Conditions: Hepatitis C Virus Infection
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 375
Healthy volunteers: no

Brief summary:
The primary objectives of this study are to evaluate the efficacy, safety, and tolerability of treatment with sofosbuvir (SOF)/velpatasvir (VEL; GS-5816) fixed-dose combination (FDC) for 12 weeks in participants with chronic hepatitis C virus (HCV) infection.

Detailed description:

Arms:
arm 1: SOF/VEL FDC for 12 weeks

Interventions: intervention 1: SOF/VEL
Intervention descriptions: intervention 1: SOF/VEL (400/100 mg) FDC tablet administered orally once daily

Protocol document:
SAP_002.pdf: 
Study Title: 
Name of Test Drug: 
Study Number: 
Protocol Version (Date): 
Analysis Type: 
Analysis Plan Version: 
Analysis Plan Date: 
Analysis Plan Author: 
~ GILEAU 
STATISTICAL ANALYSIS PLAN 
A Phase 3, Multicenter, Open-Label Study to Investigate the 
Efficacy and Safety of SofosbuvirNelpatasvir Fixed Dose 
Combination for 12 Weeks in Subjects with Cru·onic HCV 
SofosbuvirNelpatasvir Fixed-Dose Combination 
GS-US-342-1518 
Amendment 1: 21 April2015 
SVR12 and Final Analysis 
1.0 
18 January 2018 
PPD 
CONFIDENTIAL AND PROPRlET ARY INFORMATION 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................3
LIST OF ABBREVIATIONS........................................................................................................................................4
1.
INTRODUCTION ................................................................................................................................................6
1.1.
Study Objectives ......................................................................................................................................6
1.2.
Study Design............................................................................................................................................7
1.3.
Sample Size and Power............................................................................................................................8
2.
TYPE OF PLANNED ANALYSIS ......................................................................................................................9
2.1.
Data Monitoring Committee ....................................................................................................................9
2.2.
Interim Analysis.......................................................................................................................................9
2.2.1.
Posttreatment Week 4 Analysis..............................................................................................9
2.2.2.
Primary Efficacy Endpoint Analysis......................................................................................9
2.3.
Final Analysis ..........................................................................................................................................9
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................10
3.1.
Analysis Sets..........................................................................................................................................10
3.1.1.
All Enrolled Analysis Set.....................................................................................................10
3.1.2.
Full Analysis Set ..................................................................................................................10
3.1.3.
Safety Analysis Set...............................................................................................................10
3.2.
Subject Grouping ...................................................................................................................................10
3.3.
Examination of Subject Subsets.............................................................................................................11
3.4.
Missing Data and Outliers......................................................................................................................11
3.4.1.
Missing Data ........................................................................................................................11
3.4.2.
Outliers.................................................................................................................................12
3.5.
Multiple Comparisons............................................................................................................................12
3.6.
Data Handling Conventions and Transformations .................................................................................12
3.7.
Visit Windows........................................................................................................................................13
3.7.1.
Definition of Study Day .......................................................................................................13
3.7.2.
Analysis Windows................................................................................................................14
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis 
Window................................................................................................................................15
4.
SUBJECT DISPOSITION ..................................................................................................................................17
4.1.
Subject Enrollment and Disposition.......................................................................................................17
4.2.
Extent of Exposure.................................................................................................................................18
4.2.1.
Duration of Exposure to Study Drug....................................................................................18
4.2.2.
Adherence to Study Drug.....................................................................................................18
4.3.
Protocol Deviations................................................................................................................................19
5.
BASELINE CHARACTERISTICS....................................................................................................................20
5.1.
Demographics ........................................................................................................................................20
5.2.
Baseline Characteristics .........................................................................................................................20
5.3.
Medical History......................................................................................................................................21
6.
EFFICACY ANALYSES ...................................................................................................................................22
6.1.
Primary Efficacy Endpoint.....................................................................................................................22
6.1.1.
Definition of the Primary Efficacy Endpoint .......................................................................22
6.1.2.
Statistical Hypothesis for the Primary Efficacy Endpoint....................................................22


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6.1.3.
Primary Analysis of the Primary Efficacy Endpoint ............................................................22
6.1.4.
Subgroup Analysis of the Primary Efficacy Endpoint .........................................................23
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.............................................................................................................24
6.3.1.
Definition of Exploratory Efficacy Endpoints......................................................................24
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.
Safety Endpoints ....................................................................................................................................26
7.2.
Adverse Events and Deaths....................................................................................................................26
7.2.1.
Adverse Event Dictionary ....................................................................................................26
7.2.2.
Adverse Event Severity........................................................................................................26
7.2.3.
Relationship of Adverse Events to Study Drug....................................................................26
7.2.4.
Serious Adverse Events........................................................................................................26
7.2.5.
Treatment-Emergent Adverse Events...................................................................................26
7.2.6.
Summaries of Adverse Events and Deaths...........................................................................27
7.3.
Laboratory Evaluations ..........................................................................................................................29
7.3.1.
Summaries of Numeric Laboratory Results .........................................................................29
7.3.2.
Graded Laboratory Values ...................................................................................................30
7.4.
Body Weight, Height, and Vital Signs...................................................................................................31
7.5.
Prior and Concomitant Medications.......................................................................................................31
7.6.
Electrocardiogram Results .....................................................................................................................32
7.7.
Other Safety Measures ...........................................................................................................................32
7.8.
Changes From Protocol-Specified Safety Analyses...............................................................................32
8.
REFERENCES ...................................................................................................................................................33
9.
SOFTWARE.......................................................................................................................................................34
10.
SAP REVISION..................................................................................................................................................35
11.
APPENDICES ....................................................................................................................................................36
Appendix 1.
Study Procedures Table..........................................................................................................37
LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Windows for On-treatment HCV RNA, Vital Signs and Safety Laboratory 
Data ........................................................................................................................................14
Table 3-2.
Analysis Windows for Posttreatment HCV RNA, Vital Signs and Safety Laboratory 
Data ........................................................................................................................................15
Table 3-3.
Analysis Windows for On-treatment ECG Data.....................................................................15


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANC 
absolute neutrophil count
APRI
AST:platelet ratio index
APTT
activated partial thromboplastin time
AST
aspartate transaminase
ATC
anatomical therapeutic chemical
BLQ
below the limit of quantitation
BMI
body mass index
BPM
beats per minute
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CSR
clinical study report
DAA
direct acting antiviral
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EOT
end of treatment
FAS
full analysis set
FDC
fixed dose combination
FU
follow-up
GT
genotype (viral)
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HLGT
high level group term
HLT
high level term
ID
identification
IL28B
IL28B genotype
INR
International Normalized Ratio of prothrombin time
IWRS
Interactive Web Response System
LLOQ
lower limit of quantitation
LLT
lower level term
MCV
mean corpuscular volume or mean cell volume
MedDRA
Medical Dictionary for Regulatory Activities
Peg-IFN
pegylated interferon
PT
preferred term
RBC
red blood cell count


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Q1
first quartile
Q3
third quartile
RBC
red blood cell
RBV
ribavirin
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
TE
treatment-emergent
TFLs
tables, figures, and listings
TND
target not detected
ULN
upper limit of the normal range
VEL
velpatasvir (GS-5816)
WBC
white blood cell
WHO
World Health Organization


SOFNELFDC 
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1. 
INTRODUCTION 
Final 
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-342-1518. This SAP is based on the study protocol amendment I dated 
21 April 2015 and the electronic case rep01t form ( eCRF). The SAP will be fmalized before 
database finalization. Any changes made after the fmalization of the SAP will be documented in 
the CSR. 
1.1. 
Study Objectives 
The prima1y objectives of this study are as follows: 
• 
To evaluate the efficacy oftreatment with sofosbuvir (SOF)/velpatasvir (VEL, GS-5816) 
fixed dose combination (FDC) for 12 weeks in subjects with chronic HCV infection as 
measured by the prop01tion of subjects with sustained viral response 12 weeks after cessation 
of treatment (SVRI2) 
• 
To evaluate the safety and tolerability oftreatment with SOFIVEL for 12 weeks 
The secondruy objectives of this study ru·e: 
• 
To dete1mine the prop01tion of subjects with SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24) 
• 
To evaluate the prop01tion of subjects with virologic failure 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment 
• 
To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment 
The explorat01y objectives of this study are: 
p 
0 
I 
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1.2.
Study Design
This is an international, multicenter, open-label study that will evaluate the safety, tolerability 
and antiviral efficacy of SOF/VEL for 12 weeks in treatment-naïve and treatment-experienced 
adults with chronic HCV infection. Subjects with or without cirrhosis will be enrolled. 
Approximately 20% of subjects may be treatment experienced and approximately 20% of 
subjects may have compensated cirrhosis at screening.
Subjects with chronic HCV infection will be enrolled to receive SOF/VEL once daily for 
12 weeks.
This multi-regional clinical trial (MRCT) is planned to be conducted in China, Malaysia, 
Singapore, Thailand, and Vietnam. China will be considered Region 1. Malaysia, Singapore, 
Thailand, and Vietnam, which are all located in Southeast Asia, will be considered Region 2.
Approximately 360 subjects will be enrolled in the study in total. The approximate number of 
subjects to be enrolled in each region according to HCV genotype is represented in the table 
below:
HCV GT 
(Prior Rx History) 
GT-1
(TN, TE)
GT-2
(TN, TE)
GT-3
(TN, TE)
GT-4,5,6
(TN, TE)
Total
Region 1 (China)
80
60
60
60
260
Region 2 (Malaysia, Singapore, Thailand, Vietnam)
100
100
Rx = Treatment
TN = Treatment Naïve, TE = Treatment Experienced
It is expected that a small number of subjects whose HCV genotype cannot be determined by the 
central laboratory (HCV genotype indeterminate) may also be enrolled.
The schedule of assessments is provided as an appendix to the SAP (Appendix 1).
The total time to complete all study visits is up to approximately 42 weeks including the 
following periods:

42-day (6-week) screening period

12-week treatment period

Up to 24-week posttreatment period


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1.3.
Sample Size and Power
The sample size justification is based on the Region 1 population. A sample size of 260 subjects 
in Region 1 will provide more than 80% power to detect an improvement of at least 6 percentage 
points in SVR12 rate from the performance goal of 85% by using a two-sided exact one-sample 
binomial test at the significance level of 0.05. 
In addition, a confidence interval approach will be used to estimate the SVR12 rates for Region 2 
and for the overall population (ie, combined Region 1 and Region 2). With 100 subjects from 
Region 2, and 360 subjects from the overall population, the 2-sided 95% exact CIs for different 
observed SVR12 rates are presented in the table below.
Region
Observed SVR12 rate
2-sided 95% exact CI
Region 2 (n=100)
80% (80 out of 100)
71% - 87%
90% (90 out of 100)
82% - 95%
Overall (n=360)
80% (288 out of 360)
75% - 84%
90% (324 out of 360)
86% - 93%


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee
This study does not have a data monitoring committee (DMC).
2.2.
Interim Analysis
2.2.1.
Posttreatment Week 4 Analysis
A Posttreatment Week 4 analysis will be conducted for administrative purposes after all subjects 
complete the Posttreatment Week 4 visit or prematurely discontinue from the study. All safety 
and efficacy data through the Posttreatment Week 4 visit will be included (SVR12 will not be 
evaluated at this time). The results will be restricted to a limited group of individuals within 
Gilead Sciences, Inc. (Gilead). There will be no changes to the study design, study conduct, or 
the sample size as a result of this administrative analysis.
2.2.2.
Primary Efficacy Endpoint Analysis
The analyses for the primary endpoint SVR12 will be conducted for Region 1, Region 2, and 
Overall after all subjects complete the posttreatment Week 12 visit or prematurely discontinue 
from study. All the safety and efficacy data through the posttreatment Week 12 visit will be 
cleaned, finalized and included for the analysis. 
2.3.
Final Analysis
After all subjects have completed the study, outstanding data queries have been resolved, and the 
database has been cleaned and finalized, the final analysis of the data will be performed.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects [n], mean, standard deviation [SD] or standard error [SE], median, 
first quartile [Q1], third quartile [Q3], minimum, and maximum will be presented.
Statistical tests will be two-sided and performed at the 5% significance level unless otherwise 
prespecified in Section 6.1.
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 
region and 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 summarized or provided in 
a by-subject listing with reasons for exclusion by region. 
3.1.1.
All Enrolled Analysis Set
The All Enrolled Analysis Set includes all subjects who were enrolled in the study. Subjects are 
grouped within the All Enrolled Analysis Set by genotype (GT) and region. 
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all subjects who were enrolled into the study and received 
at least 1 dose of study drug. The study drug in this study is SOF/VEL. Subjects are grouped 
within the FAS by region and genotype. 
This is the primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who were enrolled into the study and received at 
least 1 dose of study drug. Subjects are grouped by region. 
This is the primary analysis set for safety analyses.
3.2.
Subject Grouping
For analyses based on All Enrolled Analysis Set and Full Analysis Set, subjects will be grouped 
by region for primary analysis of the primary endpoint and grouped by region and genotype for 
all other analyses. Unless otherwise specified, groups by genotype include GT1a, GT1b, GT1 
(Total), GT2, GT3, GT4, GT5, GT6, Indeterminate, and Total, and groups by region include 
Region 1, Region 2, and Overall. For analyses based on the Safety Analysis Set, subjects will be 
grouped by region and genotype for demographic information and grouped by region for all 
other safety analyses. 


