improvements in synthetic function (albumin) 
and decreases in bilirubin.

SOF/VEL was generally well tolerated in these subjects with decompensated liver disease, as 
evidenced by low rates of study treatment discontinuation and the majority of Grade 3 and 4 
AEs, SAEs, and laboratory abnormalities being consistent with clinical sequelae of advanced 
liver disease and RBV toxicity.
1.2.2.1.5.
Study GS-US-342-1202 (ASTRAL-5)
Study Design
This ongoing, Phase 3, open-label, multicenter study is assessing the antiviral efficacy, safety, 
and tolerability of SOF/VEL for 12 weeks in subjects with chronic HCV infection and HIV-1 
coinfection. This study is being conducted in the US, New Zealand, and Australia.
Approximately 100 subjects with genotype 1 to 6 HCV infection with HIV-1 coinfection on a 
stable regiment of HIV antiretroviral therapy (ARV) are all scheduled to receive SOF/VEL for 
12 weeks.  The primary outcome is the proportion of subjects who achieve SVR12.
1.2.2.1.6.
Study GS-US-342-1553
Study Design
This ongoing, open-label, multicenter study is assessing the antiviral efficacy, safety, and 
tolerability of SOF/VEL ±RBV for 24 weeks in subjects with chronic HCV infection who have 
participated in prior Gilead sponsored HCV treatment studies. This study is being conducted in 
the US, New Zealand, and Australia.


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Approximately 150 subjects with and without cirrhosis with genotype 1 to 6 HCV infection who 
did not achieve SVR12 in previous Gilead sponsored HCV treatment studies will all receive 
SOF/VEL + RBV for 24 weeks). The primary outcome is the proportion of subjects who achieve 
SVR12.
1.2.2.1.7.
Study GS-US-342-1446
Study Design
This ongoing, open-label, multicenter study is assessing the antiviral efficacy, safety, and 
tolerability of SOF/VEL for 12 weeks in subjects who received placebo in 
study GS-US-342-1138 (ASTRAL 1). This study is being conducted in the US, Canada, Europe, 
and Asia.
Approximately 100 subjects with genotype 1, 2, 4, 5, and 6 HCV infection who received placebo 
in ASTRAL 1 will all receive SOF/VEL 12 weeks. The primary outcome is the proportion of 
subjects who achieve SVR12.
1.2.2.2.
Clinical Pharmacology Studies
1.2.2.2.1.
Study GS-US-281-1058
GS-US-281-1058 is an open-label, Phase 1, multiple-dose drug-drug interaction (DDI) study in 
healthy female subjects of childbearing age evaluating the effect of VEL on the 
pharmacokinetics of a representative hormonal oral contraceptive medication, 
norgestimate/ethinyl estradiol (NGM/EE, OC). Following screening, eligible subjects were 
enrolled in a lead-in period (Part A) of 28 days during which they completed dosing with the 
hormonal oral contraceptive (OC) prior to baseline assessments and initiation of Cycle 1 
(Part B). Subjects with a documented history of taking OC for at least 1 menstrual cycle could be 
enrolled directly into Cycle 1. The PK, safety, and tolerability of OC and OC + VEL were 
assessed in Part B of the study, which consisted of 2 cycles: subjects received OC alone during 
Cycle 1, and OC plus VEL 100 mg once daily during days 8-14 of Cycle 2. Fifteen subjects were 
enrolled, and 13 completed the study. Two subjects were discontinued from the study prior to 
initiation of Cycle 2 (OC+VEL) for laboratory abnormalities. 
Table 1-2 presents the steady-state PK parameters and statistical comparisons of NGM 
metabolites norelgestromin (NGMN) and norgestrel (NG) and EE following administration alone 
or in combination with VEL. Steady-state VEL PK parameters were also assessed. Norgestimate 
was not quantifiable for all subjects at most time points. Similar systemic exposure of NGMN 
and NG were achieved following NGM/EE administration with VEL relative to administration of 
NGM/EE alone. A modest increase in EE Cmax was observed when administered with VEL with 
no change in overall exposure (AUC) or Ctau. The magnitude of increase in EE Cmax when 
administered with VEL is similar to that observed with the concomitant administration of other 
drugs such as voriconazole and etravirine, which did not warrant dose adjustment {Andrews et al 
2008}, {Janssen Pharmaceuticals Inc. 2013}. VEL exposures were consistent with historical data 
(Studies GS-US-281-0115, GS-US-342-0104).


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Protocol GS-US-342-2097
Final
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Table 1-2.
NGMN, NG, EE, and VEL Plasma PK Parameters Following 
Administration of NGM/EE alone or with VEL
PK Parameter
Mean (%CV)
GLSM Ratio 
(90% CI) NGM/EE + VEL vs. 
NGM/EE
NGM/EE Alone 
(N = 15)
NGM/EE + VEL 
(N = 13)
Norelgestromin
AUCtau (pg•h/mL)
17,700 (16.7)
15,700 (11.2)
0.90 (0.82, 0.98)
Cmax (pg/mL)
1650 (16.8)
1600 (13.7)
0.97 (0.88, 1.07)
Ctau (pg/mL)
454 (18.5)
416 (14.3)
0.92 (0.83, 1.03)
Norgestrel
AUCtau (pg•h/mL)
47,000 (34.4)
43,000 (32.4)
0.91 (0.73, 1.15)
Cmax (pg/mL)
2410 (30.6)
2330 (31.5)
0.96 (0.78, 1.19)
Ctau (pg/mL)
1760 (34.4)
1640 (35.7)
0.92 (0.73, 1.18)
Ethinyl Estradiol
AUCtau (pg•h/mL)
666 (30.7)
686 (27.3)a
1.04 (0.87, 1.24)
Cmax (pg/mL)
57.5 (27.3)
80.0 (28.4)a
1.39 (1.17, 1.66)
Ctau (pg/mL)
14.8 (39.3)
12.4 (43.9)a
0.83 (0.65, 1.06)
Velpatasvir
AUCtau (ng•h/mL)
--
4680 (35.1)
--
Cmax (ng/mL)
--
626 (22.0)
--
Ctau (ng/mL)
--
68.3 (47.6)
--
Note: preliminary data presented to 3 significant figures.
a
N = 12
Luteinizing hormone (LH), follicle stimulating hormone (FSH), and progesterone concentrations 
were similar in both treatment cycles, as presented in Table 1-3. Luteinizing hormone and 
progesterone median values were lower than those expected for ovulatory or luteal phases, 
respectively {Quest Diagnostics 2013b}, {Quest Diagnostics 2013a}, {Barditch-Crovo et al 
1999}. Follicle stimulating hormone was lower or within the expected range for the ovulatory 
phase {Quest Diagnostics 2013a}. These results are consistent with a possible decrease in serum 
LH and FSH by hormonal contraceptives and absence of ovulation, as assessed by very low 
progesterone values on cycle Day 21.
Table 1-3.
Summary of LH, FSH, and Progesterone Concentrations Following 
Administration of NGM/EE alone or with VEL
PD Analyte
Median (Q1, Q3)
OC Alone (N = 15)
OC + GS-5816 (N = 13)
LH (mIU/mL)
8.0 (2.9, 12.7)
9.3 (5.4, 14.4)
FSH (mIU/mL)
3.6 (2.0, 5.9)
2.6 (2.2, 5.1)
Progesterone (ng/mL)
0.24 (0.17, 0.39)
0.27 (0.18, 0.80)


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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16 March 2016
Based on these results, no loss in contraceptive efficacy is expected upon administration of 
combined oral contraceptives containing norgestimate/ethinyl estradiol with VEL. 
Study GS-US-334-0146 previously demonstrated that the use of SOF with contraceptives 
(e.g., norgestimate/ethinyl estradiol) is permitted. Accordingly, the use of hormonal 
contraceptives with VEL as a single agent or as part of SOF/VEL FDC is permitted. 
1.2.2.2.2.
Drug-Drug Interaction Studies with SOF/VEL and Gastric Acid Suppressants
GS-US-342-1346 and GS-US-342-1709 were open-label, Phase 1, single-dose drug-drug 
interaction studies in healthy volunteers evaluating the effect of gastric acid suppressants 
(H2RAs and PPIs) on the PK of SOF/VEL. A summary of results from these studies are 
presented in the table below.
Study GS-US-342-1346 demonstrated that simultaneous or staggered (12 hour) administration of 
SOF/VEL, administered under fasting conditions, with famotidine 40 mg resulted in no change 
to the AUC of SOF or VEL, suggesting that SOF/VEL can be administered simultaneously or 
staggered with H2RAs at doses comparable to famotidine 40 mg. Study GS-US-342-1346 also 
demonstrated that simultaneous or staggered (12 hour) administration of SOF/VEL, administered 
under fasting conditions, with omeprazole 20 mg resulted in a reduction in VEL AUC of 37% 
and 56%, respectively. The AUC of SOF also decreased 29% to 44%, respectively, though these 
effects are secondary to the impact of PPIs on VEL, as SOF does not demonstrated pH-
dependent solubility. Based on these data, the use of SOF/VEL under fasting conditions with 
PPIs is not recommended. 
Study GS-US-342-1709 evaluated the effect of omeprazole 20 mg or 40 mg on the PK of 
SOF/VEL when SOF/VEL is administered with food. Administration of SOF/VEL with food and 
omeprazole did not alter the overall exposure (AUC) of SOF or its metabolites, regardless of 
timing or dose of omeprazole. Administration of SOF/VEL with food and omeprazole resulted in 
a decrease in VEL exposure. The smallest decrease in VEL exposure (AUC: 26%, Cmax: 33%) 
was observed following administration of SOF/VEL with food 4 hours before omeprazole 
20 mg. A slightly greater decrease in VEL exposure (AUC: 38%, Cmax: 48%) was observed when 
SOF/VEL was administered with food 2 hours after omeprazole 20 mg. The largest decline in 
VEL exposure (AUC: 53%, Cmax: 56%) was observed following SOF/VEL administration with 
food 4 hours before omeprazole 40 mg.
Collectively, these studies indicate that PPIs can impact the PK of SOF/VEL. Administration of 
SOF/VEL with food reduces the effect of omeprazole on SOF/VEL PK. The overall exposure of 
SOF and its metabolites were not affected by omeprazole 20 mg when SOF/VEL was 
administered with food, and the reduction in VEL exposure was less when administered with 
food (26% to 38%) compared to fasted administration (37% to 56%). Staggering timing of 
omeprazole 20 mg and SOF/VEL administration also modestly impacted VEL exposure; VEL 
AUC was least impacted when administered 4 hours before omeprazole 20 mg (equivalent to 
20 hours after the previous omeprazole dose). 


SOF/VEL FDC
Protocol GS-US-342-2097
Final
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Study GS-US-342-1709 also demonstrates that the nature of VEL exposure decrease was not 
uniform across the study population. Largest decreases were observed in subjects with highest 
exposure at reference, and those with low exposure at reference were generally unaffected by 
administration with a PPI. These data suggests that gastric pH is a contributor to the natural 
variability of VEL, and the range of exposure for HCV-infected subjects on PPIs is expected to 
be within that observed in Phase 3 ASTRAL studies. Accordingly, PPI doses comparable with 
omeprazole 20 mg can be administered with SOF/VEL when SOF/VEL is administered with 
food.
Table 1-4.
Summary of Changes in SOF/VEL PK following administration with 
Representative H2RAs and PPIs 
Study
Dosing 
Scheme
SOF PK Parameters
GS-331007 PK Parameters
VEL PK Parameters
AUClast
AUCinf
Cmax
AUClast
AUCinf
Cmax
AUClast
AUCinf
Cmax
GS-US-
342-1346 
(N=60)
SOF/VEL
(fasted) with 
simultaneous 
FAM 40 mg
↔
↔
↔
↔
↔
↔
↔
↔
↔
SOF/VEL
(fasted) with 
12 hours 
after FAM 
40 mg
↔
↔
↓23%
↔
↔
↔
↔
↔
↔
SOF/VEL
(fasted) with 
simultaneous 
OME 20 mg
↓29%
↓29%
↓34%
↔
↔
↔
↓37%
↓36%
↓37%
SOF/VEL
(fasted) 12 
hours after 
OME 20 mg 
↓44%
↓44%
↓45%
↔
↔
↔
↓56%
↓55%
↓57%
GS-US-
342-1709
(N=40)
SOF/VEL
(fed) 2 hours 
After OME
20 mg
↔
↔
↓16%
↔
↔
↔
↓38%
↓38%
↓48%
SOF/VEL
(fed)  4 hours 
Before OME
20 mg
↔
↔
↓21%
↔
↔
↔
↓26%
↓26%
↓33%
SOF/VEL
(fed) 4 hours 
Before OME
40 mg
↔
↔
↓30%
↔
↔
↔
↓53%
↓53%
↓56%
FAM = famotidine; OME = omeprazole
The 90% CIs of the %GLSM ratios were within (↔), or extended below (↓) the predetermined 
PK alteration boundary of 70%.