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3.3.
Examination of Subject Subsets
Subject subsets will be explored for the primary efficacy endpoint, SVR12. The subject subsets
include the following:

age (< 65 years, 65 years)

sex (male, female)

baseline body mass index (BMI) (< 25 kg/m2 , ≥ 25 kg/m2) 

baseline HCV RNA (< 800,000 IU/mL, ≥ 800,000 IU/mL; < 5 log10 IU/mL, ≥5 log10 IU/mL)

baseline ALT (≤1.5 × upper limit of normal [ULN], > 1.5 × ULN)

IL28B (CC, non-CC; with non-CC further broken down to CT, TT)

cirrhosis (presence, absence, missing)

prior HCV treatment experience (treatment naïve, treatment experienced)

prior HCV treatment (DAA+PEG+RBV, INTERFERON+RBV, PEG+RBV, Other) for 
treatment-experienced subjects

most recent HCV treatment response (non-responder, relapse/breakthrough, early treatment 
discontinuation, met a virologic stopping rule, not otherwise listed, unknown) for 
treatment-experienced subjects

adherence to study regimen (<80%, ≥80%)
3.4.
Missing Data and Outliers
3.4.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. 
For missing last dosing date of study drug, imputation rules are described in Section 3.7.1. The 
handling of missing or incomplete dates for adverse event (AE) onset is described in 
Section 7.2.5.2, 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 the missing data imputed up to 
the time of the last dose (for on-treatment displays). If the study day associated with the 
last dosing date is greater than or equal to the lower bound of a visit window, and the value at the 
visit is missing, the value will be imputed. If the study day associated with the last dosing date is 
less than the lower bound of a visit window then the on-treatment value at that visit will remain 
missing. 


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If a 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) except for SVR24, which will be imputed according to SVR12 status. Success for 
SVR12 who have no further HCV RNA measurements collected will be counted as a success for 
SVR24 due to the high correlation between these 2 endpoints.
For the analyses of continuous HCV RNA efficacy data, when and only when a missing HCV 
RNA value is imputed as < LLOQ TND or < LLOQ detected according to the imputation rule 
described above, the corresponding continuous value will be imputed to LLOQ – 1 IU/mL. No 
other imputation will be performed for continuous HCV RNA data.
For health-related quality of life data SF-36, missing data will not be imputed.
3.4.2.
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.
3.5.
Multiple Comparisons
No multiplicity adjustment will be made.
3.6.
Data Handling Conventions and Transformations
By-subject listings will be presented for all subjects in the Safety Analysis Set and sorted by 
region, subject ID number, visit date, and time (if applicable) unless otherwise specified. Data 
collected on log forms, such as AEs, will be presented in chronological order within subject. 
Age (in years) on the date of the first dose of study drug and sex at birth will be used for analyses 
and presentation in listings.
If a subject was not dosed with study drug at all, then the date the informed consent was signed 
will be used instead of the first dose date of study drug. For some countries, only birth year is 
collected on the CRF. 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 CRF. 
Non-PK data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed as follows:

A value that is one unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “x” (where x is considered the 
limit of quantitation). For example, if the values are reported as < 50 and < 5.0, values of 
49 and 4.9, respectively, will be used for calculation of summary statistics. An exception for 
this rule is any value reported < 1. For the values reported as < 1 or < 0.1, value of 
0.9 or 0.09 will be used for calculation of summary statistics.


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
A value that is one unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “> x” (where x is considered the 
limit of quantitation). Values with decimal points will follow the same logic as above.

The limit of quantitation will be used for calculation of descriptive statistics if the datum is 
reported in the form of “≤ x” or “≥ x” (where x is considered the limit of quantitation).
The COBAS® TaqMan® HCV Quantitative Test, v2.0 was used to determine HCV RNA results 
in this study. The lower limit of quantitation (LLOQ) of the assay is 15 IU/mL.
When the calculated HCV RNA value is within the linear range of the assay, then the result will 
be reported as the “<< numeric value>> IU/mL”. This result will be referred to in this document 
as the numeric result or as “≥ LLOQ detected” for categorical result.
When HCV RNA is not detected, the result is reported as “No HCV RNA detected” or “target 
not detected”. This result will be referred to in this document as “< LLOQ target not detected” or 
“< LLOQ TND”.
When the HCV RNA IU/mL is less than LLOQ of the assay, the result is reported as 
“< 15 IU/mL HCV RNA detected”. This result will be referred to in this document as “< LLOQ 
detected”.
The overall category of HCV RNA < LLOQ includes “< LLOQ TND” and “< LLOQ detected.”
For numerical HCV RNA data, values below LLOQ will be set to the LLOQ – 1 IU/mL 
(ie, 14 HCV RNA IU/mL). HCV RNA values returned as “No HCV RNA detected” will also be 
set to 14 IU/mL.
For selected analyses, HCV RNA data (IU/mL) will be transformed to the logarithmic (base 10) 
scale (log10 IU/mL).
3.7.
Visit Windows
3.7.1.
Definition of Study Day
Study day is the day relative to the date of the first dose of study drug. Study Day 1 will be 
defined as the day of first dose of study drug administration.
Study day will be calculated from the date of first dose of study drug administration and derived 
as follows:

For postdose study days: Assessment Date – First Dose Date + 1

For days prior to the first dose: Assessment Date – First Dose Date
The last dose date will be the end date on study drug administration eCRF for the record where 
the “subject permanently discontinued” flag is ‘Yes’. 


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If there are subjects for whom the date of last study drug is unknown due to the reason that the 
subject was lost to follow-up and not able to be contacted, the date of last dose will be estimated 
using the maximum of nonmissing study drug start or stop dates, visit dates and laboratory 
collection dates (posttreatment visits and unscheduled visits are not included).
3.7.2.
Analysis Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.
In general, the baseline value will be the last nonmissing value on or prior to the first dose date 
of study drug.
HCV RNA, vital signs, and safety laboratory data collected up to the last dose date + 3 days are 
considered to be on-treatment data and HCV RNA, vital signs and safety laboratory data 
collected after the last dose date + 3 days are considered posttreatment data. The analysis 
windows for on-treatment HCV RNA, vital signs and safety laboratory data are provided in 
Table 3-1.
Table 3-1.
Analysis Windows for On-treatment HCV RNA, Vital Signs and 
Safety Laboratory Data
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 1
7
2
11
Week 2
14
12
21
Week 4
28
22
35
Week 6
42
36
49
Week 8
56
50
63
Week 10
70
64
77
Week 12
84
78
≥ 85
HCV RNA, vital sign, and safety laboratory data collected after the last dose date + 3 days will 
be assigned to the posttreatment follow-up (FU) visits. Visit windows will be calculated from the 
last dose date (ie, FU Day = collection date minus the last dose date) as shown in Table 3-2. 


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Table 3-2.
Analysis Windows for Posttreatment HCV RNA, Vital Signs and 
Safety Laboratory Data
Nominal FU a
Visit
HCV RNA
Vital Signs and Safety Laboratory Data b
Nominal FU 
Day
Lower Limit
Upper Limit
Nominal FU 
Day
Lower Limit
Upper Limit
FU-4
28
21
69
28
4
30
FU-12
84
70
146
NA
NA
NA
FU-24
168
147
210
NA
NA
NA
a
FU-x visit = posttreatment Week-x follow-up visit.
b
Vital signs and safety labs will only be summarized for the FU-4 visit (up to 30 days after last dose).
ECG data collected up to the last dose date + 3 days are considered to be on-treatment data. 
Qualitative assessments of whether the ECG is normal or abnormal will be assessed for 
on-treatment data based on the visit windows as shown in Table 3-3.
Table 3-3.
Analysis Windows for On-treatment ECG Data
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 1
7
2
45
Week 12
84
46
(none)
Note: ECGs are to be collected at screening, Day 1, Week 1, and Week 12 or End of Treatment. For purposes of analysis, 
baseline value will be the last available value prior to the first dose of study drug and end of treatment value will be the 
last available value on or prior to the last dose date + 3 days.
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window. 
If multiple valid nonmissing numeric observations exist in an analysis window, records will be 
chosen based on the following rules if a single value is needed:

For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, average (arithmetic mean) will be used for the baseline value. If multiple ECG 
measurements occur on the same day prior to first dose of any study drug, the average will be 
used considered as baseline value for continuous data, regardless of the timing of these 
multiple ECG measurements.


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


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided for each investigator. The summary will 
present the number and percentage of subjects in the Safety Analysis Set. The denominator for 
the percentage calculation will be the total number of subjects analyzed. 
A summary of subject disposition will be provided by region and genotype. This summary will 
present the number of subjects screened, the number of subjects enrolled, the number of subjects 
enrolled but never treated, and the number and percentage of subjects in each of the categories 
listed below. For the “Treated” category, the denominator for the percentage calculation will be 
the total number of subjects enrolled for each column. For all other categories, the denominator 
for the percentage calculation will be the total number of subjects in the Safety Analysis Set for 
each column. 

Treated (Safety Analysis Set) 

In FAS

Continuing study treatment if applicable

Completed study treatment

Did not complete study treatment with reasons for premature discontinuation of study 
treatment

Completed study

Did not complete the study with reasons for premature discontinuation of study
Among subjects who completed study treatment and who discontinued study treatment, the 
number and percentage of subjects will be summarized for:

Who had no HCV posttreatment Week 4 assessment and thereafter (No HCV FU-4 and 
thereafter)

Who had HCV posttreatment Week 4 assessment but no HCV posttreatment Week 12 
assessment and thereafter (With HCV FU-4 but No FU-12 and thereafter)
If a subject did not have any HCV RNA assessment ≥ 21 days after the last dose of any study 
drug (ie, lower bound of FU-4 visit for HCV RNA data), the subject is categorized as having 
“No HCV FU-4 and thereafter”. If a subject had the HCV FU-4 assessment but did not have any 
HCV RNA assessment ≥ 70 days after the last dose of any study drug (ie, lower bound of FU-12 
visit for HCV RNA data), the subject is categorized as having “With HCV FU-4 but No FU-12 
and thereafter”.


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In addition, the total number of subjects who were enrolled, and the number of subjects in each 
of the disposition categories listed above will be depicted by a flowchart.
The following by-subject listings will be provided by region and 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 
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 drug regimen specified in the protocol. 
4.2.1.
Duration of Exposure to Study Drug 
Total duration of exposure to study drug will be defined as last dose date minus first dose date 
plus 1, regardless of any temporary interruptions in study drug administration, and will be 
expressed in weeks using up to 1 decimal place (eg, 4.8 weeks). 
The total duration of exposure to study drug will be summarized using descriptive statistics 
(n, mean, SD, median, Q1, Q3, minimum, and maximum) and using the number 
(ie, cumulative counts) and percentage of subjects exposed through the following time periods: 
baseline (Day 1), Week1 (Day 7), Week 2 (Day 14), Week 4 (Day 28), Week 6 (Day 42),
Week 8 (Day 56), Week 10 (Day 70), and Week 12 (Day 84). A 3-day window is applied to the 
last planned on-treatment visit to match with the protocol-specified visit window, ie, number of 
subjects exposed through week 12 is calculated as the number of subjects who were exposed to
study drug for at least 81 days. Summaries will be provided by region 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 CRF using the following formula:



Total Number of Doses Administered
No. of Tablets Dispensed
No. of Tablets Returned




The level of adherence to the study drug regimen will be assessed based on the total amount of 
study drug administered relative to the total amount of study drug prescribed at baseline.


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The level of adherence will be expressed in percentage using the following formula:
Total Amount of Study Drug Administered 
Level of Adherence (%) 
100
Total Amount of Study Drug Prescribed at baseline  








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 mg/100 mg) prescribed for 12 weeks would 
require 84 tablets.
Subjects who prematurely discontinue study drug for lack of efficacy (ie, virologic failure) will 
have the total amount of study drug prescribed calculated up to the first date when virologic 
failure criteria were met. For virologic failure confirmed by 2 consecutive measurements the date 
of the first measurement will be used. If there are study drug bottles dispensed on or after the 
subject first met virologic failure criteria, these bottles will not be included in the calculation of 
adherence. If a bottle is dispensed and the bottle is returned empty, then the number of tablets 
returned will be entered as zero. If a bottle is dispensed but not returned (missing), the number of 
tablets taken from that bottle will be counted as zero.
Descriptive statistics for the level of adherence (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) with the number and percentage of subjects belonging to adherence categories 
(eg, < 80%, ≥ 80 to < 90%, ≥ 90%) will be provided by region and genotype for the Safety 
Analysis Set. 
No inferential statistics will be provided for duration of exposure and adherence to study drug. 
A separate by-subject listing of study drug administration and drug accountability will be 
provided by region, 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.
A by region, 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 by region 
and genotype using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) for age, and using the numbers and percentages of subjects for age categories 
(< 65 years, ≥65 years), sex, race, and ethnicity. Age is calculated in years at the date of initial 
study drug administration. If a subject did not receive study drug after enrollment, the subject’s 
age will be calculated from the date that the subject signed the informed consent form. The 
summary of demographic data will be provided for the Safety Analysis Set.
A by-subject demographic listing, which includes the date the informed consent was signed, will 
be provided by region and subject ID number in ascending order.
5.2.
Baseline Characteristics
Baseline characteristics include: 

body mass index (BMI; in kg/m2) as a continuous variable and as categories 
(< 25 kg/m2, ≥25 kg/m2) 

HCV genotype and subtype

IL28B (CC, CC, non-CC; with 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; < 5 log10 IU/mL, ≥5 log10 IU/mL)

baseline ALT (U/L) as a continuous variable and as categories (≤1.5 x ULN, > 1.5 x ULN)

cirrhosis (presence, absence, missing)

cirrhosis determination method (Liver Biopsy, Fibrotest/APRI, Transient Elastography, 
Fibrotest/APRI and Transient Elastography, and Not determined per protocol) 

prior HCV treatment experience (treatment naïve, treatment experienced)

prior HCV treatment (DAA+PEG+RBV, INTERFERON+RBV, PEG+RBV, Other) for
treatment-experienced subjects

most recent HCV treatment response (non-responder, relapse/breakthrough, early treatment 
discontinuation, met a virologic stopping rule, not otherwise listed, unknown) for 
treatment-experienced subjects

estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault equation


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eGFR 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.
These baseline characteristics will be summarized by region and genotype using descriptive 
statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for continuous variables and 
using the numbers and percentages of subjects for categorical variables. The summary of 
baseline characteristics will be provided for the Safety Analysis Set.
A by-subject listing of baseline characteristics will be provided by region and 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 data listing for prior HCV treatment and response will be provided for all 
treatment-experienced subjects. The listing will display the prior HCV regimen(s) and 
treatment(s) including the treatment duration, and the prior HCV treatment response.
5.3.
Medical History
A by-subject listing of disease-specific medical history will be provided by region and subject ID 
number (in ascending order) and medical history of abnormalities (in chronological order).


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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 12 weeks after 
discontinuation of all study drugs in the FAS. The COBAS® TaqMan® HCV Quantitative Test,
v2.0 for use with Ampliprep will be used to measure HCV RNA.
6.1.2.
Statistical Hypothesis for the Primary Efficacy Endpoint
In the primary efficacy analysis, the SVR12 rate in Region 1 will be compared to the 
pre-specified performance goal of 85% by using a two-sided exact one-sample binomial test at 
the 0.05 significance level. The null (H0) and alternative (H1) hypotheses used to assess 
superiority of SOF/VEL in Region 1 relative to the performance goal of 85% are:

H0: SVR12 rate = 85%

H1: SVR12 rate ≠ 85%
It is difficult to characterize a single historical control rate for all genotypes included in this 
study given the different standards of care of each genotype (some of which include interferon), 
and the lack of historical data for genotype 4, 5, and 6 participants. Given these difficulties, 
rather than use a historical control rate as the basis for assessing the primary endpoint, a 
pre-specified performance goal is defined as a benchmark against which the efficacy of 
SOF/VEL will be tested. The benchmark sets a high bar of 85%. The basis for this benchmark 
includes the overall trend toward increasing SVR rates in recent years, the higher SVR rates 
observed with Peg-IFN + RBV treatment in Chinese and other Asian subjects {Yu 2009}
compared with other races, and the general appeal of using a fixed clinically relevant threshold 
as a measure of treatment benefit {Weins 2013} of SOF/VEL.
6.1.3.
Primary Analysis of the Primary Efficacy Endpoint
The 2-sided 1-sample exact binomial test will be used to test the statistical hypotheses described 
above. The 2-sided 95% exact confidence interval (CI) based on the Clopper-Pearson method 
{Clopper 1934} will be provided for the SVR12 rate for Region 1.
The point-estimate with the 2-sided 95% exact confidence interval (CI) using the binomial 
distribution (Clopper-Pearson method) will also be constructed for the SVR12 rates for Region 2 
and for the overall population.


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6.1.4.
Subgroup Analysis of the Primary Efficacy Endpoint
Point estimates and 95% exact confidence intervals (CIs) of the SVR12 rates by region and 
genotype will be displayed for each subgroup outlined in Section 3.3. 
A Forest plot will graphically present estimates and 95% CIs on the SVR12 rates for each of the 
subgroups.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints include the following:

The percentage of subjects with HCV RNA < LLOQ 4 and 24 weeks after discontinuation of 
treatment (SVR 4 and SVR 24)

The percentage 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 end 
of treatment (EOT)

The percentage of subjects with virologic failure as the following:
On-treatment virologic failure
HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ, while on 
treatment, confirmed with 2 consecutive values (note, second confirmation value can be 
posttreatment), or last available on-treatment measurement with no subsequent follow-up 
values (ie, breakthrough)
1 log10IU/mL increase in HCV RNA from nadir while on treatment, confirmed with 
2 consecutive values (note, second confirmation value can be posttreatment), or last 
available on-treatment measurement with no subsequent follow-up values (ie, rebound)
HCV RNA persistently ≥ LLOQ through 8 weeks of treatment (ie, nonresponse)
Relapse 
HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA 
< LLOQ at end of treatment, confirmed with 2 consecutive values or last available 
posttreatment measurement

Characterization of HCV drug resistance substitutions at baseline, during, and after therapy 
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Analysis Methods for Secondary Efficacy Endpoints 
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For analyses ofHCV RNA < LLOQ by visit while on treatment and during the posttreatment 
(SVR) follow-up period, subjects will be assigned a value at each visit based on the analysis visit 
windows specified in Section 3.7.2. Missing values will be imputed based on the categorical 
imputationmles described in Section 3.4.1. The two-sided 95% exact confidence interval based 
on Clopper-Pearson method will be provided for the percentage of subjects with HCV RNA 
< LLOQ at each visit by region and genotype. The overall categmy for "HCV RNA < LLOQ" 
will be split into the following 2 subcategories: "< LLOQ TND" for subjects with target not 
detected and"< LLOQ detected" for subjects with < LLOQ detected in tabular displays. 
Graphs for the percentage of subjects with HCV RNA < LLOQ over time during treatment will 
be displayed. 
Sunnnaty statistics will be presented for absolute values and change from baseline in HCV RNA 
(log10 ID/mL) by visit through EOT. hnputation mles described in Section 3.4.1 will be used to 
assign HCV RNA values for missing values at a visit that are bracketed by "< LLOQ TND" 
and/or"< LLOQ detected". Othetwise, a missing = excluded analysis will be perfmmed. Plots of 
the mean± SD and median (Q1, Q3) of absolute values and changes from baseline in HCV RNA 
through EOT will be presented. 
For the SVR12 endpoint analysis, a summaty table of the mnnber and percentage of subjects 
with SVR12, virologic failure (VF), and Other by region and genotype 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 dmg completed yes/no). Subjects who do not achieve SVR12 and do not meet 
criteria for VF will be categorized as "Other". The denominator for relapse will be the mnnber of 
subjects who had HCV RNA < LLOQ on their last observed on-treatment HCV RNA 
measurement; othetwise, the denominator will be the number of subjects in the F AS. 
A concordance table between SVR12 and SVR24 will be provided by region and genotype. 
Subjects with both obsetved SVR12 and obsetved SVR24 data will be included for this analysis. 
Dmg resistant substitutions will be analyzed and presented as part of the Clinical Study Repmt. 
6.3. 
Exploratory Efficacy Endpoints 
6.3.1. 
Definition of Exploratory Efficacy Endpoints 
PD 
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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.
Safety Endpoints
The primary safety endpoint is any AE leading to permanent discontinuation of study drug(s).
7.2.
Adverse Events and Deaths
7.2.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 
MedDRA. System organ class (SOC), high-level group term (HLGT), high-level term (HLT), 
preferred term (PT), and lower-level term (LLT) will be provided in the AE dataset.
7.2.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity criteria 
specified in the protocol. The severity grade of events for which the investigator did not record 
severity will be categorized as “missing” for tabular summaries and data listings and the most 
severe will be considered (for sorting purpose only) in data presentation.
7.2.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE case report form 
(CRF) to the question of “Related to Study Treatment.” Events for which the investigator did not 
record relationships to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing from that captured on the 
CRF.
7.2.4.
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.
7.2.5.
Treatment-Emergent Adverse Events 
7.2.5.1.
Definition of Treatment Emergent
Treatment-emergent adverse events (TEAEs) are defined as one or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug.

Any AEs leading to premature discontinuation of study drug.


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7.2.5.2.
Incomplete Dates
If the onset date of the AE is incomplete, then the month and year (or year alone if month is not 
recorded) of onset determine whether an AE is treatment emergent, as long as the AE stop date is 
not prior to the first dose date of study drug. The event is considered treatment emergent if both 
of the following 2 criteria are met:

The AE onset and end dates are the same as or after the month and year (or year) of the 
first dose date of study drug

The AE onset date is the same as or before the month and year (or year) of the 30th day after
the date of the last dose of study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dose date of study drug, will be considered to be treatment emergent.
7.2.6.
Summaries of Adverse Events and Deaths
A brief high-level summary of TEAEs will be provided by region and by the number and 
percentage of subjects who had the following: any AE; any AE of Grade 3 or above; any AE of 
Grade 2 or above; any treatment-related AE; any treatment-related AE of Grade 3 or above; any 
treatment-related AE of Grade 2 or above; any SAE; any treatment-related SAE; any AE that led 
to premature discontinuation of SOF/VEL, any AE that led to interruption of SOF/VEL. All 
deaths (including those that are treatment emergent and those that are not treatment emergent) 
observed during the study will also be summarized and included in this table. 
Adverse event summaries will provide the number and percentage of subjects with TEAEs by 
SOC and PT, by region based on the Safety Analysis Set as follows:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

All SAEs

All treatment-related SAEs 

AEs leading to premature discontinuation of SOF/VEL


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
Adverse Events Leading to Interruption of SOF/VEL

Deaths
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed by region first in alphabetic order of SOC and then by PT in order of 
descending incidence within the Overall group within each SOC. In summaries by severity 
grade, the most severe grade will be used for those AEs that occurred more than once in an 
individual subject during the study. 
In addition to the above summary tables, TEAEs will be summarized by PT only and by region, 
in order of descending incidence in the Overall group for:

All AEs

AEs that occurred in at least 5% of subjects within any region

AEs of Grade 3 or above

All treatment-related AEs

All SAEs

AEs leading to premature discontinuation of SOF/VEL

AEs leading to interruption of SOF/VEL
In addition to the summaries described above, data listings by region and subject ID 
(in ascending order) will be provided for the following:

All AEs 

AEs of Grade 3 or above

SAEs

Deaths

AEs leading to premature discontinuation of SOF/VEL

Adverse Events Leading to Interruption of SOF/VEL

AE with changes other than resolution dates between the SVR12 and SVR24 analyses 
(provided only at the final analysis)


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7.3.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days 
for subjects who have permanently discontinued study drug, or all available data in the database 
snapshot for subjects who were still on treatment at the time of an interim analysis. The analysis 
will be based on values reported in conventional units. When values are below the limit of 
quantitation, they will be listed as such, and the closest imputed value will be used for the 
purpose of calculating summary statistics. For example, if “< 0.2” was recorded, a value of 
0.1 will be used for the purpose of calculating summary statistics; if “< 0.1” was recorded, a 
value of 0.09 will be used for the purpose of calculating summary statistics.
A by-subject listing for laboratory test results will be provided by region, subject ID number and 
visit in chronological order for hematology, serum chemistry, and urinalysis separately. Values 
falling outside of the relevant reference range and/or having a severity grade of 1 or higher on 
the Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
flagged in the data listings, as appropriate.
No inferential statistics will be generated.
7.3.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided 
by region for ALT, AST, total bilirubin, alkaline phosphatase, white blood cell (WBC),
neutrophils, lymphocytes, hemoglobin, platelets, reticulocytes, and 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 
will be displayed to the reported number of digits; SD to the reported number of digits plus 1.
Median (Q1, Q3) of the observed values for ALT, AST, total bilirubin, alkaline phosphatase, 
hemoglobin, reticulocytes, WBC, neutrophils, lymphocytes, and platelets will be plotted using a 
line plot by visit and region. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3 (Selection of Data in the Event of Multiple Records in a Window). 
The number of subjects with hemoglobin < 10 g/dL and < 8.5 g/dL at any postbaseline visits 
(up to 30 days after the last dose of any study drug) will be summarized by region.