SOF/VEL FDC
Protocol GS-US-342-2097
Final
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Original
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1.2.2.2.3.
Study GS-US-342-1167 
Study GS-US-342-1167 evaluated safety, tolerability, and pharmacokinetics of SOF, its 
metabolites GS-566500 and GS-331007, and GS-5816 following administration of SOF/VEL
(400/100 mg) with Atripla® (ATR; efavirenz/emtricitabine/tenofovir disoproxil fumarate 
[EFV/FTC/TDF]), Eviplera® (emtricitabine/rilpivirine/tenofovir disoproxil fumarate 
[FTC/RPV/TDF]), Tivicay® (dolutegravir [DTG]), or 
elvitegravir/cobicistat/emtricitabine/tenofovir alafemamide fumarate (EVG/COBI/FTC/TAF).
Table 1-5 summarizes the differences in PK parameters of SOF, its metabolites GS-566500 and 
GS-331007, GS-5816, and evaluated ARVs (EFV, RPV, DTG, EVG, COBI, FTC, TAF, and 
TFV) when SOF/GS-5816 or the ARVs were administered alone compared with administration 
of SOF/GS-5816 + ARVs. 
Table 1-5.
GS-US-342-1167: Summary of Changes in PK Parameters of SOF, its 
Metabolites GS-566500 and GS-331007, GS-5816, and Evaluated 
ARVs (EFV, RPV, DTG, EVG, COBI, FTC, TAF, and TFV) (PK 
Analysis Sets)
Analyte
SOF/GS-5816+ARV / ARV
ARVs
SOF/GS-5816+ARV / SOF/GS-5816
ARV PK Parameters
SOF PK Parameters
GS-566500
PK Parameters
GS-331007
PK Parameters
GS-5816
PK Parameters
AUCtau Cmax
Ctau
AUCtau
Cmax
AUCtau
Cmax AUCtau Cmax Ctau
AUCtau Cmax
Ctau
EFV/FTC/TDF
EFV/
FTC/
TDF

38%





53% 47% 57%
  EFV



  FTC



  TFV
81%
77%
121%
FTC/RPV/TDF
FTC/
RPV/
TDF










  RPV



  FTC



  TFV
40%
44%
84%
DTG
DTG










DTG



EVG/COBI/FTC/TAF
EVG/
COBI/
FTC/
TAF
37%



48%
58% 50% 30% 60%
EVG



COBI


103%
FTC



TAF

20%
NC
TFV



NC = not calculable
Note:   90% CIs of the %GLSM ratios were within (↔), extended above (↑), or extended below (↓) the predetermined alteration 
boundaries of 70% to 143%.


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Original
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Effect of EFV/FTC/TDF, FTC/RPV/TDF, DTG (Dolutegravir), or EVG/COBI/FTC/TAF 
on Sofosbuvir, GS-566500, GS-331007, and GS-5816 Pharmacokinetics
No alteration in the overall exposure of SOF, GS-566500, and GS-331007 was observed 
following coadministration of SOF/GS-5816 + EFV/FTC/TDF, FTC/RPV/TDF, or DTG. Other 
than a small increase in SOF Cmax when administered with EFV/FTC/TDF, the 90% CIs for the 
%geometric least-squares mean (%GLSM) ratios for all primary PK parameters (AUCtau, Cmax, 
and Ctau [if measurable]) were within predetermined lack of PK alteration boundaries of 70% to 
143%, confirming a lack of an effect on the PK of SOF and metabolites by EFV/FTC/TDF, 
FTC/RPV/TDF, or DTG. An increase in SOF AUC (37%) and GS-331007 AUC (48%) and Ctau
(58%) were observed when administered with EVG/COBI/FTC/TAF. Of note, GS-331007 
exposure when administered with EVG/COBI/FTC/TAF was within the range of GS-331007 
exposures observed in the LDV/SOF Phase 3 studies, as well as similar to exposures seen in 
subjects with mild renal impairment where dosing of SOF is permitted without dose adjustment.
The PK of GS-5816 was not altered by FTC/RPV/TDF or DTG. A reduction (approximately 
50%) in GS-5816 systemic exposures was observed following administration of 
SOF/GS-5816 + EFV/FTC/TDF compared to SOF/GS-5816 alone. A modest increase 
(approximately 50%) in GS-5816 systemic exposures was observed following administration of 
SOF/GS-5816 + EVG/COBI/FTC/TAF compared to SOF/GS-5816 alone.
Effect of Sofosbuvir/VEL on Efavirenz, Rilpivirine, Dolutegravir, Elvitegravir, Cobicistat, 
Emtricitabine, Tenofovir, and Tenofovir Alafenamide Pharmacokinetics
The PK of EFV, RPV, DTG, EVG, and FTC were not altered following coadministration of 
EFV/FTC/TDF, FTC/RPV/TDF, DTG, or EVG/COBI/FTC/TAF with SOF/GS-5816. The 
90% CIs for the %GLSM ratios for EFV, RPV, DTG, EVG, and FTC AUCtau, Cmax, and Ctau
remained within the protocol-predefined lack of PK alteration boundaries of 70% to 143%. An 
increase in COBI Ctau (103%) was observed with no increase in AUCtau or Cmax following 
coadministration of EVG/COBI/FTC/TAF with SOF/GS-5816. A small decrease in TAF Cmax
(20%) was observed with no decrease in AUCtau following coadministration of 
EVG/COBI/FTC/TAF with SOF/GS-5816. 
The PK of TFV was not altered following coadministration of EVG/COBI/FTC/TAF with 
SOF/GS-5816. The 90% CIs for the %GLSM ratios for TFV AUCtau, Cmax, and Ctau remained 
within the protocol predefined lack of PK alteration boundaries of 70% to 143%. Modest 
increases in TFV AUCtau, Cmax, and Ctau of approximately 81%, 77%, and 121%, respectively, 
were observed following coadministration of EFV/FTC/TDF with SOF/GS-5816. Similarly, 
modest increases in TFV AUCtau, Cmax, and Ctau of approximately 40%, 44%, and 84%, 
respectively, were observed following coadministration of FTC/RPV/TDF with SOF/GS-5816. 
Similar absolute TFV plasma exposures were achieved following administration of 
SOF/GS-5816 + EFV/FTC/TDF and SOF/GS-5816 + FTC/RPV/TDF. Furthermore, TFV 
exposures were also comparable to those achieved upon coadministration of TDF with HIV 
protease inhibitor (PIs), which did not warrant dose adjustment {Hoetelmans et al 2007}, 
{Agarwala et al 2005}. Accordingly, administration of TDF as part of FTC/RPV/TDF or 
FTC/TDF does not warrant dose adjustment when administered with SOF/GS-5816.


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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16 March 2016
Based on the safety and PK data from this study in addition to safety, efficacy, and PK of the 
agents respectively, SOF/GS-5816 may be coadministered with FTC/RPV/TDF, DTG, 
FTC/TDF, or EVG/COBI/FTC/TAF without dose adjustment to any of the agents. SOF/GS-5816 
should not be administered with EFV/FTC/TDF or EFV as part of other ARV regimens.
1.2.2.2.4.
Study GS-US 342-1326 
Study GS-US-342-1326 evaluated safety, tolerability, and pharmacokinetics of SOF, its 
metabolites GS-566500 and GS-331007, and GS-5816 following administration of 
SOF/GS-5816 (400/100 mg) with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil 
fumarate (EVG/COBI/FTC/TDF; Stribild®), emtricitabine/tenofovir disoproxil fumarate 
(FTC/TDF; Truvada®) plus ritonavir (RTV)-boosted darunavir (DRV; Prezista®), atazanavir 
(ATV; Reyataz®), and lopinavir (LPV/RTV; Kaletra®), and raltegravir (RAL; Isentress®).
Table 1-6 summarizes the differences in preliminary PK parameters of SOF, its metabolites 
GS-566500 and GS-331007, GS-5816, and evaluated ARVs (EVG, COBI, DRV, ATV, LPV, 
RTV, RAL, FTC, and TFV) when SOF/GS-5816 or the ARVs were administered alone 
compared with administration of SOF/GS-5816 + ARVs. 
Table 1-6.
GS-US-342-1326: Preliminary Summary of Changes in PK 
Parameters of SOF, its Metabolites GS-566500 and GS-331007, 
GS-5816, and Evaluated ARVs (EVG, COBI, DRV, ATV, LPV, RTV, 
RAL, FTC, and TFV)
Analyte
SOF/GS-5816+ARV / 
ARV
ARVs
SOF/GS-5816+ARV / SOF/GS-5816
ARV PK Parameters
SOF PK 
Parameters
GS-566500
PK Parameters
GS-331007
PK Parameters
GS-5816
PK Parameters
AUCtau
Cmax
Ctau
AUCtau
Cmax
AUCtau
Cmax
AUCtau Cmax Ctau AUCtau Cmax
Ctau
EVG/COBI/FTC/TDF
EVG/
COBI/
FTC/
TDF




35%

45
%


37
%
EVG



COBI


71%
FTC



TFV
35%
36%
45%
DRV + RTV + FTC/TDF
DRV+ 
RTV+
FTC/
TDF
27%
39%






24%

DRV



RTV



FTC



TFV
38%
55%
51%


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 38
16 March 2016
Analyte
SOF/GS-5816+ARV / 
ARV
ARVs
SOF/GS-5816+ARV / SOF/GS-5816
ARV PK Parameters
SOF PK 
Parameters
GS-566500
PK Parameters
GS-331007
PK Parameters
GS-5816
PK Parameters
AUCtau
Cmax
Ctau
AUCtau
Cmax
AUCtau
Cmax
AUCtau Cmax Ctau AUCtau Cmax
Ctau
ATV + RTV + FTC/TDF
ATV+ 
RTV+
FTC/
TDF






42
%
142% 55% 301
%
ATV


39%
RTV


29%
FTC



TFV

55%
39%
LPV/RTV + FTC/TDF
LPV/ 
RTV+
FTC/
TDF
29%
41%






31% 62
%
LPV



RTV



FTC



TFV

42%

RAL + FTC/TDF
RAL+ 
FTC/
TDF










  RAL


21%
  FTC



  TFV
40%
46%
70%
NC = not calculable
Note:   90% CIs of the %GLSM ratios were within (↔), extended above (↑), or extended below (↓) the predetermined alteration 
boundaries of 70% to 143%.
Effect of EVG/COBI/FTC/TDF, DRV+RTV+FTC/TDF, ATV+RTV+FTC/TDF, 
LPV/RTV+FTC/TDF, or RAL+FTC/TDF on Sofosbuvir, GS-566500, GS-331007, and 
GS-5816 Preliminary Pharmacokinetics
No alteration in the exposure (AUCtau, Cmax, or Ctau) of SOF, GS-566500, GS-331007, or 
GS-5816 was observed following administration of SOF/GS-5816 with RAL+FTC/TDF. A small 
increase in GS-331007 overall exposure (~35%) was observed with no alteration in the overall 
exposure of SOF, GS-566500, or GS-5816 when administered with EVG/COBI/FTC/TDF. 
Administration of SOF/GS-5816 with DRV+RTV+FTC/TDF or LPV/RTV+FTC/TDF resulted 
in a modest decrease in the overall exposure of SOF (~27% and ~29%, respectively) with no 
alteration in the overall exposure of GS-566500, GS-331007, or GS-5816. Administration of 
SOF/GS-5816 with ATV+RTV+FTC/TDF resulted in an increase in GS-5816 AUCtau (~142%), 
Cmax (~55%), and Ctau (~301%) with no change in the overall exposure of SOF or its metabolites 
(GS-566500 and GS-331007). 