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7.3.2.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 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. 
7.3.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of 
last dose of study drug plus 30 days for subjects who permanently discontinued study drug, or all 
available data in the database snapshot for subjects who were still on treatment at the time of an 
interim analysis. If the relevant baseline laboratory value is missing, then any abnormality of at 
least Grade 1 will be considered treatment emergent.
7.3.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by analyte and region; subjects will be categorized according to 
the most severe postbaseline abnormality grade for a given analyte:

Graded laboratory abnormalities

Grade 3 or above laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after last dose 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 region, 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.
A by-subject listing of medical history and prior and concomitant medications for subjects with 
treatment-emergent grade 3 or above laboratory abnormalities of glucose will be provided by
region, subject ID number and date in chronological order.


SOF/VEL FDC
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Version 1.0
CONFIDENTIAL
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18 January 2018
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 at each visit will be summarized for the Safety Analysis Set using 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) by region. The 
baseline value will be defined as the last available value collected on or prior to the date/time of 
first dose of study drug. Change from baseline to a postbaseline visit will be defined as the 
postbaseline value minus the baseline value.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3 (Selection of Data in the Event of Multiple Records in a Window). No 
inferential statistics will be generated.
A by-subject listing of vital signs (systolic and diastolic blood pressure [mmHg], pulse 
[beats/min], respiration [breaths/min], and body temperature [oC]) will be provided by region, 
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, concomitant, or both using the following definitions:

Prior medications: any medications taken and stopped prior to or on the date of first study 
drug administration

Concomitant medications: any medications taken after the date of first study drug 
administration and up to the last dosing date of study drug
Concomitant medications will be summarized by Anatomical Therapeutic Chemical (ATC) drug 
class Level 2, and preferred name using the number and percentage of subjects for each region. 
A subject reporting the same medication more than once will be counted only once when 
calculating the number and percentage of subjects who received that medication. 
Summaries will be based on the Safety Analysis Set by region. No inferential statistics will be 
generated. 
For purposes of analysis, any medication with a stop date that is on or prior to the initial study 
drug dosing date or a start date that is after the last study drug dosing date will be excluded from 
a concomitant medication summary. If a partial stop date is entered, any medication with the 
month and year (if day is missing) or year (if day and month are missing) prior to the initial 
study drug dosing date will be excluded from the concomitant medication summary. If a partial 
start date is entered, then any medication with the month and year (if day is missing) or year 
(if day and month are missing) after the study drug stop date will be excluded from the 
concomitant medication summary. Medications with completely missing dates will be included 
in the concomitant medication summary.


SOF/VEL FDC
GS-US-342-1518
Final
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Version 1.0
CONFIDENTIAL
Page 32
18 January 2018
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by region, subject ID number and administration date in chronological 
order.
7.6.
Electrocardiogram Results
A shift table of the investigators’ assessment of ECG results at each visit compared with baseline 
values will be presented by region using the following categories: normal; abnormal, not 
clinically significant; abnormal, clinically significant; or missing. The number and percentage of 
subjects in each cross-classification group of the shift table will be presented. Subjects with a 
missing value at baseline or postbaseline will not be included in the denominator for percentage 
calculation. No inferential statistics will be provided.
A by-subject listing for ECG assessment results for all subjects will be provided by region, 
subject ID number and visit in chronological order.
A by-subject listing for clinically significant ECG assessment results will be provided by region, 
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.
7.8.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


SOF/VEL FDC
GS-US-342-1518
Final
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 33
18 January 2018
8.
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.
Weins BL, Lystig TC, Berry SM. Recent Statistical Contributions to Medical Device 
Development. Therapeutic Innovation & Regulatory Science 2013:1-8.
Yu ML, Chuang WL. Treatment of chronic hepatitis C in Asia: when East meets West. J 
Gastroenterol Hepatol 2009;24 (3):336-45.


SOF/VEL FDC
GS-US-342-1518
Final
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 34
18 January 2018
9.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


SOF/VEL FDC
GS-US-342-1518
Final
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 35
18 January 2018
10.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


SOF/VEL FDC
GS-US-342-1518
Final
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 36
18 January 2018
11.
APPENDICES
Appendix 1.
Study Procedures Table


SOF/VEL FDC
GS-US-342-1518
Final
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 37
18 January 2018
Appendix 1.
Study Procedures Table
Study Visits
Screening
Day 1
On-treatment Study Week (± 3 days)
Post treatment 
Study Week (± 5 days)i
1
2
4
6
8
10
12/ET
4
12
24
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
Height
X
Weight
X
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGc
X
X
X
X
AEs 
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling
X
X
X
Health Related Quality of Life Survey, SF-36
X
X
X
X
Review of Study 
Medication Complianceg
X
X
X
X
X
X
X
Study Drug Dispensinga
X
X
X


SOFNELFDC 
GS-US-342-1518 
Statistical Analysis Plan 
Final 
Version 1.0 
Post treatment 
On-treatment Study Week (± 3 days) 
Study Week(± 5 days)i 
Screening 
Day1 
1 
Laboratory Assessments 
Hematology, Chemistry 
X 
X 
X 
Coagulation Tests 
X 
X 
HCVRNA 
X 
X 
X 
Viral RNA Sequencing I Phenotyping Sample! 
X 
X 
Pregnancy Testing d 
X 
X 
Urinalysis, 
X 
Urine Drug Screen 
HCV Genotyping, IL28B 
X 
HCV, HIV, HBV Serology 
X 
HbA 1 c, Fibrotest® 
X 
f PD 
Pharmacogenomic Sample• 
X 
Imaging for Hepatocellular Carcinoma (Heel 
X 
Day 1 assessments must be performed prior to dosing. 
a 
b 
Vital signs include resting blood pressure, pulse, respiratory rate, and temperature. 
I 2 
X 
X 
X 
I 4 I 6 I 8 I 10 
112/ET 
4 I 12 I 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
c 
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 gross abnormalities. 
24 
X 
X 
d 
Females of childbearing potential only. Serum ~-hCG pregnancy test performed at screening and confirmation of positive urine pregnancy test. All females of childbearing 
potential will have urine pregnancy testing every 4 weeks during the dosing period. If urine is positive, confrrm immediately with serum ~-hCG. 
e 
f 
g 
h 
Only for subjects who have provided consent for this sample and testing. This sample can be obtained at a subsequent visit if not obtained at Day 1. 
If presence of cirrhosis is determined, then appropriate diagnostic imaging (e.g., CT or ultrasound) should be performed to exclude the presence ofhepatocellular carcinoma 
(HCC) 
Subjects must be instructed to bring back all medication in the original container at every post-Day 1 study visit through the end of treatment. Study medication will be 
reconciled at eve!}' post-Day 1 visit by the investigator in order to monitor the subject's adherence with the medication regimen. 
EPD 
-1 
AIIsu~ects wil~Post treatment Week""4. Subjects with HCV RNA < LLOQ at the post treatment Week 4 and/or Week 12 visits will complete the subsequent 
post treatment visits, unless viral relapse is determined. 
Plasma samples will be collected for possible viral resistance and other Virology studies 
CONFIDENTIAL 
Page 38 
18 January 2018 
I 

Prot_001.pdf: 
Study Title: 
Sponsor: 
ClinicalTrials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Sciences Study 
Director 
Protocol Version/Date: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3, Multicenter, Open-Label Study to Investigate the 
Efficacy and Safety ofSofosbuvir/GS-5816 Fixed Dose 
Combination for 12 Weeks in Subjects with Chronic HCV 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 USA 
Not Available 
Hepatitis C Vims fufection 
GS-US-342-1518 
Name: 
Telephone: 
Fax: 
Email: 
Original: 
Amendment 1 
16 Janumy 2015 
21 April2015 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document, pmiicularly 1mpublished data, is the propelty or 
1mder 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 infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the inf01mation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaty to obtain inf01med consent from those 
persons to whom the dmg may be administered. 


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 2
21 April 2015
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................10
1.
INTRODUCTION ..............................................................................................................................................13
1.1.
Background ............................................................................................................................................13
1.2.
HCV in China and Southeast Asia .........................................................................................................14
1.3.
Sofosbuvir/GS-5816 Fixed Dose Combination......................................................................................16
1.4.
Additional Clinical Study Experience....................................................................................................16
1.4.1.
Study GS-US-281-1058 .......................................................................................................16
1.5.
Rationale for the Current Study .............................................................................................................19
1.6.
Rationale for Dose Selection..................................................................................................................20
1.7.
Overall Risk/Benefit Assessment...........................................................................................................21
2.
OBJECTIVES.....................................................................................................................................................22
3.
STUDY DESIGN................................................................................................................................................23
3.1.
Treatment Plan and Regimen .................................................................................................................23
3.2.
Visit Schedule ........................................................................................................................................23
3.3.
Virologic Response-Based Stopping Criteria.........................................................................................24
3.4.
Treatment Discontinuation Criteria........................................................................................................24
3.5.
Discontinuations.....................................................................................................................................25
3.6.
Substudies ..............................................................................................................................................25
3.6.1.
Optional Pharmacogenomics (PG) Substudy .......................................................................25
4.
SUBJECT POPULATION..................................................................................................................................26
4.1.
Number of Subjects and Subject Selection ............................................................................................26
4.2.
Inclusion Criteria....................................................................................................................................26
4.3.
Exclusion Criteria...................................................................................................................................28
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................30
5.1.
Enrollment..............................................................................................................................................30
5.2.
Description and Handling of SOF/GS-5816 FDC..................................................................................30
5.2.1.
Formulation..........................................................................................................................30
5.2.2.
Packaging and Labeling .......................................................................................................30
5.2.3.
Storage and Handling...........................................................................................................30
5.2.4.
Dosage and Administration of Sofosbuvir/GS-5816 FDC ...................................................31
5.3.
Study Drug Adherence and Drug Accountability...................................................................................31
5.4.
Concomitant Medications ......................................................................................................................31
5.5.
Investigational Medicinal Product Return or Disposal...........................................................................32
6.
STUDY PROCEDURES ....................................................................................................................................33
6.1.
Subject Enrollment.................................................................................................................................33
6.2.
Screening Assessments ..........................................................................................................................33
6.2.1.
Screening Visit .....................................................................................................................33
6.3.
Treatment Assessments..........................................................................................................................35
6.3.1.
Day 1 Visit ...........................................................................................................................35
6.3.2.
Week 1, 2, 4, 6, 8, and 12 Visits (± 3 days)..........................................................................36
6.4.
Early Termination (ET)/Unscheduled Visit ...........................................................................................37


SOF/GS-5816 FDC 
Protocol GS-US-342-1518 
Gilead Sciences, Inc. 
Final 
Amendment 1 
6.5. 
Post Treatment Assesstnents .................................................................................................................. 38 
6.5.1. 
Post Treatment Week 4 (± 5 days) ....................................................................................... 38 
6.5.2. 
Post Treatment Weeks 12 and 24, if applicable(± 5 days) .................................................. 38 
6.6. 
Procedlu·es and Specifications ................................................................................................................ 39 
6.6.1. 
Clinical Laboratoty Analytes ............................................................................................... 39 
6.6.2. 
Medical Histoty .................................................................................................................... 40 
6.6.3. 
Complete Physical Examination ........................................................................................... 40 
6.6.4. 
Vital Signs ............................................................................................................................ 40 
6.6.5. 
Creatinine Clearance ............................................................................................................ 40 
6.6.6. 
12-Lead ECGs ...................................................................................................................... 41 
6.6.7. 
Viral RNA Sequencing I Phenotyping Sample .................................................................... .41 
6.6.8. 
PPD 
........................................................... 41 
6.6.9. 
PPD 
....................................................................... 42 
6.6.10. 
6.6.11. 
Pregnancy Testing ................................................................................................................ 42 
Health Related Quality of Life Sm-vey (HRQoL) ................................................................ .42 
7. 
TOXICITYMANAGEMENT ............................................................................................................................ 43 
7.1. 
Subject Stopping Rules .......................................................................................................................... 43 
8. 
ADVERSE EVENTS MANAGEMENT ............................................................................................................ 44 
8.1. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events ................................. 44 
8.1.1. 
Adverse Events ..................................................................................................................... 44 
8.1.2. 
Serious Adverse Events ........................................................................................................ 44 
8.1.3. 
Clinical Laboratmy Abnonnalities and Other Abnonnal Assessments as 
Adverse Events or Serious Adverse Events ........................................................................ .45 
8.2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................ .45 
8.2 .1. 
Assessment of Causality for Study Dmgs and Procedmes ................................................... 45 
8.2.2. 
Assesstnentof Severity ........................................................................................................ 46 
8.3. 
Investigator Requirements and Instructions for Repmting Adverse Events and Serious 
Adverse Events to Gilead ....................................................................................................................... 46 
8.4. 
Gilead Repotting Requirements ............................................................................................................. 48 
8.5. 
Special Situations Reports ...................................................................................................................... 48 
8.5.1. 
Definitions of Special Situations .......................................................................................... 48 
8.5.2. 
Instmctions for Reporting Special Situations ...................................................................... .49 
9. 
STATISTICAL CONSIDERATIONS ................................................................................................................ 51 
9.1. 
Analysis Objectives and Endpoiilts ........................................................................................................ 51 
9.1.1. 
Analysis Objectives .............................................................................................................. 51 
9 .1.2. 
Pritnary Endpoint ................................................................................................................. 51 
9 .1.3. 
Secondary Endpoint ............................................................................................................. 51 
9.1.4. 
Safety Endpoints .................................................................................................................. 52 
9.1.5. 
Other Endpoints of Interest .................................................................................................. 52 
9.2. 
Analysis Conventions ............................................................................................................................. 52 
9.2.1. 
Analysis Sets ........................................................................................................................ 51 
9.2.2. 
Data Handling Conventions ................................................................................................. 52 
9.2 .3. 
Interim Analysis ................................................................................................................... 53 
9.3. 
Demographic Data and Baseline Characteristics ................................................................................... 53 
9.4. 
Efficacy Analysis ................................................................................................................................... 54 
9 .4.1. 
Pritnruy Analysis .................................................................................................................. 54 
9.4.2. 
Secondary Analysis .............................................................................................................. 54 
9.5. 
Safety Analysis ....................................................................................................................................... 55 
9.5.1. 
Extent ofExposw·e ............................................................................................................... 55 
9.5.2. 
Adverse Events ..................................................................................................................... 55 
9.5.3. 
Laboratoty Evaluations ........................................................................................................ 56 
CONFIDENTIAL 
Page 3 
21 April2015 


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 4
21 April 2015
9.5.4.
Other Safety Evaluations......................................................................................................56
9.6.
Sample Size............................................................................................................................................56
10.
RESPONSIBILITIES..........................................................................................................................................58
10.1.
Investigator Responsibilities ..................................................................................................................58
10.1.1.
Good Clinical Practice..........................................................................................................58
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval...............................................................................................................................58
10.1.3.
Informed Consent.................................................................................................................58
10.1.4.
Confidentiality......................................................................................................................59
10.1.5.
Study Files and Retention of Records ..................................................................................59
10.1.6.
Electronic Case Report Forms (eCRF).................................................................................60
10.1.7.
Drug Accountability.............................................................................................................61
10.1.8.
Inspections............................................................................................................................61
10.1.9.
Protocol Compliance............................................................................................................61
10.2.
Sponsor Responsibilities ........................................................................................................................61
10.2.1.
Protocol Modifications.........................................................................................................61
10.2.2.
Study Report and Publications .............................................................................................61
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................62
10.3.1.
Access to Information for Monitoring..................................................................................62
10.3.2.
Access to Information for Auditing or Inspections ..............................................................62
10.3.3.
Study Discontinuation..........................................................................................................62
11.
REFERENCES ...................................................................................................................................................63
12.
APPENDICES ....................................................................................................................................................69
Appendix 1.
Investigator Signature Page....................................................................................................70
Appendix 2.
Study Procedures Table Study Visits .....................................................................................71
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............74
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................99
LIST OF IN-TEXT TABLES
Table 1-1.
Summary Characteristics by Country.....................................................................................14
Table 1-2.
Preliminary NGMN, NG, EE, and GS-5816 Plasma PK Parameters Following 
Administration of NGM/EE alone or with GS-5816..............................................................18
Table 1-3.
Preliminary Summary of LH, FSH, and Progesterone Concentrations Following 
Administration of NGM/EE alone or with GS-5816..............................................................19
Table 5-1.
List of Disallowed Medications..............................................................................................32


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 5
21 April 2015
PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 3, Multicenter, Open-Label Study to Investigate the Efficacy 
and Safety of Sofosbuvir/GS-5816 Fixed Dose Combination for 
12 Weeks in Subjects with Chronic HCV
ClinicalTrials.gov 
Identifier:
Not Available
Study Centers:
Approximately 32 sites in China, Malaysia, Singapore, Thailand, and 
Vietnam
Number of Subjects:
Approximately 360 subjects
Target Population:
Adults with chronic hepatitis C virus (HCV) infection 
Treatment Duration:
Subjects will be treated for 12 weeks
Objectives:
The primary objectives of this study are:

To evaluate the efficacy of treatment with sofosbuvir 
(SOF)/GS-5816 fixed dose combination (FDC) for 12 weeks in 
subjects with chronic HCV infection as measured by the 
proportion of subjects with sustained viral response 12 weeks 
after cessation of treatment (SVR12)

To evaluate the safety and tolerability of treatment with 
SOF/GS-5816 for 12 weeks
The secondary objectives of this study are:

To determine the proportion of subjects with SVR at 4 and 
24 weeks after cessation of treatment (SVR4 and SVR24)

To evaluate the proportion of subjects with virologic failure

To evaluate the kinetics of circulating HCV RNA during 
treatment and after cessation of treatment

To evaluate the emergence of viral resistance to SOF and 
GS-5816 during treatment and after cessation of treatment


SOF/GS-5816 FDC 
Protocol GS-US-342-1518 
Gilead Sciences, Inc. 
Study Design: 
CONFIDENTIAL 
The exploratoty objectives ofthis study are: 
~ 
D 
I 
Final 
Amendment 1 
Intemational, multicenter, open-label study in treatment-naive and 
treatment-experienced adults with chronic HCV infection. Subjects 
with or without cinhosis will be enrolled. 
Approximately 20% of subjects may be treatment experienced and 
approximately 20% of subjects may have compensated cinhosis at 
scree rung. 
Subjects with chronic HCV infection will be enrolled to receive 
SOF/GS-5816 once daily for 12 weeks. 
This multi-regional clinical trial (MRCT) is planned to be conducted 
in China, Malaysia, Singapore, Thailand, and Vietnam. China will be 
considered Region I. Malaysia, Singapore, Thailand, and Vietnam, 
which are all located in Southeast Asia, will be considered Region 2. 
Approximately 360 subjects will be enrolled in the study in total. The 
approximate number of subjects to be enrolled in each region 
according to HCV genotype is represented in the table below: 
HCVGT 
(Previous 
Rx Histor·y) 
Region 1 
(China) 
Region2 
(Malaysia, 
Singapore, 
Thailand, 
Vietnam) 
GT = Genotype 
Rx =Treatment 
GT-1 
GT-2 
(TN, TE) 
(TN, TE) 
80 
60 
100 
TN =Treatment Naive, TE = Treatment Experienced 
GT-3 
GT-4,5,6 
(TN, TE) 
(TN, TE) 
Total 
60 
60 
260 
100 
It is expected that a small number of subjects whose HCV genotype 
cam10t be detemlined by the centrallaboratoty (HCV genotype 
indetemlinate) may also be enrolled. 
Page 6 
21 April2015 


SOF/GS-5816 FDC 
Protocol GS-US-342-1518 
Gilead Sciences, Inc. 
Sub-Study: 
Diagnosis and Main 
Eligibility Criteria: 
Study Procedmes/ 
Frequency: 
CONFIDENTIAL 
Final 
Amendment 1 
Chronic HCV-infected, male and non-pregnant/non-lactating female 
subjects, ages 18 years or older. 
Refer to Sections 4.2 and 4.3 for detailed Inclusion and Exclusion 
Criteria. 
Screening assessments will be completed within 28 days of the Day 1 
visit. The screening window can be extended to 42 days for subjects 
requiring liver biopsy or additional HCV genotyping. 
All subjects will complete the following study visits: Screening, 
Day 1, on-treatment visits at the end of Weeks 1, 2, 4, 6, 8, 10, 
and 12. Following the last dose of study dmg, all subjects will 
complete post treatment Week 4, including those subjects who 
tetminate study dmg treatment early. Subjects who achieve SVR4 
(HCV RNA < LLOQ at the post treatment Week 4 visit) will attend 
the post treatment Week 12 visit and those who achieve SVR12 
(HCV RNA < LLOQ) will complete the post treatment Week 24 
visit. Viral breakthrough or relapse must be confmned. 
Screening assessments will include physical examination, medical 
histmy, height, weight, vital signs, 12-lead ECG, adverse events 
related to screening procedmes, concmnitant medications, safety 
laboratmy tests (including hematology, chemistry and coagulation), 
HCV RNA, serology (HIV, HCV, HBV), hemoglobin Ale (HbAl c), 
assessment of the presence or absence of cirrhosis, screening for 
hepatocellular carcinoma (HCC) for subjects with cinhosis, serum 
~-hCG (females of child bearing potential only), IL28B and HCV 
genotyping, urinalysis and mine dmg screen. 
Page 7 
21 April2015 


SOF/GS-5816 FDC 
Protocol GS-US-342-1518 
Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
Evaluation Criteria: 
Safety: 
Efficacy: 
CONFIDENTIAL 
Final 
Amendment 1 
Based on the study visit, on-treatment assessments include physical 
examination, adverse events (AEs), concomitant medications, weight, 
vital signs, safety laboratmy tests, HCV RNA, viral sequencing 
samples, 12-lead ECG, Health Related Quality of Life (HRQoL) 
Survey SF-36, study medication dispensing and pill count, and urine 
pregnancy tests and pregnancy prevention cmmseling (females of 
child bearing potential only) as applicable. 
At the time of ECG collection, Day 1 (prior to study drug 
administration) and at Week 1 and Week 12 or Early Tennination, 
printed copies (paper) will be reviewed by qualified study staff (as 
detennined by the Investigator) and compared to the subject's Day 1 
ECG as patt of routine safety monitoring. 
Post treatment assessments inc.lude weight, vital signs, AEs, 
concomitant medications, HRQoL SF-36, safety laboratmy tests, 
HCV RNA, viral sequencing samples, and urine pregnancy tests 
(females of child bearing potential only). 
PD 
SOF/GS-5816 fixed dose combination (FDC) is manufactured as a 
400 mg/100 mg FDC tablet for oral administration. Subjects will take 
1 tablet daily with or without food. 
AEs and laboratmy tests will be collected throughout the study. 
Efficacy will be evaluated using scheduled assessments ofHCV RNA 
perfmmed using CO BAS® TaqMan® HCV Test, v2.0 for use with 
Ampliprep. 
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Statistical Methods:
The primary efficacy endpoint for the study is SVR12 in all enrolled
and treated subjects. 
The hypothesis to be tested will be that the SVR12 rate in Region 1 is 
superior to the pre-specified performance goal of 85%. A confidence 
interval approach will be used to estimate the SVR12 rates for 
Region 2 and for the overall population (ie, combined Region 1 and 
Region 2).
In the primary efficacy analysis, the SVR12 rate I Region 1 will be 
compared to 85% by using a two-sided exact one-sample binomial 
test at the 0.05 significance level. In addition, the point-estimate with 
the 2-sided 95% exact confidence interval (CI) using the binomial 
distribution (Clopper-Pearson method) will be constructed for the 
SVR12 rates by region and the overall population.
The sample size justification is based on the Region 1 population. A 
sample size of 260 subjects in Region 1 will provide more than 80% 
power to detect an improvement of at least 6 percentage points in 
SVR12 rate from the performance goal of 85% by using a two-sided 
exact one-sample binomial test at significance level of 0.05.
The point-estimate with the 2-sided 95% exact confidence interval 
(CI) using the binomial distribution (Clopper-Pearson method) will be 
constructed for the SVR12 rates by region and the overall study 
population. 
Secondary efficacy endpoints include SVR4 and SVR24.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
β-hCG
β-human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
APRI
AST:platelet ratio index
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase  (also SGOT)
AUC
area under the curve
AUCtau
area under the plasma concentration versus time curve over the dosing interval 
(tau)
BW
body weight
CI
confidence interval
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Ctau
observed drug concentration at the end of the dosing interval (tau)
CRF
case report form(s)
CRO
Contract (or clinical) research organization 
DAA
Direct acting antiviral
DCV
Daclatasvir (HCV NS5A Inhibitor)
dL
Deciliter
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
ESA
Erythropoiesis stimulating agent
Emax
maximal effect
ESLD
End Stage Liver Disease
ET
Early Termination
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
Fixed dose combination
g
grams
GBD
Global Burden of Disease
GCP
Good Clinical Practice (Guidelines)
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
HbA1c
Hemoglobin A1c
HBV
Hepatitis B virus


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HDPE
High-density polyethylene
HIV
Human immunodeficiency virus
HLGT
High-Level Group Term
HLT
High-Level Term
IB
Investigator Brochure
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IFN
Interferon
IL28B
IL28B gene
IND
Investigational New Drug (Application)
INR
International Normalized Ratio of prothrombin time
IRB
institutional review board
IUD
intrauterine device
IV
Intravenous
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDL
low-density lipoprotein
LDV
ledipasvir
LLN
lower limit of the normal range
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MCV 
mean corpuscular volume or mean cell volume
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PCR
Polymerase Chain Reaction
Peg-IFN
pegylated interferon
P-gp
P-glycoprotein 
PG
Pharmacogenomic
PT
preferred term or prothrombin time 
RBC
Red blood cell count 
RBV
Ribavirin


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
RNA
ribonucleic acid
SADR
Serious adverse drug reaction
Scr
serum creatinine (mg/dL)
SAE
serious adverse event
SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
SOC
System Organ Class
SOF
Sofosbuvir, formerly GS-7977
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
ULN
upper limit of the normal range
US
United States
WBC
white blood cell count
WHO
World Health Organization


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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 {28346}. In the United States (US), approximately 
2.7 million people have chronic HCV infection {28338} and HCV infection causes over 
15,000 deaths each year {20446}, 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 
{28339}. Successful treatment of chronic HCV infection reduces the need for liver transplant, the 
incidence of HCC and overall mortality {25891}. 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 with different 
regimens and durations dependent on the HCV genotype {34475}.The next wave of therapies for 
the treatment of HCV includes combinations of direct acting antivirals (DAAs) including SOF 
that will obviate the need for administration of Peg-IFN and RBV. 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 or 12 weeks resulted in 
high SVR12 rates in subjects with GT1 HCV infection {28583}, {28585}, {28587}.
Most current HCV drug development effort focuses on GT1 HCV infection as this is the most 
prevalent HCV genotype worldwide, including in developing countries {32174}, {31525}. 
However, over half of all HCV infections are non-GT1: estimates from 2 recent meta-analyses 
indicate GT3 HCV is the next most common accounting for 22-30% of infections, while GT2 
and GT4 each account for approximately 8 to 13%, GT6 for approximately 2 to 5%, and GT5 for 
approximately 1% of HCV infections worldwide. The availability of a well-tolerated, all oral, 
short duration therapy that is effective across all HCV genotypes would be a major advance for 
the treatment of HCV infection globally, particularly in regions where HCV genotyping is not 
part of routine medical care.
Although some individualization of care will be necessary, particularly for patients with 
advanced disease, the development of a pangenotypic regimen of short-duration that may not 
require HCV genotyping, response guided therapy, or intensive safety monitoring due to use of 
Peg-IFN or RBV will enable more patients to be treated.