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 39
16 March 2016
Effect of Sofosbuvir/GS-5816 on Elvitegravir, Cobicistat, Darunavir, Atazanavir, 
Lopinavir, Ritonavir, Raltegravir, Emtricitabine, and Tenofovir Preliminary 
Pharmacokinetics
The overall exposure (AUCtau) and maximal exposure (Cmax) of EVG, COBI, DRV, ATV, LPV, 
RTV, RAL, and FTC were not altered when administered with SOF/GS-5816, as the 90% CIs for 
the %GLSM ratios for AUCtau were within the protocol-predefined lack of PK alteration 
boundaries of 70% to 143%. An increase in the Ctau of COBI (~71%), ATV (~39%), and RTV 
(~29%) when administered as part of ATV+RTV+FTC/TDF was observed following 
coadministration with SOF/GS-5816. A small decrease in the Ctau of RAL (~21%) was observed 
following coadministration with SOF/GS-5816 with no change in overall or maximal RAL 
exposure. 
Modest increases in TFV AUCtau (Range: 35-40%), Cmax (Range: 36-55%), and Ctau
(Range: 45-70%) were observed following administration of EVG/COBI/FTC/TDF, 
DRV+RTV+FTC/TDF, or RAL+FTC/TDF with SOF/GS-5816. A modest increase in TFV Cmax
(~55%) and Ctau (~39%) with no alteration in TFV AUCtau was observed following 
administration of ATV+RTV+FTC/TDF with SOF/GS-5816. A modest increase in TFV Cmax
(~42%) with no alteration in TFV AUCtau or Ctau was observed following administration of 
LPV/RTV+FTC/TDF with SOF/GS-5816.
Based on available safety and PK data from this study in addition to the safety, efficacy, and PK 
of these agents respectively, SOF/GS-5816 may be coadministered with EVG/COBI/FTC/TDF, 
DRV+RTV+FTC/TDF, ATV+RTV+FTC/TDF, LPV/RTV+FTC/TDF, or RAL+FTC/TDF 
without dose adjustment to any of the agents. 
1.3.
Ribavirin (RBV)
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of 
RNA and DNA viruses {Roche Laboratories Inc. 2010}, {Roche Products Limited 2010}. Ribavirin 
monotherapy has little or no effect on the replication of HCV in vivo but can result in 
normalization of serum ALT activity and improvement in liver histology. When combined with 
IFN or PEG therapy, RBV decreases substantially the relapse rate seen after cessation of IFN 
therapy {Poynard et al 1998}, {McHutchison et al 1998}.
Ribavirin is a known teratogen (FDA category X). Furthermore, RBV is known to accumulate 
intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, extreme care 
must be taken to avoid  pregnancy during RBV therapy and for up to 6 months following 
completion of treatment, and in the case of males, impregnating a female while on RBV and up 
to7 months following completion of therapy.
A comprehensive review of RBV is contained in the SmPC.


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1.4.
Rationale for This Study
This Phase 2 study is designed as a multicenter, randomized, open-label study evaluating 
SOF/VEL FDC for 12 weeks and SOF/VEL + RBV for 12 weeks in subjects with Chronic GT3 
HCV infection and compensated cirrhosis. Patients with genotype 3 HCV infection and cirrhosis 
have previously been studied as subgroups within 1 Phase 2 study (GS-US-342-0109) and 
2 Phase 3 studies (GS-US-342-1140 [ASTRAL-3] and GS-US-342-1137 [ASTRAL-4]) 
evaluating either SOF + VEL or SOF/VEL FDC. GS-US-342-0109 is described in detail in the 
investigators brochure.  Briefly, 27 and 26 patients with GT3 HCV infections without cirrhosis 
received SOF 400 mg + VEL 100 mg and SOF 400 mg + VEL 100mg + RBV, respectively, for 
12 weeks, while 26 and 26 patients with compensated cirrhosis received SOF 400 mg + VEL 
100mg and SOF 400 mg + VEL 100 mg + RBV, respectively, for 12 weeks.  All patients without 
cirrhosis achieved SVR12, regardless of the addition of RBV, suggesting the RBV provides no 
additional efficacy when given to such patients.  Among the patients with compensated cirrhosis, 
88.5% achieved SVR12 without RBV while 96.2% achieved SVR12 with the addition of RBV, 
suggesting that RBV provides additional efficacy when added to regimens of SOF + VEL FDC 
in patients with GT3 HCV infections and cirrhosis.  In ASTRAL-3 (described in 
Section 1.2.2.1.3), 277 patients with genotype 3 HCV were given SOF/VEL for 12 weeks, 80 
(29%) of whom had underlying cirrhosis.  The SVR12 rate for the cirrhotic patients was 91% 
compared to 97% for the non-cirrhotic patients.  In ASTRAL-4 (described in Section 1.2.2.1.4)
14, 13, and 12 patients with genotype 3 HCV and decompensated cirrhosis (CPT B) received 12 
weeks of SOF/VEL , 12 weeks of  SOF/VEL + RBV, and 24 weeks of SOF/VEL, respectively.  
Of those patients, 7 (50%), 11 (85%), and 6 (50%) subjects achieved SVR12, suggesting that 
RBV provides additional efficacy on top of SOF/VEL when given to patients with GT3 HCV 
infections and decompensated cirrhosis.  
In this study, approximately 200 subjects with genotype 3 HCV and compensated cirrhosis will 
be randomized 1:1 into 2 treatment groups: SOF/VEL for 12 weeks and  SOF/VEL + RBV for 
12 weeks.  This study design will approximately double the number of patients with genotype 3 
HCV and compensated cirrhosis treated with a non-RBV SOF/VEL regimen in clinical trials to 
better characterize the efficacy and safety of SOF/VEL in this important subgroup.  Furthermore, 
though based on small numbers of patients with GT3 HCV infections and cirrhosis, both 
GS-US-342-0109 and ASTRAL-4 suggest that the regimen of SOF/VEL + RBV for 12 weeks is
potentially an important regimen in these patients.  This study design will also provide safety and 
efficacy data of the SOF/VEL + RBV regimen in patients with genotype 3 HCV and cirrhosis. 
In summary, this study will expand the knowledge of the safety and efficacy of SOF/VEL
± RBV in patients with genotype 3 HCV and cirrhosis, and will further characterize the use of 
SOF/VEL as a once-daily pangenotypic regimen for the treatment of chronic HCV infection. 
1.5.
Rationale for Dose Selection
Sofosbuvir 400 mg, once daily, when dosed in combination with RBV with or without PEG has 
demonstrated broad genotypic efficacy and favorable safety profile in over 1700  HCV-infected 
subjects across multiple patient populations in Phase 2 and 3 trials. This dose is the approved 


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marketed dose of sofosbuvir for the treatment of HCV-infection and as such, has been selected 
for co-formulation with VEL into a fixed-dose combination tablet.
VEL 100 mg has been administered in combination with SOF 400 mg for 12 weeks to 
237 HCV-infected subjects in Phase 2 studies. VEL 100 mg was selected for co-formulation with 
SOF and evaluation in this study based on the Phase 2 safety, PK and antiviral activity (studies 
GS-US-342-0102, GS-US-342-0109, and GS-US-337-0122 [Cohort 4]). The Phase 1 
study GS-US-281-0102 established the anti-HCV activity of VEL and indicated that the 
exposures achieved following administration of doses > 25 mg provide at least 80% of maximal 
antiviral response in all HCV genotypes. 
The favorable safety and efficacy profiles of SOF 400 mg and VEL 100 mg support further 
evaluation of this combination and doses in clinical development.
1.6.
Overall Risk/Benefit Assessment
This study will provide information on the safety and efficacy of SOF/VEL ± RBV, a potent 
HCV nucleotide inhibitor and a potent HCV NS5A inhibitor, in patients with GT3 HCV 
infections and cirrhosis. The potential benefits of SOF/VEL ± RBV over the current standard of 
care for the treatment of chronic GT3 HCV in patients with cirrhosis are:

Increasing the cure rate of GT3 HCV beyond that of currently approved therapies for patients 
with concomitant cirrhosis

Providing the first PEG and RBV-free treatment option for patients with GT3 HCV and 
cirrhosis

A once-daily, single tablet, single duration, pangenotypic therapy for HCV infection could 
simplify treatment algorithms and impact worldwide disease prevalence

A reduction in the AEs currently associated with the use of PEG and RBV

A short duration of therapy which should lead to better outcomes through improved 
adherence.
The safety profile of SOF in clinical studies includes over 1700 chronic HCV-infected subjects 
that have been administered 12 weeks of SOF and RBV+/-PEG-IFN.  No clinical safety issues 
specifically related to SOF have been identified to date. 
The safety profile of SOF + VEL 25mg or VEL 100mg administered for 8 or 12 weeks has been 
established in over 800 patients in Phase 2 studies. The safety profile of the proposed therapeutic 
regimen of SOF 400 mg and VEL 100 mg administered for 12 weeks has been established in 
237 subjects enrolled in Phase 2 studies. No clinical safety issues specifically related to VEL or 
SOF + VEL have been identified to date. No clinical safety issues specifically related to the 
NS5A inhibitor class including daclatasvir (DCV) and LDV have been identified to date {Afdhal 
et al 2014b}, {Afdhal et al 2014a}, {Kowdley et al 2014}.


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The safety profile of SOF/VEL has been studied in 4 Phase 3 trials (ASTRAL 1-4) in 
1302 patients.  Twelve weeks of SOF/VEL was generally well tolerated, and led to a similar 
incidence of AEs and SAEs compared to placebo in patients with GT 1, 2, 4, 5, or 6 HCV. When 
12 weeks of SOF/VEL was compared to SOF + RBV for 12 weeks in patients with GT2 or 3 
HCV, therapy with SOF/VEL was again well tolerated with few differences in AEs or SAEs, 
minus the avoidance of RBV associated toxicities. Patients who received SOF/VEL for either 12 
or 24 weeks with decompensated cirrhosis experienced AEs and SAEs typical for patients with 
decompensated cirrhosis in no pattern that could be attributed to study drug.  Patients with 
decompensated cirrhosis who received SOF/VEL + RBV for 12 weeks also experienced AEs and 
SAEs consistent with underlying liver disease as well as toxicities expected with RBV treatment.
In summary, SOF/VEL ± RBV has the potential to increase SVR12 rates of GT3 HCV infections 
among patients with cirrhosis. If high rates of SVR can be obtained with a short, PEG-free ± 
RBV regimen, the anticipated improvements in safety and tolerability would offer a favourable 
risk-benefit determination for patients with chronic GT3 HCV infection and cirrhosis.
1.7.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


SOFNELFDC 
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2. 
OBJECTIVES 
The primaty objectives of this study are: 
Final 
Original 
• 
To evaluate the efficacy of study treatment with SofosbuvirNelpatasvir (SOFNEL) FDC 
and SOFNEL FDC and Ribavirin (RBV) for 12 weeks as measured by the propotiion of 
subjects with sustained viralogic response 12 weeks after cessation of treatment regimen 
(SVR12) 
• 
To evaluate the safety and tolerability of each treatment regimen 
The secondaty objectives of this study are: 
• 
To detemline the prop01tion of subjects who attain SVR at 4 weeks after cessation of each 
treatment regimen (SVR4) 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
each treatment regimen 
• 
To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of study treatment regimen 
The explorat01y objective of this study is: 
• 
PPD 
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3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is a multicenter, randomized, open-label study that will evaluate the safety, tolerability and 
antiviral efficacy of SOF/VEL FDC with and without RBV for 12 weeks in subjects with chronic 
genotype 3 HCV infection and compensated cirrhosis with or without HIV co-infection.
Approximately 200 subjects with chronic genotype 3 HCV infection and compensated cirrhosis 
will be randomized (1:1) to either:

Group 1 (n = 100): SOF/VEL once daily for 12 weeks
OR

Group 2 (n = 100): SOF/VEL + RBV for 12 weeks 
Randomization will be stratified by prior treatment experience (treatment naïve/treatment-
experienced).
3.2.
Visit Schedule
All subjects will complete screening, on-treatment, and post-treatment assessments. 
Screening assessments will be completed within 28 days of the Day 1 visit. The screening 
window can be extended to 42 days for subjects requiring liver biopsy, additional HCV 
genotyping or for extenuating circumstances. 
All subjects will complete the following study visits: Screening, Baseline/Day 1, on-treatment 
visits at the end of Weeks 2, 4, 8 and 12. All subjects will complete the post-treatment Week 4 
visit.  Subjects with HCV RNA < LLOQ at the post-treatment Week 4 visit will complete the 
post-treatment Week 12 visit. Subjects with HCV RNA ≥LLOQ at post-treatment Week 12 visit 
will be asked to return for a confirmatory visit.  
The assessments performed at each visit are described in Section 6 and shown in Appendix 2.
3.3.
Virologic Response
3.3.1.
HCV Virologic Response-Based Treatment Stopping Criteria
The following on-treatment HCV virologic response-based treatment stopping criteria will be 
utilized:

Confirmed HCV RNA ≥ LLOQ after 2 consecutive HCV RNA < LLOQ

Confirmed > 1 log10 increase from nadir

HCV RNA ≥ LLOQ through 12 weeks of treatment


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Confirmation should be performed as soon as possible and must occur no later than 2 weeks after 
an initial observation indicating virologic failure. 
If HCV viral relapse is detected at post-treatment Week 4 or 12 visits, subjects will be asked to 
return for a confirmatory visit.
3.3.2.
HIV Virologic Rebound Criteria
Subjects who have at least two consecutive post-baseline visit plasma HIV-1 RNA levels 
≥400 copies/mL (at least two weeks apart) will be considered to have HIV virologic rebound. 
Following an initial HIV-1 RNA result of ≥ 400 copies/mL, subjects will continue to take their 
current ARV regimen and be asked to return to the clinic after 2 weeks for a scheduled or 
unscheduled blood draw for confirmation of HIV virologic rebound. If HIV virologic rebound is 
confirmed at the scheduled or unscheduled visit, the blood samples from this visit will be used 
for HIV-1 genotype/phenotype testing. If no resistance to the subject’s current ARV regimen is 
detected, the subject may continue on current ARV regimen.  If resistance to the subject’s 
current ARV regimen is detected, then it is strongly recommended that whenever possible, the 
subject be switched to an alternative approved regimen, as outlined in Section 4.2 of this 
protocol.   
HCV study drug should be continued unless safety events warrant the discontinuation of the 
study drug, as outlined is Section 3.5 of the protocol, or if a subject must be switched to an 
unapproved HIV regimen based upon acquired resistance.
Please refer to Figure 3-1 for the management of subjects who meet the criteria for HIV virologic 
rebound.