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1.2.
HCV in China and Southeast Asia
The prevalence of HCV infection in East and Southeast Asia is difficult to quantify due to 
differences in the level of public health surveillance systems and access to general medical care. 
A recent literature review estimated the prevalence of anti-HCV antibodies in the Global Burden 
of Disease (GBD) regions as defined by the World Health Organization (WHO). In East Asia, 
which includes China, the prevalence was estimated to be 3.7% while in Southeast Asia, which 
includes Vietnam, Thailand, and Malaysia, the prevalence was estimated to be 2.0% {29744}. 
Although geographically Singapore is in Southeast Asia, it is classified by WHO as part of “High 
income Asia-Pacific” GBD and HCV prevalence in this region is 1.4% {29744}. 
Genotype diversity is high in both these regions {31525}. Although there are inter- and 
intra-country differences, the most frequently observed HCV genotypes in both regions are GT1, 
2, 3 and 6 (Table 1-1). In China, GT1, GT2 and GT6 are generally the most common, although 
regional differences in genotype distribution, such as GT3 in the South, are apparent {24217}. 
GT6 is also common in Vietnam and Thailand while GT3 is the most common genotype in 
Thailand and Malaysia, and GT2 is found in both countries. Although GT1 is the predominant 
genotype in Singapore, approximately 20% of infections are GT2 or GT3.
Table 1-1.
Summary Characteristics by Country
China
Vietnam
Thailand
Malaysia
Singapore
Estimated HCV Ab 
Seroprevalence
1.3n,p-3.2%a
2.5%b
2.7%n,p
1.5%n,p
HCV Genotype 
Distribution
GT-1 – 58.2%c
GT-2 – 15.5%c
GT-3 – 8.7%c
GT-6 – 6.3%c
Other– 11.3%c
GT-1 ~ 47%b
GT3 ~ 6%b
GT-6 ~ 47%b
GT1 ~34%n
GT2 ~ 4%
GT3 ~41%
GT4 <1%
GT6 ~23%
GT1 ~39%n
GT2 ~4%
GT3 ~56%
GT4 ~1%
GT1 ~81%n
GT2 ~ 7%
GT3 ~ 12%
Estimated % IL28B-
CC Genotype
~85%-88%c,g
~90%d
77%o
Estimated Peg-IFN 
+RBV SVR rates
    GT-1
~44-70%h,j,k,m
~53%f
74%
    GT-2
75%j
-
    GT-3
-
80%
    GT-6
~65-86%h,i,l,m
~74%f
65%r
References: a{24428}; {24397}; {24800}; {24799}; {24798};{24235}; b{19682}; c{24217};{24212}; {24211}; {24388};  
{24242};  {24382}; {24410}; {24209};  d{22075};f{24413}; g{24383}; h{24797}; i{24395}; j{13261}; k{24391}; l{24393}; 
m{24411}, 
In these Asian countries the predominant modes of HCV transmission have been iatrogenic in 
nature with large proportions of infected patients being exposed prior to the implementation of 
routine HCV antibody screening at blood banks, improved sterilization techniques for 
medical/dental equipment, and the widespread availability of disposable medical supplies 


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{24216}, {24239}, {24396}, {32905}, {32906}, {32907}. Transmission of HCV infection through 
traditional medical approaches including acupuncture is also common {24239}, {24428}. Due to 
the timing of introduction of practices aimed at reducing HCV transmission, the seroprevalence 
of HCV antibodies is seen to increase with age and is generally highest in those over 60 years of 
age in China {24384}.  Elderly patients are more likely to be treatment-experienced and may be 
at higher risk of developing progressive liver disease. Comorbid conditions such as 
cardiovascular disease and diabetes are common with increasing age, which pose additional 
challenges to patient management {24398}, {22156}. The use of IFN is particularly challenging in 
elderly patients who generally report a higher frequency of adverse events and of greater severity 
compared to younger patients. Lower levels of treatment adherence are also observed. These 
factors likely contribute to the overall lower SVR rates generally observed in the elderly {24390}. 
As these patients continue to age, the number who will develop hepatic complications including 
cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver disease (ESLD) is significant 
{22077}, which will pose a significant burden on the healthcare systems in the region.
In addition to blood transfusions and medical procedures, intravenous drug abuse (IVDA) is a 
significant risk factor in Malaysia, Thailand and Vietnam, as well as parts of China {19682}, 
{33030}. The use of interferon (IFN)-based therapy is also problematic in the IVDA population. 
The risk for developing severe IFN-related psychiatric events including depression, suicidal 
ideation, cognitive disturbances, psychotic symptoms, fatigue, and habit relapse is high. 
Adherence to therapy may be low and effective treatment requires multidisciplinary support 
{25091}.
Treatment of chronic infection in many countries in Asia is currently based upon weekly 
subcutaneous administration of pegylated interferon (Peg-IFN) with orally administered ribavirin 
(RBV) for 24 to 48 weeks dependent upon genotype and virologic response. In Caucasians, this 
treatment regimen affords sustained virologic response rates (SVR) on the order of 42-46% in 
treatment-naïve patients with GT1 and 76-82% in patients with GT2/3 infection {23342}, 
{23351}. Observed SVR rates using the same interferon (IFN) based treatment regimens are 
generally higher in Asian patients: Yu and Chuang {24218} summarize SVR rates in Asian 
patients in general as approximately 70% for those with HCV GT1 infection, 90% for GT2/3 
infection, and 80% for GT6 infection. Although data are limited, published SVR rates for the 
countries included in this study are included in Table 1-1. The higher SVR rates have been 
largely attributed to a higher proportion of Asian patients (>85%) possessing the host IL28B-CC 
genotype which confers a favorable virologic outcome following treatment with IFN-containing 
regimens {22075}, {24243}, {22156}, {21337}, {22098}. Although relatively high SVR rates can 
be achieved in Asian patients with IFN+RBV, the safety and tolerability of IFN-containing 
regimens is sub-optimal. Contraindications to IFN preclude its use by a significant number of 
patients {22156} while management of adverse effects commonly result in dose reductions and 
may lead to treatment discontinuation. Safety and tolerability are particularly problematic in an 
aging population with chronic hepatitis C. Moreover, lower SVR rates are also observed in older 
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Recently, first generation protease inhibitors (PI) (i.e., telaprevir [TVR] and boceprevir [BCV]) 
have been approved in some countries for use in patients with GT1 infection when combined 
with Peg-IFN+RBV. The Peg-IFN+RBV+PI regimens have incrementally improved SVR rates 
in GT1 treatment-naïve patients to approximately 70%; however, they are associated with 
significant safety and tolerability concerns {17996}, {17492} and their use is limited to GT1 
HCV.
1.3.
Sofosbuvir/GS-5816 Fixed Dose Combination
SOF/GS-5816 fixed-dose combination (SOF/GS-5816 FDC) combines two HCV specific direct 
acting antivirals (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 a component of an antiviral treatment 
regimen. GS-5816 is a HCV NS5A inhibitor that has demonstrated activity against HCV 
genotypes 1, 2, 3 and 4 HCV in a 3-day monotherapy study. Phase 2 studies of SOF +GS-5816 
administered as single agents have demonstrated that the combination of SOF 400 mg and 
GS-5816 100 mg administered for 12 weeks is well tolerated and results in high SVR rates 
across a broad range of HCV genotypes. The SOF/GS-5816 FDC (400 mg/100 mg) is a 
co-formulation of SOF 400 mg and GS-5816 100 mg for Phase 3 evaluation that has 
demonstrated similar exposure of each component compared to co-administration of the single 
agents.  
The development of SOF/GS-5816 may have a major impact of the global prevalence and burden 
of HCV as it may represent a simple, well tolerated, highly efficacious pangenotypic treatment 
for all HCV infected patients.
Please refer to the Investigator’s Brochure (IB) for additional information on SOF/GS-5816, and 
the individual components, including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.4.
Additional Clinical Study Experience
1.4.1.
Study GS-US-281-1058
GS-US-281-1058 is an open-label, Phase 1, multiple-dose drug-drug interaction study in healthy 
female subjects of childbearing age evaluating the effect of GS-5816 on the pharmacokinetics of 
a representative hormonal contraceptive medication, norgestimate/ethinyl estradiol (NGM/EE, 
OC). The study is summarized herein, as the data are relevant to the current study. Following 


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screening, eligible subjects were enrolled in a lead-in period (Part A) of 28 days during which 
they completed dosing with the hormonal 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 + GS-5816 were assessed in Part B of the study, which consisted of 2 cycles: subjects 
received OC alone during Cycle 1, and OC plus GS-5816 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+GS-5816) 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 GS-5816. Steady-state GS-5816 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 GS-5816 relative to 
administration of NGM/EE alone. A modest increase in EE Cmax was observed when 
administered with GS-5816 with no change in overall exposure (AUC) or Ctau. The magnitude of 
increase in EE Cmax when administered with GS-5816 is similar to that observed with the 
concomitant administration of other drugs such as voriconazole and etravirine, which did not 
warrant dose adjustment {13886}, {24911}. GS-5816 exposures were consistent with historical 
data (Studies GS-US-281-0115, GS-US-342-0104).


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Table 1-2.
Preliminary NGMN, NG, EE, and GS-5816 Plasma PK Parameters 
Following Administration of NGM/EE alone or with GS-5816
PK Parameter
Mean (%CV)
GLSM Ratio 
(90% CI) NGM/EE + 
GS-5816 vs. NGM/EE
NGM/EE Alone 
(N = 15)
NGM/EE + GS-5816 
(N = 13)
Norelgestromin
AUCtau (pg•h/mL)
17,700 (16.7)
15,700 (11.2)
0.89 (0.85, 0.94)
Cmax (pg/mL)
1650 (16.8)
1600 (13.7)
0.97 (0.90, 1.04)
Ctau (pg/mL)
454 (18.5)
416 (14.3)
0.92 (0.86, 0.98)
Norgestrel
AUCtau (pg•h/mL)
47,000 (34.4)
43,000 (32.4)
0.91 (0.73, 1.14)
Cmax (pg/mL)
2410 (30.6)
2330 (31.5)
0.96 (0.80, 1.17)
Ctau (pg/mL)
1760 (34.4)
1640 (35.7)
0.92 (0.74, 1.15)
Ethinyl Estradiol
AUCtau (pg•h/mL)
666 (30.7)
686 (27.3)a
1.06 (0.98, 1.14)
Cmax (pg/mL)
57.5 (27.3)
80.0 (28.4)a
1.42 (1.28, 1.58)
Ctau (pg/mL)
14.8 (39.3)
12.4 (43.9)a
0.84 (0.77, 0.92)
GS-5816
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
Preliminary 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 {25217}, {25218}, {25219}. Follicle stimulating hormone was lower or 
within the expected range for the ovulatory phase {25218}. 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.


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Table 1-3.
Preliminary Summary of LH, FSH, and Progesterone Concentrations 
Following Administration of NGM/EE alone or with GS-5816
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)
Based on these results, no loss in contraceptive efficacy is expected upon administration of 
combined oral contraceptives containing norgestimate/ethinyl estradiol with GS-5816. 
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 GS-5816 as a single agent or as part of SOF/GS-5816 FDC is permitted. 
1.5.
Rationale for the Current Study
This Phase 3 study has been designed as a multicenter, open-label, non-randomized study 
evaluating SOF/GS-5816 for 12 weeks. Approximately 360 subjects will be enrolled. 
The population of the study will be subjects with chronic HCV infection of any genotype, with 
approximately 20% having prior treatment failure and approximately 20% having evidence of 
compensated cirrhosis at screening.  
Although favorable virologic response rates can be achieved in Asian patients with currently 
available therapy, there are significant advantages to the development of novel, all-oral, safe and 
effective IFN-free regimens. The NEUTRINO study (GS-US-334-0110) demonstrated that SOF 
+ Peg-INF/RBV treatment for 12 weeks results in high SVR rates in subjects with genotype 1 
and 4 HCV infection and in the small number of subjects with genotype 5 and 6 HCV infection 
{24715}. However, the side effects of SOF + Peg-INF/RBV occurred across multiple organ 
systems and the availability of a Peg-INF-and RBV-free regimen would be an advancement for 
patients with genotype 1, 4, 5, and 6 HCV infection. Although SOF +RBV for 12 or 24 weeks 
resulted in high SVR rates in subjects with genotype 2 or 3 HCV infections, respectively, the 
availability of a RBV-free regimen would be an advancement in treatment as well. 
Therapies which are not administered by injection nor associated with IFN-related adverse 
events are likely to improve patient treatment adherence and support high rates of viral cure. It is 
also likely that agents with favorable safety profiles which do not require frequent dose 
modification nor intensive monitoring of clinical adverse events and laboratory abnormalities 
will facilitate patient management particularly in rural areas.
Phase 2 evaluation of SOF + GS-5816 demonstrated that co-administration of the single agents 
for 8 or 12 weeks was well tolerated and resulted in high SVR rates across a broad range of HCV 
genotypes. In the Phase 2 study GS-US-342-0102 , administration of SOF 400mg + GS-5816 


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100mg for 12 weeks to treatment-naïve subjects without cirrhosis with genotype 1, 2, 3, 4, or 6 
HCV infection resulted in SVR12 rate of 100% (28/28), 100% (10/10), 93% (25/27), 86% (6/7), 
and 100% (5/5), respectively. In addition, one treatment naïve subject with genotype 5 HCV 
infection administered SOF +GS-5816 25mg for 12 weeks achieved SVR12. The 
GS-US-342-0109 study evaluated SOF + GS-5816 with and without RBV in populations of 
patients considered more difficult to cure, including subjects who had failed a prior interferon 
based regimen and those with cirrhosis. Administration of SOF 400mg + GS-5816 100 mg for 
12 weeks resulted in SVR12 rates of 88% (23/26) and 100% (27/27) in treatment experienced 
subjects with genotype 3 HCV infection with and without cirrhosis, respectively. Administration 
of SOF 400mg + GS-5816 100mg for 12 weeks resulted in an SVR12 rates of 100% (27/27) in 
subjects with genotype 1 HCV infection who had failed prior treatment with  a protease inhibitor 
with Peg-IFN/RBV. Seven of these 27 subjects had cirrhosis. 
The Phase 2 data suggest that SOF 400 mg +GS-5816 100mg has the potential to cure HCV 
infected patients across a broad range of HCV genotypes, when administered for 12 weeks 
without RBV and regardless of prior treatment experience or cirrhosis status. The co-formulation 
of SOF/GS-5816 (400 mg/100 mg) adds to the simplicity of the regimen in allowing for a once
daily pill. Data from this study will support the development of a well-tolerated, short duration, 
RBV-free regimen for all genotypes of HCV infection that has the potential to make an impact 
on the global prevalence and burden of HCV infection. 
This study will assess the safety and efficacy of GS-5816/SOF in Asian patients. Each of the 
countries selected for inclusion in the study has a high burden of disease associated due to HCV 
infection. In China, estimates of the seroprevalence of HCV range from 1.3 to 3.2% which 
corresponds to approximately 15 to 30 million people. Seroprevalence estimates are similar in 
Malaysia, Thailand, and Vietnam although data is limited. The genotype distribution in the 
selected countries will facilitate enrollment of subjects with genotypes 1, 2, 3 and 6 HCV 
infection—the most common HCV genotypes across East and Southeast Asia.    
In particular, the availability of a single, pangenotypic regimen is anticipated to be especially 
beneficial in Asia where genotype diversity is high and genotyping may not be available or 
routinely done. Access to treatment for patients with HCV infection would be expanded as a 
result.  
1.6.
Rationale for Dose Selection
Sofosbuvir 400 mg, once daily, when dosed in combination with RBV with or without Peg-IFN
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 marketed dose of sofosbuvir for the treatment of HCV-infection and as 
such, has been selected for co-formulation with GS-5816 into a fixed-dose combination tablet.
GS-5816 100 mg has been administered in combination with SOF 400 mg for 12 weeks to 
237 HCV-infected subjects in Phase 2 studies. GS-5816 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 


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study GS-US-281-0102 established the anti-HCV activity of GS-5816 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 GS-5816 100 mg support further 
evaluation of this combination in clinical development.
1.7.
Overall Risk/Benefit Assessment
This study will provide information on the safety and efficacy of SOF/GS-5816, which combines 
a potent HCV nucleotide inhibitor and a potent HCV NS5A inhibitor. This combination has the 
potential to be a once-daily pangenotypic regimen for the treatment of chronic HCV infection. 
The potential benefits of SOF/GS-5816 over the current standard of care for the treatment of 
chronic HCV are:

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-IFN 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/GS-5816 has not been established. The safety profile of SOF + 
GS-5816 25mg or GS-5816 100mg administered for 8 or 12 weeks has been established in over 
800 subjects in Phase 2 studies. The safety profile of the proposed therapeutic regimen of SOF 
400mg and GS-5816 100mg administered for 12 weeks has been established in 237 subjects 
enrolled in Phase 2 studies. No clinical safety issues specifically related to GS-5816 or SOF + 
GS-5816 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 {28583}, 
{28585}, {28587}.
During the conduct of the study, the sponsor will perform ongoing safety review.
In summary, if high rates of SVR can be obtained with a short, IFN-free, RBV-free, 
pangenotypic regimen, the anticipated improvements in safety and tolerability would offer a 
favourable risk-benefit determination for patients with chronic HCV infection and enhance 
access to treatment.


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2. 
OBJECTIVES 
The primaty objectives of this study are: 
Final 
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• 
To evaluate the efficacy of treatment with SOF/GS-5816 for 12 weeks in subjects with 
chronic HCV infection as measmed by the proportion of subjects with SVR12 
• 
To evaluate the safety and tolerability oftreatment with SOF/GS-5816 for 12 weeks 
The secondruy objectives of this study ru·e: 
• 
To detetmine the prop01tion of subjects with SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24) 
• 
To evaluate the prop01tion of subjects with virologic failme 
• 
To evaluate the kinetics of circulating HCV RNA dming treatment and after cessation of 
treatment 
• 
To evaluate the emergence of viral resistance to SOF and GS-5816 dming treatment and after 
cessation of treatment 
The explorat01y objectives of this study are: 
~ 
0 
I 
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3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is an international, multicenter, open-label study that will evaluate the safety, tolerability 
and antiviral efficacy of SOF/GS-5816 for 12 weeks in treatment-naïve and 
treatment-experienced adults with chronic HCV infection. Subjects with or without cirrhosis will 
be enrolled. 
Approximately 20% of subjects may be treatment experienced and approximately 20% of 
subjects may have compensated cirrhosis at screening. 
Subjects with chronic HCV infection will be enrolled to receive SOF/GS-5816 once daily for 
12 weeks.
This multi-regional clinical trial (MRCT) is planned to be conducted in China, Malaysia, 
Singapore, Thailand, and Vietnam. China will be considered Region 1. Malaysia, Singapore, 
Thailand, and Vietnam, which are all located in Southeast Asia, will be considered Region 2.
Approximately 360 subjects will be enrolled in the study in total. The approximate number of 
subjects to be enrolled in each region according to HCV genotype is represented in the table 
below: 
HCV GT
(Prior Rx History)
GT-1
(TN, TE)
GT-2
(TN, TE)
GT-3
(TN, TE)
GT-4,5,6
(TN, TE)
Total
Region 1 (China)
80
60
60
60
260
Region 2 
(Malaysia, 
Singapore, 
Thailand, Vietnam)
100
100
Rx = Treatment
TN = Treatment Naïve, TE = Treatment Experienced
It is expected that a small number of subjects whose HCV genotype cannot be determined by the 
central laboratory (HCV genotype indeterminate) may also be enrolled.
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 or additional HCV 
genotyping. 


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All subjects will complete the following study visits: Screening, Day 1, on-treatment visits at the 
end of Weeks 1, 2, 4, 6, 8, 10, and 12. Following the last dose of study drug, all subjects will 
complete post treatment Week 4, including those subjects who terminate study drug treatment 
early. Subjects who achieve SVR4 (HCV RNA < LLOQ) will attend the post treatment Week 12 
visit and those who achieve SVR12 (HCV RNA < LLOQ) will complete the post treatment 
Week 24 visit. Viral breakthrough or relapse must be confirmed.  
The assessments performed at each visit are described in Section 6 and shown in Appendix 2.
3.3.
Virologic Response-Based Stopping Criteria
The following on-treatment virologic response-based treatment stopping criteria will be utilized:

Confirmed HCV RNA ≥ LLOQ after 2 consecutive HCV RNA < LLOQ

Confirmed > 1 log10 increase from on-treatment nadir

HCV RNA ≥ LLOQ through 8 weeks of treatment 
Confirmation should be performed as soon as possible and must occur no later than 2 weeks after 
an initial observation indicating virologic failure during the on-treatment phase. 
All subjects who terminate treatment early will complete the early termination (ET) and post
treatment Week 4 visit. Subjects who achieve SVR4 will attend the post treatment Week 12 visit 
and those who achieve SVR12 will complete the post treatment Week 24 visit.
3.4.
Treatment Discontinuation Criteria
When medically feasible, the Medical Monitor must be consulted prior to subject 
discontinuation. 
Study drug(s) must be discontinued in the following instances:

Unacceptable toxicity, as defined in Section 7 of the protocol, or toxicity that, in the 
judgment of the investigator, compromises the ability to continue study-specific procedures 
or is considered not to be in the subject’s best interest

Pregnancy of female subject

Efficacy failure as defined in Section 3.3

Significant protocol violation

Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy or other reason

Discontinuation of the study at the request of Gilead, regulatory agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC)


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3.5. 
Discontinuations 
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Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an early termination visit (see Section 6.4). All subjects who temlinate treatment early 
will complete the early tennination (ET) visit and post treatment Week 4 and Week 12 visits. 
3.6. 
Substudies 
3.6.1. 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 360 subjects will be enrolled in this study.  A detailed breakdown of the number 
of subjects to be enrolled in each region according to HCV genotype is presented in Section 3.1. 
Approximately 20% of subjects may be treatment experienced and approximately 20% of 
subjects may have compensated cirrhosis at screening. 
In order to manage the total study enrollment, Gilead Sciences, Inc., at its sole 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) Bodyweight 40 kg
4) HCV RNA 104 IU/mL at Screening
5) HCV genotype 1, 2, 3, 4, 5, 6, or indeterminate as assessed at Screening by the Central 
Laboratory 
6) Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy
7) Classification as treatment naïve or treatment experienced (approximately 20% of subjects 
may be treatment experienced):
a) Treatment naïve is defined as having never been exposed to approved or experimental 
HCV-specific direct-acting antiviral agents or prior treatment of HCV with interferon or 
ribavirin
b) Treatment experienced is defined as prior treatment failure to a regimen containing 
interferon either with or without RBV that was completed at least 8 weeks prior to Day 1.  
Subject must not have discontinued the prior regimen that resulted in virologic 
failure due to an adverse event.
i)
The subject’s medical records must include sufficient detail of prior virologic failure 
to allow for categorization of prior response (Reference Section 6.2.1), as either:
(1) Non-Responder: Subject did not achieve undetectable HCV RNA levels while on 
treatment, or 
(2) Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels during 
treatment or within 4 weeks of the end of treatment but did not achieve SVR


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8) Cirrhosis Determination (approximately 20% of subjects may have cirrhosis)
a) Cirrhosis is defined as any one of the following:
i)
Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥5)
ii) FibroTest® score > 0.75 AND an AST:platelet ratio index (APRI) > 2 during 
Screening
iii) Fibroscan® with a result of >12.5 kPa 
b)
Absence of cirrhosis is defined as any one of the following:
i)
A liver biopsy performed within 2 years of Day 1 showing absence of cirrhosis
ii) FibroTest score ≤ 0.48 AND APRI ≤ 1 performed during Screening
iii) Fibroscan with a result of ≤ 12.5 kPa within ≤ 6 months of Day 1
In the absence of a definitive diagnosis of presence or absence of cirrhosis by Fibrotest/APRI
using the above criteria, a liver biopsy or Fibroscan is required. Liver biopsy results will 
supersede Fibrotest/APRI or Fibroscan results and be considered definitive.
9) Liver imaging within 6 months of Day 1 is required in cirrhotic patients only to exclude 
hepatocellular carcinoma (HCC)
10) Females of childbearing potential (as defined in Appendix 4) must have a negative serum 
pregnancy test at Screening and a negative urine pregnancy test on Day 1 prior to enrollment
11) 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 4
12) Lactating females must agree to discontinue nursing before the study drug is administered
13) Subject must be of generally good health, with the exception of chronic HCV infection, as 
determined by the Investigator 
14) Subject must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Current or prior history of any of the following:
a) Clinically-significant illness (other than HCV) 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) are also excluded.  
b) Gastrointestinal disorder or post-operative 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) Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage).
e) Solid organ transplantation.
f)
Significant pulmonary disease, significant cardiac disease or porphyria.
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 6 months prior to Day 1 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)
Significant drug allergy (such as anaphylaxis or hepatotoxicity). 
2) Screening ECG with clinically significant abnormalities
3) Subjects has the following laboratory parameters at screening: 
a) ALT > 10 the upper limit of normal  (ULN)
b) AST > 10 ULN
c) Direct bilirubin > 1.5 ULN
d) Platelets < 50,000/L