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Figure 3-1.
HIV Virologic Rebound Schema
a
HCV study drug should be continued unless safety events warrant the discontinuation of these study drugs, as outlined in
Section 3.5 of the protocol
b
If virologic rebound is not confirmed, the subject should remain on their current ARV regimen.
c
If virologic rebound is confirmed, the HIV-1 genotype and phenotype (reverse transcriptase and protease) will be analyzed.
d
Based on the results of the genotype and phenotype assays, the subject may remain on their ARV regimen at the discretion 
of the Investigator (e.g. virologic rebound due to non-adherence). If the genotype and/or phenotype assay fails to provide 
results, a new ARV regimen may be configured at the discretion of the Investigator in consultation with the Medical 
Monitor.
e
A new ARV regimen should be configured or the ARV regimen held for the duration of SOF/VEL dosing at the 
Investigator’s discretion in consultation with the Medical Monitor. If a new ARV regimen is required, it is strongly 
recommended to use an alternative regimen that is approved in this protocol.  If an unapproved ARV regimen is prescribed, 
then SOF/VEL ± RBV must be discontinued after consultation with the medical monitor.
HIV-1 RNA ≥ 400 copies/mL
Continue current ARV regimen and return for 
scheduled/unscheduled visit (at least 2 weeks apart) 
HIV-1 RNA and potential genotype/phenotype 
HIV-1 genotype/phenotype
Unconfirmed 
virologic rebound: 
remain on current 
regimenb
Confirmed virologic reboundc
If no resistance to the subject’s current 
ARV regimen is detected, may 
continue on current ARV regimend
Study Period
(On-Treatment and Posttreatment)
If resistance to the subject’s current 
ARV regimen is detected, discontinue 
and construct a new ARV regimen
e


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3.4.
Stopping Rules for Individual Subjects
Subjects who meet any of the following criteria should be discontinued from the study and 
complete an Early Termination Visit and return for Posttreatment Follow-up visits:

Elevation of ALT and/or AST that is greater than the ULN and > 5x baseline or nadir 
confirmed by immediate repeat testing unless laboratory results are assessed by both the 
investigator and Gilead Medical Monitor as having an explanation other than drug induced 
liver injury and it is deemed in the best interest of the subject to continue HCV treatment

Confirmed elevation of ALT >15 x ULN (unrelated to any interventional procedures)

Confirmed total bilirubin >10 x ULN (unrelated to any interventional procedures)

Confirmed total bilirubin >3x baseline or 3x nadir (unrelated to any interventional 
procedures)

Any Grade 3 or greater rash associated with constitutional symptoms

Any non-laboratory Grade 4 events assessed as related to administration of SOF/VEL

Worsening of disease state as evidenced by progressing hepatic decompensation and/or 
progression of Child-Pugh Score (CPT) to ≥ 10
The Gilead Medical Monitor should be consulted prior to discontinuation of SOF/VEL and /or 
RBV unless the investigator believes that immediate action is warranted to ensure the continued 
safety of the subject. 
Any questions regarding toxicity management should be directed to Gilead Medical Monitor.
3.5.
Discontinuations
If the subject meets the Virologic Response-Based Stopping Criteria (Section 3.3.1), they should 
complete an Early Termination Visit as soon as possible after SOF/VEL is discontinued and 
complete post-treatment visits up to 30 days after the last dose of SOF/VEL and/or 60 days after 
the last dose of RBV to assess for safety.
If the subject meets the Stopping Rules for Individual Subjects (Section 3.4) or other criteria for 
discontinuation of study treatment (Section 3.7), prior to completion of SOF/VEL dosing period, 
the subject should complete an Early Termination Visit as soon as possible after SOF/VEL is 
discontinued and complete the post-treatment assessments as described in Section 6.3 and in 
Study Procedures Appendix 2. 
Subjects discontinuing treatment prior to completion of dosing period for reasons other than 
those described in Sections 3.3, 3.4 and 3.7 should complete an Early Termination Visit as soon 


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as possible after SOFNEL is discontinued. The subject should also complete the post-treatment 
assessments as described in Section 6.3 and in Study Procedures Appendix 2. 
3.6. 
Assessments for Premature Discontinuation from Study 
If a subject discontinues SOFNEL dosing (for example, as a result of an adverse event [AE]), 
every attempt should be made to keep the subject in the study and continue to perf01m the 
required study-related post-treatment assessments and procedures (see Section 6.3). If this is not 
possible or acceptable to the subject or investigator, the subject may be withdrawn from the 
study. 
3.7. 
Criteria for Discontinuation of Study Treatment 
When medically feasible, the Medical Monitor must be consulted prior to subject 
discontinuation. 
Study dmg must be discontinued in the following instances: 
• 
Intercunent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree 
• 
Unacceptable toxicity, as defined in the toxicity management section 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 
• 
Subject requests to discontinue for any reason; it is imp01tant to dete1mine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy , or other reason 
• 
Subject non-compliance 
• 
Pregnancy of female subject. Subjects randomized to Group 2 who have female pminers 
who become pregnant must immediately contact the Principal Investigator in order to discuss 
the risks and benefits of continuing treatment with RBV. It is pennissible to stop RBV but 
continue SOFNEL in subjects that have pregnant female pa1tners. 
• 
Discontinuation of the study at the request of Gilead, regulat01y agency or an IRBIIEC 
3.8. 
Biomarker Testing 
3.8.1. 
Biomarker Samples for Optional Future Research 
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3.8.2. 
Biomarker Samples for Optional Pharmacogenomic Research 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 200 chronic HCV Genotype 3 infected subjects will be randomized 1:1 into 
2 treatment groups in this study. Patients will be stratified by treatment experience (treatment 
naïve versus treatment experienced). 
In order to manage the total study enrollment, Gilead Sciences, Inc., at its discretion, may 
suspend screening and/or enrollment at any site or study-wide at any time.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1. Willing and able to provide written informed consent
2. Male or female age ≥ 18 years 
3. Chronic HCV infection (≥ 6 months) as documented by prior medical history or liver biopsy
4. HCV RNA ≥104 IU/mL at Screening
5. Confirmation of cirrhosis by any of the following methods:
a.
Liver biopsy showing cirrhosis (eg., Metavir score=4 or Ishak score ≥ 5)
b. Fibroscan results > 12.5 kPa
c.
Fibrotest result >0.75 AND an AST platelet ratio index (APRI) >2 during Screening
d. Liver imaging within 6 months of Baseline/Day 1 to exclude hepatocellular carcinoma 
(HCC)
6. Subjects must have a determination of treatment experience (treatmenet naïve v. treatment 
experienced). Treatment naïve is defined as having never been exposed to an approved or 
experimental HCV-specific direct acting antiviral agents or prior treatment of HCV with 
interferon or ribavirin.  All other patients will be considered treatment experienced.
7. If treatment experienced, the subject’s medical records must include details of prior treatment 
regimen(s).  Any prior use of SOF or other nucleotide analogue HCV NS5B inhibitors should 
be documented. Previous use of an NS5A inhibitor is not allowed.
8. A negative serum pregnancy test is required for female subjects (unless permanently sterile 
or greater than two years post-menopausal).


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9. 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.
10. Lactating females must agree to discontinue nursing before the first dose of study drug is 
administered.
11. Subject must be able to comply with the dosing instructions for study drug administration 
and be able to complete the study schedule of assessments.
Subjects with HIV coinfection may be eligible, provided they satisfy these additional inclusion 
criteria:
12. Completed at least 3 months of any prior HIV ARV therapy and maintained HIV RNA 
<50 copies/mL (or <LLOQ if the local laboratory assay’s LLOQ is 50≥ copies/mL) and CD4 
T-cell count > 100 cells/mm3 prior to Screening. Subjects with an isolated or unconfirmed
HIV RNA >50 copies/mL (or >LLOQ if the local laboratory assay’s LLOQ is 
50≥copies/mL) are not excluded
13. No history of HIV-associated opportunistic infections within 6 months of Screening. (see 
Appendix 6)
14. On a stable, protocol-approved, ARV regimen for ≥ 8 weeks prior to Screening and is 
expected to continue the current ARV regimen through the end of study. HIV ARV agents 
allowed in this study are the following and should be administered per the prescribing 
information in the package insert:
— cobicistat/elvitegravir/emtricitabine/tenofovir disoproxil fumarate (Stribild)
OR
— emtricitabine/tenofovir disoproxil fumarate, emtricitabine/tenofovir alafenamide, or
abacavir/lamivudine plus:
o
ritonavir boosted atazanvir;  or
o
ritonavir boosted  darunavir; or
o
ritonavir boosted lopinavir; or
o
raltegravir; or
o
rilpivirine 
OR
cobicistat/elvitegravir/emtircitabine/tenofovir alafenamide (Genvoya®)


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a) Single tablet regimens containing emtricitabine/tenofovir disoproxil fumarate (Truvada®) 
plus rilpivirine (Eviplera®) or emtricitabine/tenofovir alafenamide plus rilpivirine) 
respectively are permitted.
b) Alternative combinations of the above listed medications may be allowed after discussion 
and approval by the Gilead Medical Monitor. Subjects taking ARV regimens not on the 
above list are excluded from this study.
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 any of the following:
a.
Clinically-significant illness (other than HCV or HIV) or any other major medical 
disorder that may interfere with subject treatment, assessment or compliance with the 
protocol; subjects currently under evaluation for a potentially clinically-significant illness 
(other than HCV/HIV) are also excluded.
b. Gastrointestinal disorder or postoperative condition that could interfere with the 
absorption of the study drug. 
c.
Difficulty with blood collection and/or poor venous access for the purposes of 
phlebotomy.
d. Solid organ or bone marrow transplantation.
e.
Significant pulmonary disease, significant cardiac disease, or porphyria.
f.
Clinically significant hemoglobinopathy (e.g., sickle cell disease, thalassemia).
g. Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of 
their psychiatric illness within the last 5 years. Subjects with psychiatric illness (without 
the prior mentioned conditions) that is well-controlled on a stable treatment regimen for 
at least 12 months prior to enrollment or has not required medication in the last 
12 months may be included. 
h. Malignancy within the 5 years prior to screening, with the exception of specific cancers 
that have been cured by surgical resection (basal cell skin cancer, etc). Subjects under 
evaluation for possible malignancy are not eligible.
i.
Active, serious infection (other than HIV or HCV) requiring parental antibiotics, 
antivirals or antifungals within 30 days prior to baseline.
2. Child-Pugh-Turcotte (CPT) Score >7 at Screening


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3. Current, uncontrolled ascites, variceal hemorrhage, hepatic encephalopathy, hepatorenal 
syndrome, hepatopulmonary syndrome, or other signs of decompensated cirrhosis
4. Screening ECG with clinically significant abnormalities
5. Subjects with the following laboratory parameters at screening: 

HIV-1 RNA >50 copies/mL 

CD4 T-cell count <100 cells/mm3

ALT > 10 the upper limit of normal  (ULN)

AST > 10 ULN

Direct bilirubin > 1.5 ULN
o
For subjects receiving ritonavir boosted atazanavir regimen, a direct bilirubin > 1.5 x 
ULN will be allowed if < 25% of the total bilirubin

Platelets < 50,000/L

HbA1c > 8.5%

Creatinine clearance (CLcr) < 60 mL /min as calculated by the Cockcroft-Gault equation 
{Cockcroft et al 1976}

Hemoglobin < 10 g/dL

Albumin < 3 g/dL

INR > 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR

HIV-2 positive test

Presence of HBV surface antigen
6. Prior exposure to VEL or any HCV NS5A inhibitor.
7. Pregnant or nursing female or male with pregnant female partner. 
8. Females who may wish to become pregnant and/or plan to undergo egg harvesting during the 
course of the study and up to 6 months of the last dose of study drug 
9. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alfa-1 antitrypsin deficiency, cholangitis).


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10. Active infection with hepatitis B virus (HBV).
11. Infection with HIV 2
12. Clinically-relevant alcohol or drug abuse within 12 months of screening, as determined by 
the investigator. A positive drug screen will exclude subjects unless it can be explained by a 
prescribed medication; the diagnosis and prescription must be approved by the investigator.
13. Use of any prohibited concomitant medications as described in Section 5.5
14. Chronic use of systemically administered immunosuppressive agents (e.g., prednisone 
equivalent > 10 mg/day).
15. Known hypersensitivity to VEL, SOF (and metabolites), or RBV.
16. The presence of contraindications to RBV.
17. Participation in a clinical study with an investigational drug or biologic within 3 months prior 
to Baseline/Day 1.
18. Treatment for HCV infection with experimental or approved regimens within 3 months of 
Baseline/Day 1.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, and Study Drug Supply
An Interactive Web Response System (IWRS) will be employed to manage subject 
randomization, treatment assignment, and study drug re-supply. Randomization will be stratified 
by prior treatment experience. Treatment naïve is defined as having never been exposed to an 
approved or experimental HCV-specific direct acting antiviral agents or prior treatment of HCV 
with interferon or ribavirin. All other patients will be considered treatment experienced. If 
treatment experienced, the subject’s medical records must include details of prior treatment 
regimen (See Section 6.2.1).
5.2.
Description and Handling of SOF/VEL FDC
5.2.1.
Formulation
The SOF/VEL (400/100 mg) tablets are pink, diamond-shaped, film-coated tablets, debossed 
with “GSI” on one side and “7916” on the other side. In addition to the active ingredients, the 
SOF/VEL tablets contain copovidone, microcrystalline cellulose, croscarmellose sodium, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron 
oxide red.
5.2.2.
Packaging and Labeling
SOF/VEL (400/100 mg) tablets are packaged in white, high density polyethylene (HDPE) 
bottles. Each bottle contains 28 tablets and polyester packing material. Each bottle is enclosed 
with a white, continuous thread, child-resistant screw cap with an induction-sealed, 
aluminum-faced liner.
SOF/VEL bottles to be distributed to centers in participating countries shall be labeled to meet 
all applicable requirements of the United States Food and Drug Administration (FDA), EU 
Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal Products), 
and/or other local regulations.
5.2.3.
Storage and Handling
SOF/VEL tablets should be stored at controlled room temperature until required for 
administration. Controlled room temperature is defined as 25C (77 F); excursions are permitted 
between 15C and 30C (59F to 86F).
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 


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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 tablets.
Sufficient quantities of SOF/VEL to complete the entire study will be shipped to the investigator 
or qualified designee from the Gilead Supply Management Team (or its designee).
5.3.
Dosage and Administration of SOF/VEL FDC
SOF/VEL tablet is to be administered once daily with or without food. Each subject must be 
given instructions to maintain approximately the same daily dosing interval between study drug 
doses.
For missed dose(s) of study medication, subjects should be instructed to take the missed dose of 
study medication as soon as possible during the same day.  Subjects should be cautioned never to 
double the next dose with a missed dose of study drug under any circumstances.
5.4.
Description and Handling of Ribavirin (RBV)
5.4.1.
Formulation
RBV tablets, 200 mg, are blue, capsule-shaped, film-coated tablets debossed with “3RP” on one 
side and “200” on the other side. In addition to the active ingredient, RBV tablets contain the 
following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose 
sodium, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, 
FD&C blue #2. 
The RBV tablets being supplied by Gilead Sciences are a US marketed formulation of RBV.
5.4.2.
Packaging and Labeling
The RBV tablets are packaged in white, HDPE bottles. Each bottle contains 168 tablets and 
rayon coil packing material and is enclosed with a white, continuous thread, child-resistant screw 
cap with an induction-sealed, aluminum-faced liner. 
All RBV bottles to be distributed to centers in the participating countries and shall be labeled to 
meet all applicable requirements of the US Food and Drug Administration (FDA), EU Guideline 
to Good Manufacturing Practices- Annex 13 (Investigational Medicinal Products), and/or other 
local regulations as applicable.
RBV tablets (200 mg) will be supplied by Gilead Sciences for all Group 2 subjects.
5.4.3.
Storage and Handling
RBV tablets should be stored at 25 °C (77 °F); excursions are permitted between 15 and 30 °C 
(59 and 86 °F).


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All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling RBV.
5.4.4.
Dosage and Administration 
Subjects in Group 1 will take SOF/VEL once daily with or without food.  
Subjects in Group 2 will take SOF/VEL once daily and RBV 1000–1200 mg taken in a divided 
daily dose (1000 mg for subjects weighing < 75 kg and 1200 mg for subjects weighing ≥75 kg). 
Subjects who are to receive total daily doses of 1000 mg will take 3 × 200 mg tablets in the 
morning and 2 × 200 mg tablets in the evening (or 2 x 200 mg tablets in the morning and 
3 x 200 mg tablets in the evening). For those who are to receive 1200 mg of RBV, subjects 
should take 3 × 200 mg tablets twice daily. RBV should be taken with food. 
Body Weight kg (lbs.)
RBV Daily Dose
RBV Number of tablets
< 75 kg
1000mg
3 X 200mg tablets A.M.
2 X 200mg tablets P.M.
≥75 kg
1200mg
3 X 200mg tablets A.M.
3 X 200mg tablets P.M
All subjects should be instructed to maintain approximately the same daily dosing interval 
between study drug doses. To aid compliance, it is suggested that SOF/VEL is administered with 
either the morning or evening dose of RBV with food.
For missed dose(s) of SOF/VEL, subjects should be instructed to take the missed dose of study 
medication as soon as possible during the same day.  Subjects should be cautioned never to 
double the next dose of SOF/VEL with a missed dose under any circumstances.  
For missed dose(s) of RBV, subjects should be instructed to take the missed dose(s) of study 
drug as soon as possible, unless more than 6 hours has elapsed since the scheduled time of the 
missed dose. In this case, the subject should be instructed to wait and take the next dose at the 
regularly scheduled time. No more than the daily dose of RBV (1000 mg or 1200 mg) should be 
taken on any calendar day. Subjects should be cautioned never to double the next dose with a 
missed dose of study drug under any circumstances. 
No food restrictions apply to SOF/VEL. However as RBV must be taken with food hence it is 
suggested that when SOF/VEL is taken with RBV, both drugs should be taken together and with 
food for optimal adherence.


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Dose modifications due to anemia or other reasons, may be made at the discretion of the 
Investigator.
5.5.
Prior and Concomitant Medications
Concomitant medications taken within 30 days of Screening, up to and including the date of the 
visit four weeks after discontinuation of study drug, need to be recorded in the source documents 
and eCRFs. All concomitant medications should be recorded in the source documents (including 
all blood products).
The following medications are prohibited from 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)

Chronic 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 (inducers of drug 
transporters i.e. P-gp) with study drug may result in pharmacokinetic interactions resulting in 
increases or decreases in exposure of study drug or these medication. The use of such agents is 
prohibited from 21 days prior to Baseline/Day 1 through the end of study drug dosing. The use of 
amiodarone is prohibited from 60 days prior to Baseline/Day 1 through the end of study drug 
dosing.
Examples of representative medications which are prohibited or are to be used with caution are 
listed below:


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Table 5-1.
List of Disallowed /Use with Caution Medications
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Anticonvulsantsb
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Antimycobacterialsb
Rifabutin, Rifapentine, Rifampin
Cardiac Medicationsc
Amiodaronef
Diltiazem, Verapamil, Dronedarone, 
Quinidine, Ranolazine, Bosentan, 
Olmesartan, Valsartan, Digoxind
Herbal/Natural 
Supplementsb
St. John’s Wort, Echinacea. Milk thistle 
(ie, silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorse
Rosuvastatin (≤10 mg/day),
Other
Modafinil b, Sulfasalazinec, Methotrexatec
a
Proton pump inhibitor (PPI dose comparable with omeprazole (20 mg) can be administered with SOF/VEL when SOF/VEL
is administered with food.  H2-receptor anagonist must not exceed a dose of 40 mg famotidine or equivalent and can be 
taken simultaneously with SOF/VEL and/or staggered by 12 hours.  Antacids that directly neutralize stomach acid (i.e. 
Tums, Maalox) may not be taken within 4 hours (before or after ) SOF/GS-5816 administration.
b
May result in a decrease in the concentration of study drugs.
c
May result in an increase in the concentration of study drugs and/or concomitant medications
d
Monitor for signs and sympotoms of digoxin toxicity.
e
Use with SOF/VEL may result in an increase in the concentration of HMG-CoA Reductase Inhibitors. Monitor for signs and 
symptoms of muscle weakness or myopathy, including rhabdomyolysis
f
May result in symptomatic bradycardia.  Mechanism is not currently known.  The use of amiodarone is prohibited from 
60 days prior to Baseline/Day 1 through the end of treatment.
Medications for disease conditions excluded from the protocol (eg, active cancer, 
transplantation) are not listed under this Concomitant Medication section and are disallowed in 
the study.
Subjects may not take any approved HCV medications during their participation in the study 
period.
Should subjects have a need to initiate treatment with any excluded concomitant medication, the 
Medical Monitor must be consulted prior to initiation of the new medication. In instances where 
an excluded medication is initiated prior to discussion with the Sponsor, the Investigator must 
notify Gilead as soon as he/she is aware of the use of the excluded medication.
5.6.
Acceptable HIV Antiretroviral Regimens
Acceptable HIV antiretroviral medications allowed in this study include the following and 
should be administered per the prescribing information in the package insert:


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
cobicistat/elvitegravir/emtricitabine/tenofovir disoproxil fumarate (Stribild)
OR

emtricitabine/tenofovir disoproxil fumarate, emtricitabine/tenofovir alafenamide, or
abacavir/lamivudine plus:
— ritonavir boosted atazanvir; or
— ritonavir boosted darunavir; or
— ritonavir boosted lopinavir; or
— raltegravir; or 
— rilpivirine
OR
— cobicistat/elvitegravir/emtircitabine/tenofovir alafenamide (Genvoya®)
Single tablet regimens containing emtricitabine/tenofovir disoproxil fumarate (Truvada®) plus 
rilpivirine (Eviplera®) or emtricitabine/tenofovir alafenamide plus rilpivirine) respectively are 
permitted. 
Alternative combinations of the above listed medications may be allowed on a case by case basis 
with approval from the Gilead Medical Monitor. ARV regimens not on the above list are 
excluded from this study at enrollment. ARVs not on the approved list may be allowed in the 
cases of HIV virologic breakthrough during the study period if approved by the Medical 
Monitor. HIV medications will not be supplied by Gilead.
5.7.
Study Drug Adherence and Drug Accountability
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug (SOF/VEL FDC) ± RBV. This includes acknowledgement of receipt of each shipment of 
study drugs (quantity and condition). All used and unused study drugs dispensed to subjects must 
be returned to the site.
SOF/VEL FDC ± RBV accountability records will be provided to each study site:

Record the date received and quantity of study drug bottles

Record the date, subject number, subject initials, the study drug bottle number dispensed

Record the date, quantity of used and unused study drug returned, along with the initials of 
the person recording the information.


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
At the Baseline/Day 1 visit, subjects will be dispensed 2 bottles of SOF/VEL so that they 
have sufficient tablets to cover the 3 day time window around the Week 4 and Week 8 visit. 
Subjects must be instructed to bring back the study drug in the original container at every 
post Day 1 study visit through the end of study treatment. The extra bottle dispensed at 
Baseline/Day 1 visit must be brought back to each on-treatment visit for accountability 
purposes and will be re-dispensed to the subject except at Week 12 or EOT visit.

Subjects will be dispensed bottles of RBV based on their weight-based dose of RBV at the 
Baseline/Day 1 visit, as applicable.  Subjects should bring back the study drug in the original 
container at every post Day 1 study visit through the end of study treatment.  Any extra 
bottles dispensed should be brought back to each on-treatment visit for accountability 
purposes and will be re-dispensed to the subject except at Week 12 or EOT visit.
5.8.
Study Drug Return or Disposal
Refer to Section 10.1.7 for information on return and disposal of study drugs.


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The study procedures to be conducted for each subject emolled in the study are presented in 
tabula!' fonn in Appendix 2 and described in the text that follows. All eligible subjects will 
complete Screening, Baseline/Day 1, On-Treatment visits at the end of Weeks 2, 4, 8 and 12 and 
post-treatment Visits at Weeks 4 and 12, as appropriate. Subjects with HCV RNA ~LLOQ at 
post-treatment Week 4 visit will complete a confumat01y visit within 2 weeks of the Week 4 
post-treatment visit. Subjects with HCV RNA ~LLOQ at post-treatment week 12 visit will be 
asked to return for confumat01y visit within 2 weeks of the Week 12 post-treatment visit. Viral 
breakthrough or relapse must be confi1med. 
lnf01mation on the specific laborat01y parameters to be measured and clinical assessment to be 
perf01med are provided in Section 6.5. 
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 
This is an open-label study. An Interactive Web Response System (IWRS) will be employed to 
manage subject enrollment, treatment assigmnent (Group 1 or Group 2), and study dmg 
dispensing and re-supply. Randomization will be stratified by prior treatment experience 
(treatment naive/treatment -experienced). 
6.2. 
Screening Assessments 
6.2.1. 
Screening Visit (Day 28 to Day 0) 
Subjects will be screened within 28 days of the Baseline/Day 1 visit. The screening window can 
be extended to 42 days for subjects requiring liver biopsy, additional HCV genotype testing or 
for extenuating circumstances. 
The following will be perf01med and documented at screening: 
• 
Obtain written inf01med consent 
PD 
• 
Determine inclusion and exclusion eligibility 
• 
Appropriate diagnostic imaging (CT or Ultrasound) must be perf01med within 6 months of 
Baseline/Day 1 to exclude the presence of hepatocellular carcinoma 
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
Obtain medical history, including
Hepatitis C history
Liver biopsy results (if applicable)
Determine cirrhosis status as defined in Section 2
Exclusion of hepatocellular carcinoma (HCC). Appropriate diagnostic imaging (CT or 
Ultrasound) should be performed or confirmed to have been performed within 6 months
of Screening to exclude the presence HCC.
Determine treatment experience status as defined in Section 4.2
■
If treatment experience, record the duration(s) and type(s) of the prior treatment 
administered.
■
If treatment experienced, record whether or not any past treatment regimens 
contained SOF or other nucleotide analogue HCV NS5B inhibitors

Complete physical examination including, vital signs (resting blood pressure, pulse, 
respiratory rate and temperature), body weight, and height

Obtain details of concomitant medications 

Perform 12-lead ECG

Calculate CPT score

Obtain blood samples for tests as listed in Section 6.7.1:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Determination of HCV viral genotype and subtype
— HCV antibody, HIV, and HBV antibody
— HbA1c
— IL28B


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— Serum β-hCG pregnancy test for females of childbearing potential only
— HIV-1 RNA will only be collected and analyzed for co-infected subjects

Obtain urine sample for:
— Urinalysis
— Urine drug screen

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form.

Retests of Screening labs are permitted only if there is reason to believe the retest value will 
be within accepted parameters, for example, if the initial exclusionary value was either due to 
a sample processing error or due to an extenuating circumstance such as intercurrent illness.

Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to 
the clinic for the Baseline/Day 1 Visit assessments and enrollment into the study
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events case report form (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.
6.3.
Treatment Assessments
6.3.1.
Baseline/Day 1 Visit
The following baseline tests and procedures must be completed prior to enrollment and
dosing/dispensation of study drug:

Confirm eligibility (Reference Sections 4.2 & 4.3)

Perform complete physical examination, including body weight

Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature)

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counseling

Obtain blood samples for:
— Hematology
— Chemistry


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Coagulation tests 
HCVRNA 
Viral sequencing 
HIV-1 RNA will only be collected and analyzed for co-infected subjects 
• 
Obtain blood sample for Pharmacogenomics testing (for subjects who have consented) 
• 
PPD 
• 
Obtain urine samples for the following procedures: 
Urinalysis 
Pregnancy test for females of child bearing potential only 
• 
Study Drug Administration 
Dispense study drug as directed by the IWRS 
Instruct the subject on the packaging, storage and administration of the study drugs 
Final 
Original 
Observe the subject taking the first dose of study drug and record the time of first dose 
and whether it was taken with or without food. 
6.3.2. 
Week 2 (±3 days) 
The following procedures/assessments are to be completed at the end of Week 2. 
• 
Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature) 
• 
Assessment of AEs and concomitant medications 
• 
Obtain blood samples for: 
Hematology 
Chemistry 
HCVRNA 
Viral sequencing 
PK sample 
HIV-1 RNA will only be collected and analyzed for co-infected subjects 
• 
Assess adherence with study drug dosing regimen including pill count 
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6.3.3.
Weeks 4 and 8 (3 days)
The following procedures/assessments are to be completed at the end of Weeks 4 and 8:

Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature)

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counseling

Obtain blood samples for:
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing
— PK sample
— HIV-1 RNA will only be collected and analyzed for co-infected subjects

Obtain urine sample for pregnancy test (for females of child bearing potential only)

Assess adherence with study drug dosing regimen including pill count

Dispense study drugs as directed by the IWRS
6.3.4.
Week 12 or Early Termination (3 days)
The following procedures/assessments are to be completed at the end of Week 12 or ET:

Perform complete physical examination, including weight

Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature)

Calculate CPT score

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Obtain blood samples for:
— Hematology
— Chemistry


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Coagulation tests 
HCVRNA 
Viral sequencing 
PK sample 
HIV-1 RNA will only be collected and analyzed for co-infected subjects 
• 
I PD 
• 
Obtain urine samples for 
Urinalysis 
Pregnancy test for females of child bearing potential only 
Final 
Original 
• 
Assess adherence with study drug dosing regimen including pill count. Study drug should be 
returned at this visit 
6.3.5. 
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. At all unscheduled visits initiated for the purpose 
of confirming HCV or HIV virologic failure, a sample for HCV RNA Sequencing I Phenotyping, 
or a sample for HIV RNA Genotyping/Phenotyping, respectively, must be collected. 
The Sponsor (e.g. Medical Monitor and Clinical Trial Manager) and CRO must be informed, as 
soon as possible, when a subject comes offtreatment due to an AE. 
6.4. 
Posttreatment Assessments 
The post-treatment Week 4 and 12 visits should be timed from the date oflast administration of 
study drug. All subjects must complete the post-treatment Week 4 visit. All subjects who achieve 
SVR4 will attend the Week 12 visit. The end of study will occur at the post-treatment Week 4 
visit in the case of subjects who do not achieve SVR4, and the post-treatment Week 12 visit in 
the case of patients who do achieve SVR4. 
6.4.1. 
Post-treatment Week 4 (±5 days) 
The following procedures/assessments are to be completed for all subjects, 4 weeks after taking 
the last dose of study drug: 
• 
Perform complete physical examination 
• 
Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature) 
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
Calculate CPT score

Assessment of AEs and concomitant medications

Pregnancy Prevention Counseling

Obtain blood samples for:
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing
— HIV-1 RNA will only be collected and analyzed for co-infected subjects

Obtain urine sample for pregnancy test (for females of child bearing potential only)
6.4.2.
Post-treatment Week 12 (± 5 days)
The following procedures/assessments are to be completed for all subjects who achieve SVR4, 
12 weeks after taking the last dose of study drug:

Perform complete physical examination

Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature)

Calculate CPT score

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Obtain blood samples for:
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing
— HIV-1 RNA will only be collected and analyzed for co-infected subjects


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
Obtain urine sample for pregnancy test (for females of child bearing potential only)
6.5.
Confirmatory Visit
Subjects with HCV RNA ≥LLOQ at either post-treatment Week 4 or 12 visits will be asked to 
return for confirmatory visit within 2 weeks. A sample for viral HCV RNA 
sequencing/phenotyping will be collected.
6.6.
End of Study
Discontinuation from study drug dosing and discontinuation from the overall study, including the 
Post-treatment period, will be collected as two separate events.
The end of study will occur at the post-treatment Week 4 visit in the case of subjects who do not 
achieve SVR4, and the post-treatment Week 12 visit in the case of patients who do achieve 
SVR4.
6.7.
Procedures and Specifications
6.7.1.
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: international normalized ratio (INR), Prothrombin time (PT), Activated partial 
thromboplastin time (APTT).
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Creatine Kinase (CK) , Creatinine, Total Bilirubin (reflex to 
Direct Bilirubin), Glucose, Lipase, Potassium, Sodium, Uric Acid, Fibrotest®/APRI calculation 
and Direct Bilirubin at Screening only.
Virological Tests: Serologies for HCV and HBV, Serology and/or antigen testing for HIV, 
including reflex testing, as necessary. HCV RNA will be measured using the COBAS®
AmpliPrep®/COBAS® TaqMan® HCV Quantitative Test, v2. HCV genotype and subtype will be 
determined using the Siemens VERSANT® HCV genotype INNO-LiPA 2.0 Assay. HIV RNA 
will be measured using the AmpliPrep/COBAS® TaqMan® HIV-1 Test, v2.0. If HIV-1 virologic 
rebound is confirmed, HIV-1 genotype/phenotype will be determined using the PhenoSense
Integrase HIV, GeneSeqIntegrase HIV, PhenoSenseHIV, GenoSure MG, GeneSeqHIV, 
and PhenoSense GT.  Gilead reserves the right to use alternate assays for HCV RNA, HIV 
RNA, HCV genotype, and HIV-1 genotype/phenotype should the above assays become 
unavailable or the results are indefinitive.
IL28B genotype will be determined by polymerase chain reaction (PCR) amplification of the 
SNP, rs12979860, with sequence specific forward and reverse primers and allele specific 
fluorescently labeled TaqMan® MGB probes. Gilead reserves the rights to use an alternate assay 
for IL28B determination should the above assay become unavailable.


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Pregnancy Tests: Serum β-hCG or Urine β-hCG (if positive, requires immediate confirmation 
with Serum β-hCG)
Additional Tests: Urine Drug screen (for Amphetamines, Cocaine, Methadone, Opiates) and 
Hemoglobin A1c (HbA1c), CD4 T-lymphocyte Absolute Count and %
Urinalysis: Appearance, Blood, Color, Glucose, Leukocyte esterase, pH, Protein, Urobilinogen. 
Reflex to microscopic urinalysis if dipstick result is abnormal. At each visit this is tested, it will 
be recorded whether female subjects of childbearing potential are currently menstruating. 
6.7.2.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history, including prior HCV treatment history 
if available will be collected on all subjects during screening.
6.7.3.
Complete Physical Examination
A complete physical examination must include source documentation of general appearance, and 
the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, mouth and tongue; 
chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, nails; 
musculoskeletal; neurological. 
6.7.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
6.7.5.
Creatinine Clearance
Creatinine clearance will be calculated at all visits where blood is drawn.  Creatinine clearance is 
calculated by the Cockcroft-Gault equation {Cockcroft et al 1976} using actual body weight 
(BW).
Male:
CLcr (mL/min) = [140 - age (years)] BW(kg)
72 Scr
Female:
CLcr (mL/min) = [140 - age (years)] BW(kg) 0.85
72 Scr


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Scr = serum creatinine (mg/dL) 
6.7.6. 
12-Lead ECGs 
Final 
Original 
Subjects will be required to rest in a supine position for ~ 5 minutes prior to making a recording. 
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abnormalities. On treatment ECGs should be compared to the subject's 
baseline as part of routine safety monitoring. 
6.7.7. 
HCV Viral RNA Sequencing I Phenotyping Sample (Archive) 
Plasma samples will be collected at Baseline/Day 1 and each subsequent visit for HCV viral 
sequence analysis. At any unscheduled visit initiated for the purpose of confirming HCV 
virologic breakthrough, a HCV viral sequence/phenotype plasma sample must also be collected. 
Unused samples may be archived. 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. 
6.7.8. 
HIV Viral RNA Genotyping/Phenotyping Sample (Archive) 
Plasma samples will be collected at Baseline/Day 1 and each subsequent visit for HIV viral 
sequence analysis. At any unscheduled visit initiated for the purpose of confirming HIV 
virologic failure, an HIV genotype/phenotype plasma sample must also be collected. Unused 
samples may be archived. 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. 
6.7.9. 
Single Phannacokinetic (PK) Sample 
Single PK blood samples will be collected for all subjects at each on-treatment visit and archived 
for PK analysis of SOF (and metabolites), and VEL. 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. 
6.7.10. 
Phannacogenomics Testing 
An additional and distinct informed consent document will be provided to allow the Sponsor to 
obtain and test a subject's blood sample taken on Baseline/Day 1 for pharmacogenomics 
discovery research. If not obtained at Baseline/Day 1, the sam2le may be drawn at any time 
during the study. PD 
L-------------------------------------------------------~ 
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6.7.11. 
Sample Storage 
PD 
6.7.12. 
Pregnancy Testing 
Final 
Original 
All females of childbearing potential will have urine pregnancy testing evety 4 weeks during the 
dosing period and 30 days after last dose of SOFNEL, 6 months after the last dose ofRBV, or 
last visit of the study, whichever comes last. 
If a positive urine pregnancy test is reported, an immediate confinnation with Semm ~-hCG is 
required. 
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7.
TOXICITY MANAGEMENT
7.1.
Dose Modification Due to Toxicity
7.2.
Group 1:  Subjects administered SOF/VEL
There is no option for dose reduction or modification of SOF/VEL
7.3.
Group 2:  Subjects administered SOF/VEL+ RBV
Dose modification for subjects administered SOF/VEL+RBV should be performed according to 
the prescribing information.
Dose reduction of SOF/VEL is not permitted.
Table 7-1.
Ribavirin Dose Modification Guideline for Coadministration with 
SOVALDI
Laboratory Values
Reduce Ribavirin Dose to 
600 mg/daya If:
Discontinue Ribavirin If:b
Hemoglobin in patients with no 
cardiac disease
<10 g/dL
<8.5 g/dL
Hemoglobin in patients with history 
of stable cardiac disease
≥2 g/dL decrease in hemoglobin 
during any 4 week treatment period 
<12 g/dL despite 4 weeks at reduced 
dose
a
The daily dose of ribavirin is administered orally in two divided doses with food. 
b
Once ribavirin has been withheld due to either a laboratory abnormality or clinical manifestation, an attempt may be made to 
restart ribavirin at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that 
ribavirin be increased to the original assigned dose (1000 mg to 1200 mg daily).
If RBV is permanently discontinued, SOF should also be discontinued.
7.3.1.
Subject Stopping Rules
See Section 3.4 for individual subject stopping rules.. 
7.4.
Subject Stopping Rules
See Section 3.4 for individual subject stopping rules.
7.5.
Special Situations Reports
7.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  


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Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  


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8.
ADVERSE EVENTS MANAGEMENT
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
8.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.5.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
8.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity


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
A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is 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.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to SOF/VEL interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 8.1.1 and 8.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 3.4.
8.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the 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 study drug.


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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)
8.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale 
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs associated 
with laboratory abnormalities, the event should be graded on the basis of the clinical severity in 
the context of the underlying conditions; this may or may not be in agreement with the grading 
of the laboratory abnormality.
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead 
Requirements for collection prior to study drug initiation:

After informed consent, but prior to initiation of study medication, the following types of 
events should be reported on the case report form (eCRF): all SAEs and adverse events 
related to protocol-mandated procedures.
Adverse Events

Following initiation of study medication, all AEs, regardless of cause or relationship, 
pregnancy and other special situation reports, until 30 days after last administration of study 
drug must be collected/ reported 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 post-treatment follow-up period, must be reported to 
the eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This 
also includes any SAEs resulting from protocol-associated procedures performed after 
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
Any SAEs and deaths that occur after the post-treatment follow-up visit but within 30 days of 
the last dose of study drug, regardless of causality, should also be reported.

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 report the event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:
Gilead DSPH
Email: Safety_FC@gilead.com
Fax:
+1 650-522-5477

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.
8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 


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worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
8.5.
Toxicity Management 
8.5.1.
Instructions for Reporting Special Situations
8.5.1.1.
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 post study drug follow-up 
period, to the Gilead DSPH using the pregnancy report form within 24 hours of becoming aware 
of the pregnancy.
Refer to Section 8.3 and 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 
Sections 8.1.1 and 8.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH. Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477


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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 DSPH using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead DSPH, fax number 
+1 650 522-5477 or email Safety_FC@gilead.com.
Clinical staff should also report any pregnancies to the Ribavirin Pregnancy Registry at 
1-800-593-2214 (see also https://www.ribairinpregnancyregistry.com) Refer to Appendix 5 for 
Pregnancy Precautions, Definition for Female of Childbearing Potential, and Contraceptive 
Requirements.
8.5.1.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study drug 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 8.3 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.


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Analysis Objectives and Endpoints 
9.1.1. 
Analysis Objectives 
The prima1y objectives of this study are as follows: 
Final 
Original 
• 
To evaluate the efficacy of study treatment with SOFNEL FDC and SOFNEL FDC and 
Ribavirin (RBV) for 12 weeks as measmed by the proportion of subjects with sustained 
viralogic response 12 weeks after cessation of treatment regimen (SVR12) 
• 
To evaluate the safety and tolerability of each treatment regimen 
The secondmy objectives of this study are: 
• 
To determine the prop01tion of subjects who attain SVR at 4 weeks after cessation of each 
treatment regimen (SVR4) 
• 
To evaluate the kinetics of circulating HCV RNA dming treatment and after cessation of 
each treatment regimen 
• 
To evaluate the emergence of viral resistance to SOP and VEL dming treatment and after 
cessation of treatment 
The explorat01y objective of this study is: 
• 
PD 
9.1.2. 
Primary Endpoints 
The prima1y efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after cessation of study 
treatment regimen) in the Full Analysis Set (F AS). 
The prima1y safety endpoint is any AE that led to pe1manent discontinuation of study dmg. 
9.1.3. 
Secondary Endpoints 
The secondmy efficacy endpoints include the prop01tion of subjects who attain sustained 
virologic response at 4 weeks after cessation of the study treatment regimen (SVR4); the 
prop01tion of subjects who have HCV RNA < LLOQ by visit while on study treatment; absolute 
and change from baseline/Day 1 in HCV RNA through Week 12; and the prop01tion of subjects 
with virologic failme. 
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9.1.4.
Other Endpoints of Interest
Additional efficacy evaluations may include ALT normalization.
9.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using SASsoftware (SAS Institute, Cary, North Carolina, USA).
The study drug in this study is SOF/VEL or SOF/VEL +RBV. Last dose of study drug refers to 
the last dose of any of the study drugs in a treatment group and will be used in the definition of 
treatment-emergent AEs and laboratory abnormalities as well as the efficacy endpoints of SVR 
at various post-treatment time points.
9.2.1.
Analysis Sets
9.2.1.1.
All Randomized 
All Randomized Analysis Set includes all subjects who were randomized in the study.
9.2.1.2.
Efficacy
The primary analysis set for efficacy analysis will be the FAS which include all randomized
subjects who received at least 1 dose of study drug. 
9.2.1.3.
Safety
The primary analysis set for safety analyses will be the Safety Analysis Set which includes all 
subjects who took at least 1 dose of study drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose of the
study drug through the last dose date of the study drug plus 30 days.
9.2.1.4.
Pharmacokinetics
The Pharmacokinetic (PK) Analysis Set includes all subjects who took at least 1 dose of study 
drug and have at least 1 nonmissing postdose concentration value for the corresponding analyte 
in plasma.  The analytes of interest may include SOF (and its metabolites GS-566500 and 
GS-331007), VEL, and RBV if applicable.  The PK analysis set will be used for analyses of 
general PK.
9.3.
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. 


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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).
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject took at least 1 dose of study medication, the subject will be included in a 
summary of AEs according to the treatment received; otherwise, if the subject is not dosed 
then they will be excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the pre-dose value and the change from pre-dose values.
Values for missing safety laboratory data will not be imputed; however, a missing Baseline/Day 
1 result will be replaced with a screening result, if available. If no pretreatment laboratory value 
is available, the Baseline/Day 1 value will be assumed to be normal (i.e., no grade [Grade 0]) for 
the summary of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing Baseline/Day 1 result
will be replaced with a screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for 
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).
HIV RNA in this study will be measured using the AmpliPrep/COBAS® TaqMan® HIV-1 Test, 
v2.0. The LLOQ of the assay is 20 cp/mL.
When the calculated HIV RNA value is within the linear range of the assay, then the result will 
be report as the “<< numeric value>> cp/mL”. When HIV RNA is not detected, the result is 


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rep01ied as "No HIV-1 RNA detected". When the calculated HIV RNA cp/mL is less than 
LLOQ of the assay, the result is repotied as "<20 cp/mL HIV-1 RNA Detected". 
Final 
Original 
For numerical HIV RNA data analysis, values retumed as "<20 cp/mL HIV-1 RNA Detected" or 
"No HIV-1 RNA detected" will be set to the LLOQ minus 1 (ie, 19 HIV RNA cp/mL). If 
methods based on the assumption that the data are nonnally distributed are not adequate, 
analyses may be perf01med on transf01med data (eg, log10 scale) or nonpal'ametric analysis 
methods may be used, as appropriate. 
9.4. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be summarized using standard descriptive 
methods 
Demographic summaries will include age, sex, self-identified race and ethnicity. 
Baseline characteristic data will include body mass index, absence or presence of cinhosis, 
baseline HCV RNA level (log10 IU/mL), HCV genotype, IL28B genotype, HIV co-infection and 
additional endpoints as necessaty. 
9.5. 
Efficacy Analysis 
9.5.1. 
Primary Analysis 
The primaty efficacy endpoint for this study will be the propotiion of subjects with SVR12 as 
defined as HCV RNA < LLOQ 12 weeks after cessation of study treatment regimen in the F AS 
population. Point estimate and 95% confidence interval (using the Clopper-Peru·son method) of 
SVR12 will be computed for each treatment group. 
9.5.2. 
Secondary Analyses 
The propotiion of subjects with HCV RNA below LLOQ over time (including SVR endpoints) 
will be presented in tabular and graphical fotm. 
Descriptive summru·ies and listings will be provided for additional efficacy evaluations including 
serum HCV RNA actual values and change from baseline through Week 12, the proportion of 
subjects who experience virologic failure and AL T nonnalization. 
PD 
Details on efficacy analyses will be described in the statistical analysis plan. 
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9.6.
Safety Analysis
Safety will be evaluated by assessment of clinical laboratory tests (including HIV-1 RNA and 
CD4 T-cell count for HCV/HIV co-infection subjects), physical examinations, vital signs 
measurements and AEs will be documented at various time points during the study.
All safety data collected on or after the first dose of study drug administration up to 30 days after 
the last dose of study drugs will be summarized.
9.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug data will be generated from the study drug 
administration page of the CRF. Exposure data will be summarized by treatment group. 
9.6.2.
Adverse Events
Clinical and laboratory adverse events (AEs) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
AE will be defined as any AE with an onset date on or after the study drugs start date and no 
later than 30 days after permanent discontinuation of the study drugs; or any AE leading to 
premature discontinuation of the study drugs.
Summaries (number and percentage of subjects) of treatment-emergent AEs (by SOC and PT) 
will be provided for:

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 any study drug

All AEs leading to premature discontinuation from SOF/VEL
All AEs collected during the study will be presented in data listings.


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9.6.3.
Laboratory Evaluations
Selected laboratory data (including HIV RNA and CD4 T-cell count for HCV/HIV co-infection 
subjects) will be summarized (n, mean, SD, median, Q1, Q3, minimum, and maximum) by 
treatment group and by study visit along with corresponding change from Baseline/Day 1.
Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme in 
Appendix 3 of this protocol. Incidence of treatment-emergent laboratory abnormalities, defined 
as values that increase at least one toxicity grade from Baseline/Day 1 at any time post baseline 
up to and including the date of last dose of study drug plus 30 days will be summarized by 
treatment group. 
Values for missing safety laboratory data will not be imputed; however, a missing Day 1 result 
will be replaced with a screening result, if available. If no pre-treatment laboratory value is 
available, the Baseline/Day 1 value will be assumed to be normal (i.e., no grade [Grade 0]) for 
the summary of graded laboratory abnormalities. If Baseline/Day 1 data are missing, then any 
post-baseline graded abnormality (ie, at least Grade 1) will be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
9.6.4.
Other Safety Evaluations
Individual data and change from baseline for vital signs measurements will be listed by subject 
and summarized by treatment group and overall by descriptive statistical summaries (n, mean, 
SD, median, Q1, Q3, minimum, and maximum). 
9.6.5.
HIV RNA Analysis
Subjects with HCV/HIV co-infection RNA < 50 copies/mL at Baseline/Day 1 will be 
summarized by visit to assess the proportion of subjects that maintain HIV-1 RNA 
< 50 copies/mL while on HCV treatment.
Details on HIV-1 RNA related safety analyses will be described in the statistical analysis plan.
9.7.
Pharmacokinetic Analysis
Concentrations of SOF (and its metabolites GS-566500 and GS-331007) and VEL (GS-5816) in 
plasma may be determined using validated bioanalytical assays and listed.
9.8.
Sample Size
Approximately 200 cirrhotic subjects with chronic genotype 3 HCV infection will be enrolled in 
this study. This sample size is based on the number of subjects who meet the eligibility criteria 
who could practically be enrolled.  With a sample size of 100 for each treatment, a two-sided 
95% exact confidence interval will extend at most 21% in length for each treatment.


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, South Africa, 
Washington DC, Seoul and Brazil), 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 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.
10.1.2.
Institutional Review Board (IRB)/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.
10.1.3.
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 
and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IEC or local 


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requirements. The consent form will inform subjects about pharmacogenomic testing and sample 
retention, and their right to receive clinically relevant pharmacogenomic analysis results.
10.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IEC or laboratory. Laboratory specimens 
must be labeled in such a way as to protect subject identity while allowing the results to be 
recorded to the proper subject. Refer to specific laboratory instructions 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 information received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRF, the study drugs, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
10.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IEC
and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);


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
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 study drug, 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.
Biological samples at the conclusion of this study may be retained in storage by the Sponsor for 
a period of up to 15 years for purposes of this study
10.1.6.
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. The 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 


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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 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 (e.g. 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 10.1.5.
10.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused study drugs 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 study drug disposal 
procedures and provide appropriate instruction for destruction of unused study drugs. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, 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 study drug is destroyed on site, the investigator must maintain accurate records for all study 
drug destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the study drug. 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.
10.1.8.
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.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IEC in 
accordance with local requirements and receive documented IEC approval before modifications 
can be implemented.
10.2.2.
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 10.1.4).
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.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings.  If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.


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10.3.2.
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.
10.3.3.
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.
10.3.4.
Study Discontinuation
The sponsor reserves the right to terminate the study at any time. Should this be necessary, both 
the sponsor and the investigator will arrange discontinuation procedures and notify the 
appropriate regulatory authority (ies), IRBs, and IECs. In terminating the study, Gilead and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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11.
REFERENCES
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and 
sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 
2014a;370 (16):1483-93.
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for 
untreated HCV genotype 1 infection. N Engl J Med 2014b;370 (20):1889-98.
Agarwala S, Eley T, Villegas C, Wang EH, Grasela D. Pharmacokinetic interaction between 
tenofovir and atazanavir coadministered with ritonavir in healthy subjects 
[poster]. 6th International Workshop on Clinical Pharmacology of HIV Therapy; 
2005 April 26-29; Quebec, Canada. 
Andrews E, Damle BD, Fang A, Foster G, Crownover P, LaBadie R, et al. Pharmacokinetics and 
tolerability of voriconazole and a combination oral contraceptive co-administered 
in healthy female subjects. Br J Clin Pharmacol 2008;65 (4):531-9.
Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA. A sustained virologic 
response reduces risk of all-cause mortality in patients with hepatitis C. Clin 
Gastroenterol Hepatol 2011;9 (6):509-16 e1.
Barditch-Crovo P, Trapnell CB, Ette E, Zacur HA, Coresh J, Rocco LE, et al. The effects of 
rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a 
combination oral contraceptive. Clin Pharmacol Ther 1999;65 (4):428-38.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Curry MP, O'Leary JG, Bzowej N, Muir AJ, Korenblat KM, Fenkel JM, et al. Sofosbuvir and 
Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med 
2015.
Denniston MM, Jiles RB, Drobeniuc J, Klevens RM, Ward JW, McQuillan GM, et al. Chronic 
Hepatitis C Virus Infection in the United States, National Health and Nutrition 
Examination Survey 2003 to 2010. Ann Intern Med 2014;160:293-300.
Feld JJ, Jacobson IM, Hezode C, Asselah T, Ruane PJ, Gruener N, et al. Sofosbuvir and 
Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med 2015.
Foster GR, Pianko S, Brown A, Forton D, Nahass RG, George J, et al. Efficacy of Sofosbuvir 
Plus Ribavirin With or Without Peginterferon-Alfa in Patients With Hepatitis C 
Virus Genotype 3 Infection and Treatment-Experienced Patients With Cirrhosis 
and Hepatitis C Virus Genotype 2 Infection. Gastroenterology 2015;149 (6):1462-
70.


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Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing Information.  
Foster City, CA. December 2013:
Hoetelmans RM, Marien K, De Pauw M, Hill A, Peeters M, Sekar V, et al. Pharmacokinetic 
interaction between TMC114/ritonavir and tenofovir disoproxil fumarate in 
healthy volunteers. Br J Clin Pharmacol 2007;64 (5):655-61.
Janssen Pharmaceuticals Inc. INTELENCE® (etravirine) tablets for oral use. US Prescribing 
Information. 2008 Titusville NJ. Revised February 2013.
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and 
sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 
2014;370 (20):1879-88.
Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing burden of 
mortality from viral hepatitis in the United States between 1999 and 2007. Ann 
Intern Med 2012;156 (4):271-8.
Mahajan R, Xing J, Liu SJ, Ly KN, Moorman AC, Rupp L, et al. Mortality Among Persons in 
Care With Hepatitis C Virus Infection: The Chronic Hepatitis Cohort Study 
(CHeCS), 2006-2010. Clin Infect Dis 2014.
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon 
alfa-2b alone or in combination with ribavirin as initial treatment for chronic 
hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998;339 
(21):1485-92.
Nelson DR, Cooper JN, Lalezari JP, Lawitz E, Pockros PJ, Gitlin N, et al. All-oral 12-week 
treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus 
genotype 3 infection: ALLY-3 phase III study. Hepatology 2015;61 (4):1127-35.
Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of 
interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon 
alpha2b plus placebo for 48 weeks for treatment of chronic infection with 
hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). 
Lancet 1998;352 (9138):1426-32.
Quest Diagnostics. FSH and LH Reference Ranges.  2013a:
Quest Diagnostics. Progesterone, LC/MS/MS Reference Ranges.  2013b:
Roche Laboratories Inc. COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. 
Nutley, NJ. Revised: January 2010.


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Roche Products Limited. Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
Characteristics. Welwyn Garden City, United Kingdom. Revised: March 2010.
World Health Organization (WHO). Hepatitis C Fact sheet N°164. Available at: 
http://www.who.int/mediacentre/factsheets/fs164/en/#. Accessed: 20 March.  
2014.


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12.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 4.
Child-Pugh-Turcotte Classification of the severity of cirrhosis
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 6.
Opportunistic Infections


SOFNELFDC 
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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
~ 
FOSTER CITY, CA 94404, USA 
STUDY ACKNOWLEDGEMENT 
Final 
Original 
A Phase 2, Multicenter, Randomized, Open-Label Study to Evaluate the Efficacy and Safety of 
SofosbuvirN elpatasvir Fixed Dose Combination (FDC) ap.d SofosbuvirN elpatasvir FDC and 
Ribavirin in Subjects with Chronic Genotype 3 H,CV Infection and Cirrhosis 
GS-US-342-2097, Original, 16 March 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PPD 
Brian McNabb, MD 
Signature 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page97 
16 March 2016 


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Appendix 2.
Study Procedures Table
Screen
Baseline/Day 1b
On-treatment Week
Post-treatment Week
2
4
8
12/ET
4
12
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
X
X
Height
X
Weight
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
12-Lead ECG
X
CPT score
X
X
X
X
Adverse Events and 
Concomitant Medications
X
X
X
X
X
X
X
X
Pregnancy Prevention 
Counseling
X
X
X
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
Study Drug Dispensinga
X
X
X
Laboratory Assessments
Hematology, Chemistry g
X
X
X
X
X
X
X
X
Coagulation Tests
X
X
X
Urinalysis
X
X
X
HCV RNAc
X
X
X
X
X
X
X
Xf


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Screen
Baseline/Day 1b
On-treatment Week
Post-treatment Week
2
4
8
12/ET
4
12
HIV-1 RNAh
X
X
X
X
X
X
X
X
Viral Sequencingc  
X
X
X
X
X
X
Xf
Single PK
X
X
X
X
Serum β-hCG or Urine 
Pregnancy Testd
X
X
X
X
X
X
X
Urine Drug Screen
X
HCV Genotyping, IL28B 
X
HCV, HIV, HBV Serology
X
HbA1c, Fibrotest®
X
Archive Samplee
X
X
Pharmacogenomic Samplee
X
a
The IWRS will provide direction on the specifics of each subject’s study drug dispensing
b
Baseline/Day 1 assessments must be performed prior to dosing
c
Viral sequencing samples for virologic sequencing required at baseline and after any visit where a previously undetectable HCV RNA becomes detectable 
d
Serum β-hCG pregnancy test performed at screening and for confirmation of positive urine pregnancy test.
e
Only for subjects who have provided consent for this sample and testing. The  Week 12 / Early Termination visit will be the last opportunity for this to be collected.
f
Only for subjects with HCV RNA ≥LLOQ at post-treatment week 12 visit will be asked to return after for a confirmatory visit where additional samples are collected.
g
CrCl will be calculated at all visits where a blood sample is drawn
h
HIV-1 RNA will only be collected and analyzed for co-infected subjects


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 100
16 March 2016
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L


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Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 101
16 March 2016
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 


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Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 102
16 March 2016
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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Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant  <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 t o <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant  <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 104
16 March 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL                          
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL              
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL                      
1.51 to < 1.74 mmolL
< 6.1 mg/dL                           
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*) 
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


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Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 105
16 March 2016
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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Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 106
16 March 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


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Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years 
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 108
16 March 2016
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to < 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


SOF/VEL FDC
Protocol GS-US-342-2097
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated


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


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


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


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


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


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


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


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


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


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


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


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Appendix 4.
Child-Pugh-Turcotte Classification of the severity of cirrhosis
POINTS*
1
2
3
Encephalopathy
None
Grade 1-2
(or precipitant-induced)
Grade3-4
(or chronic)
Ascites
None
Mild/Moderate
(diuretic-responsive)
Severe
(diuretic-refractory)
Bilirubin (mg/dL)
< 2
2-3
> 3
Albumin (g/dL)
> 3.5
2.8-3.5
< 2.8
PT (sec 
prolonged)
or INR
< 4
< 1.7
4-6
1.7-2.3
> 6
> 2.3
*
CPT score is obtained by adding the score for each parameter
CPT class: A = 5-6 points
B = 7-9 points
C = 10-15 points
a
U.S. Department of Veterans Affairs. Child -Pugh-Turcotte Classification of the severity of cirrhosis. 
Available at http://www hepatitis.va.gov/provider/tools/child-pugh-calculator.asp, Accessed May 29, 2012.


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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Background
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects have 
been demonstrated in all animal species tested. Pregnancy must be excluded before the start of 
treatment with study drugs and prevented thereafter by reliable contraceptive methods. 
Pregnancy tests will be performed regularly throughout this study. Furthermore, RBV is known 
to accumulate intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, 
extreme care must be taken to avoid pregnancy during RBV therapy and for up to 6 months 
following completion of treatment (7 months for males). Please refer to the latest version of the 
product insert for additional information. 
2) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following menarche until becoming post-menopausal, unless permanently sterile or with 
medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.  
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
3) Study Drug Effect on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of SOF have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception.  Non-clinical toxicity studies of 
SOF have demonstrated no adverse effect on fertility or embryo-fetal development.
Data from clinical pharmacokinetic interaction studies of VEL have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception.  Non-clinical toxicity studies of GS-
5816 have demonstrated no adverse effect on fertility or embryo-fetal development.
However, the risks of treatment with SOF/VEL during pregnancy in humans have not been 
evaluated.  Please refer to the latest version of the Investigator’s Brochure for additional 
information.


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4) Contraception Requirements for Female Subjects of Childbearing Potential
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 Baseline/Day 1 visit prior to first dose of study drug.  
Pregnancy testing will occur at regular intervals throughout the duration of the trial.  In the event 
of a delayed menstrual period (over one month between menstruations), a pregnancy test must be 
performed to rule out pregnancy.  This is even true for women of childbearing potential with 
infrequent or irregular periods.  They must also agree to one of the following from Screening 
until 30 days after the last dose of SOF/VEL or 6 months after the last dose of RBV, whichever 
occurs last.

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below, in 
addition to a male partner who correctly used a condom from the date of Screening until 
30 days after the last dose of SOF/VEL or 6 months after the last dose of RBV, whichever 
occurs last.
— Intrauterine device (IUD) 
— Intrauterine hormone-releasing system (IUS) 
— Tubal sterilization
— Essure micro-insert system 
— Vasectomy in the male partner 
— Barrier methods 
■
Female barriers: Diaphragm with spermicide or Cervical cap with spermicide
— Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel or etonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring


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Female subjects must also refrain from egg donation and in vitro fertilization during study 
treatment and until at least 30 days after the last dose of SOF/VEL or 6 months after the last dose 
of RBV, whichever occurs last.
5) 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 treatment or 7 months after the last dose 
or RBV, whichever comes last, 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 or 7 months after last dose of RBV, whichever comes last.
Male subjects must also refrain from sperm donation during treatment and until at least 30 days 
after the last dose of SOF/VEL or 7 months after the last dose of RBV, whichever comes last.
6) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
7) 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, if they become pregnant within 30 days of last dose of SOF/VEL , or if they become 
pregnant within 6 months of the last dose of RBV. 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 within 30 days of the last dose of SOF/VEL or 7 months after the last 
dose of RBV, whichever occurs last, must report the information to the investigator.
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in
Section 8.5.1.1


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Appendix 6.
Opportunistic Infections
Non-inclusive list of opportunistic infections base on AIDS-Indicator Conditions from CDC 
Classification System for HIV Infection Clinical Category C:  
1. Bacterial pneumonia, recurrent (two or more episodes in 12 months)
2. Candidiasis of the bronchi, trachea, or lungs
3. Candidiasis, esophageal
4. Cervical carcinoma, invasive, confirmed by biopsy
5. Coccidioidomycosis, disseminated or extrapulmonary
6. Cryptococcosis, extrapulmonary
7. Cryptosporidiosis, chronic intestinal (>1 month in duration)
8. Cytomegalovirus disease (other than liver, spleen, or nodes)
9. Encephalopathy, HIV-related
10. Herpes simplex: chronic ulcers (>1 month in duration), or bronchitis, pneumonitis, or 
esophagitis
11. Histoplasmosis, disseminated or extrapulmonary
12. Isosporiasis, chronic intestinal (>1-month in duration)
13. Kaposi sarcoma
14. Lymphoma, Burkitt, immunoblastic, or primary central nervous system
15. Mycobacterium avium complex (MAC) or Mycobacterium kansasii, disseminated or 
extrapulmonary
16. Mycobacterium tuberculosis, pulmonary or extrapulmonary 
17. Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
18. Pneumocystis jiroveci (formerly carinii) pneumonia (PCP)
19. Progressive multifocal leukoencephalopathy (PML)
20. Salmonella septicemia, recurrent (nontyphoid)
21. Toxoplasmosis of brain
22. Wasting syndrome caused by HIV (involuntary weight loss >10% of baseline body weight) 
associated with either chronic diarrhea (two or more loose stools per day for ≥1 month) or 
chronic weakness and documented fever for ≥1 month