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e) HbA1c > 8.5% 
f)
Creatinine clearance (CLcr) < 60 mL /min as calculated by the Cockcroft-Gault equation 
{2202}
g) Hemoglobin < 11 g/dL for female subjects; < 12 g/dL for male subjects.
h) Albumin < 3 g/dL 
i)
INR > 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR
4) Prior exposure to SOF or other nucleotide analogue HCV NS5B inhibitor or any HCV NS5A 
inhibitor.
5) Pregnant or nursing female or male with pregnant female partner. 
6) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alfa-1 antitrypsin deficiency, cholangitis).
7) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV).
8) Clinically-relevant alcohol or drug abuse within 12 months of screening. A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator.
9) Use of any prohibited concomitant medications as described in Section 5.4
10) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone 
equivalent > 10 mg/day).
11) Known hypersensitivity to GS-5816, SOF, or formulation excipients.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Enrollment
An Interactive Web Response System (IWRS) will be employed to manage subject enrollment
and study drug re-supply.  Eligible subjects will be enrolled and assigned to the open-label 
treatment. Every subject will receive SOF/GS-5816 tablet for 12 weeks.
5.2.
Description and Handling of SOF/GS-5816 FDC
5.2.1.
Formulation
The SOF/GS-5816 (400 mg/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/GS-5816 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/GS-5816 (400 mg/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/GS-5816 bottles to be distributed to study centers shall be labeled to meet applicable 
requirements of the US Food and Drug Administration (FDA) and/or other local regulations as 
applicable.
5.2.3.
Storage and Handling
SOF/GS-5816 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 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling SOF/GS-5816.
Sufficient quantities of SOF/GS-5816 tablets to complete the entire study will be shipped to the 
investigator or qualified designee from Gilead Sciences Clinical Supply Management (or its 
designee).


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5.2.4.
Dosage and Administration of Sofosbuvir/GS-5816 FDC
SOF/GS-5816 (400 mg/100 mg) 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(s) 
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.
5.3.
Study Drug Adherence and Drug Accountability
Subjects must be instructed to bring back all bottles of study medication(s) in the original 
container at every post-Day 1 study visit through the end of treatment.
Study medication will be reconciled using medication pill count at all on treatment visits by the 
investigator or designee (i.e. pharmacist) in order to monitor the subject’s adherence with the 
medication regimen.
5.4.
Concomitant Medications
Concomitant medications taken within 30 days prior to Screening, approximately and including 
30 days after the last dose of study drug need to be recorded in the source documents and 
electronic case report forms (eCRFs).
The following medications are prohibited from 28 days prior to the Day 1 visit through the end 
of treatment:

Hematologic stimulating agents (e.g. erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)

Chronic systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (e.g., infliximab)

Investigational agents or devices for any indication
Concomitant use of certain medications or herbal/natural supplements (e.g., substrates, inhibitors 
or inducers of drug transporters or metabolizing enzymes [e.g., P-gp or CYP3A]) with study 
drug(s) may result in pharmacokinetic interactions resulting in increases or decreases in exposure 
of study drug(s) or these medications. The use of the following agents is prohibited from 21 days 
prior to Day 1 through the end of treatment.  The use of amiodarone is prohibited from 60 days 
prior to Baseline/Day 1 through the end of treatment.
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 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
Amiodaroned
Diltiazem, Verapamil, , Dronedarone, 
Quinidine, Ranolazine, Bosentan, 
Olmesartan, Valsartan, Digoxine
Herbal/Natural 
Supplementsb
St. John’s Wort, Echinaccea. Milk thistle 
(i.e. silymarin), Chinese herb sho-saiko-
to (or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsf
Rosuvastatin (≤10 mg/day), Atorvastatin, 
Simvastatin, Pravastatin, Pitavastatin, 
Fluvastatin, Lovastatin
Other
Modafinil b, Sulfasalazinec, Methotrexatec
a
The 21 day washout period does not apply to PPIs, which can be taken up to 7 days before baseline Day 1. H2-receptor 
antagonists must not exceed a dose of 20 mg famotidine or equivalent and can be taken simultaneously with SOF/GS-5816 
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) of 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
May result in symptomatic bradycardia. Mechanism is not currently known
e
Monitor for signs and symptoms of digoxin toxicity. 
f
Use with SOF/GS-5816 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.
Medications for disease conditions excluded from the protocol (e.g., HIV-1 infection, active 
cancer, transplantation) are not listed under this Concomitant Medication section and are 
disallowed in the study.
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.
5.5.
Investigational Medicinal Product Return or Disposal
Please refer to Section 10.1.7 for Investigational Medicinal Product Accountability and Return.


SOF/GS-5816 FDC 
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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. 
The investigator must docmnent any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO). 
6.1. 
Subject Enrollment 
Study visits will occur at Screening, Day 1, and on-treatment at the end of Weeks 1, 2, 4, 6, 8, 
10, and 12. Post treatment Visits will occur at Weeks 4, 12, and 24 (if applicable) following the 
last dose of study medications. 
All subjects will complete post tTeatment Week 4 regardless of treatment duration. Subjects with 
HCV RNA < LLOQ at the post treatment Week 4 and/or Week 12 visits will complete the 
subsequent post treatment visits, unless viral relapse is detemlined. The end of study will occur 
at the post treatment Week 24 visit. 
Inf01mation on the specific laboratory parameters to be measured and clinical assessments to be 
perf01med are provided in (Section 6.6.1 ). 
6.2. 
Screening Assessments 
6.2.1. 
Screening Visit 
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 or additional HCV 
genotyping. 
The following will be perf01med and documented at screening: 
• 
Obtain signed informed consent 
_ 
PPD 
• 
Determine inclusion eligibility (Reference Section 4.2 and 4.3) 
-
If the presence of cinhosis is detetmined, then appropriate diagnostic imaging (CT or 
Ultrasound) should be perf01med to exclude the presence ofhepatocellulaT carcinoma 
(HCC) 
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
Obtain medical history 
If treatment experienced, record the duration of the prior treatment and the type of 
interferon and/or ribavirin or DAA administered
Record whether the subject had a Non-response or Relapse/Breakthrough during prior 
treatment 
■
Non-Response: Subject did not achieve undetectable HCV RNA while on treatment. 
■
Relapse/Breakthrough: Subject achieved undetectable HCV RNA during treatment or 
within 4 weeks of the end of treatment, but did not achieve SVR

Perform complete physical examination

Obtain body height and weight

Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature)

Perform 12-lead ECG

Assessment of adverse events (AEs) and concomitant medications

Obtain blood samples for tests:
— Hematology & Chemistry
— Coagulation tests
— HCV RNA
— Serum -hCG pregnancy test for females of childbearing potential only
— IL28B genotype 
— Determination of genotype of HCV infection
— HCV antibody, HIV 1/2 antibody, and HBV surface antigen (HBsAg)
— HbA1c
— Fibrotest

Obtain urine sample for:
— Urinalysis
— Drug screen


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Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic after screening for the Day 1 visit assessments and enrollment into the study.
A single retest of screening labs are permitted only if there is reason to believe the retest value 
will be within accepted parameters, if the initial exclusionary value was either due to a sample 
processing error or due to extenuating circumstances such as intercurrent infection.
6.3.
Treatment Assessments
Treatment procedures/assessments will occur at Day 1, at the end of Weeks 1, 2, 4, 6, 8, 10, and 
12.
6.3.1.
Day 1 Visit
Day 1 tests and procedures must be completed prior to enrollment and dosing/dispensing of 
study drug.
At the Day 1 visit, the following procedures/assessments are to be completed according to the 
Study Procedures Table in Appendix 2.

Perform complete physical examination

Obtain body weight

Obtain vital signs

Perform 12-lead ECG 

Assessment of AEs and concomitant medications

Subject completes Health Related Quality of Life (HRQoL) Survey, SF-36

Obtain blood samples for tests:
— Hematology & Chemistry
— Coagulation tests 
— HCV RNA
— Viral RNA Sequencing / Phenotyping Sample

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only 

Pregnancy prevention counseling


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• 
PPD 
• 
PPD 
• 
Confirm Eligibility 
• 
Drug Administration 
Dispense study drug as directed by IWRS 
Final 
Amendment 1 
Instruct the subject on the packaging, storage, and administration of study drug 
Observe the subject taking the first dose of study drug 
6.3.2. 
Week 1, 2, 4, 6, 8, and 12 Visits(± 3 days) 
The following procedures/assessments are to be completed at the end of Weeks 1, 2, 4, 6, 8, 10, 
and 12 according to the Study Procedures Table in Appendix 2. 
• 
Perform complete physical examination (Week 12 only) 
• 
Obtain body weight (Week 12 only) 
• 
Obtain vital signs 
• 
Perform 12-lead ECG (Weeks 1 and 12 only) 
• 
Assessment of AEs and concomitant medications 
• 
Subject completes Health Related Quality of Life (HRQoL) Survey, SF-36 (Week 12 only) 
• 
Obtain blood samples for tests: 
Hematology & Chemistry 
Coagulation tests (Week 12 only) 
HCVRNA 
Viral RNA Sequencing I Phenotyping Sample 
• 
Obtain urine sample for: 
P-hCG pregnancy test for females of childbearing potential only (Weeks 4, 8, and 12 
only) 
• 
Pregnancy prevention counseling (Week 12 only) 
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• 
PPD 
• 
Complete medication dosage unit counts 
• 
Drug Administration: 
Dispense study drug as directed by IWRS (Weeks 4 and 8 only) 
6.4. 
Early Termination (ET)/Unscheduled Visit 
Final 
Amendment 1 
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 virologic failure, a Viral RNA Sequencing I Phenotyping Sample must be 
collected. 
For subjects who have completed an ET visit, the post treatment Week 4, and, if applicable, 
Weeks 12 and 24 follow-up visits will be scheduled after last dose ofthe study drug. 
If the subject discontinues treatment early, for any reason, the following assessments for the 
early termination (ET) visit must be performed: 
• 
Perform complete physical examination 
• 
Obtain body weight 
• 
Obtain vital signs 
• 
Perform 12-lead ECG 
• 
Assessment of AEs and concomitant medications 
• 
Subject completes Health Related Quality of Life (HRQoL) Survey, SF-36, if available 
• 
Obtain blood samples for tests: 
Hematology & Chemistry 
Coagulation tests 
HCVRNA 
Viral RNA Sequencing I Phenotyping Sample 
• 
Obtain urine sample for: 
P-hCG pregnancy test for females of childbearing potential only (Weeks 4, 8, and 12 
only) 
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• 
Pregnancy prevention counseling 
• 
PPD 
• 
Complete medication dosage unit counts 
Final 
Amendment 1 
The Sponsor (e.g. Medical Monitor and Clinical Program Manager) and CRO must be informed, 
as soon as possible, when a subject discontinues treatment. 
6.5. 
Post Treatment Assessments 
The post treatment Week 4, 12, and 24 visits should be timed from the date of last administration 
of study drugs. All subjects must complete the post treatment Week 4 visit. Subjects with HCV 
RNA < LLOQ at the post treatment Week 4 and/or Week 12 visits will complete the subsequent 
post treatment visits, unless viral relapse is determined. 
6.5.1. 
Post Treatment Week 4 (± 5 days) 
The following procedures/assessments are to be completed at the post treatment Week 4 visit 
according to the Study Procedures Table in Appendix 2. 
• 
Obtain vital signs 
• 
Assessment of AEs and concomitant medications 
• 
Pregnancy prevention counseling 
• 
Subject completes Health Related Quality of Life (HRQoL) Survey, SF-36 
• 
Obtain blood samples for: 
Hematology & Chemistry 
HCVRNA 
Viral RNA Sequencing I Phenotyping Sample 
• 
Obtain urine sample for: 
P-hCG pregnancy test for females of childbearing potential only 
6.5.2. 
Post Treatment Weeks 12 and 24, if applicable(± 5 days) 
The following procedures/assessments are to be completed at the post treatment Week 12 and 24, 
visits according to the Study Procedures Table in Appendix 2. 
• 
Obtain body weight 
• 
Obtain vital signs 
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
Subject completes Health Related Quality of Life (HRQoL) Survey, SF-36 (Post Treatment 
Week 12 only)

Obtain blood samples for:
— HCV RNA
— Viral RNA Sequencing / Phenotyping Sample 
6.6.
Procedures and Specifications
6.6.1.
Clinical Laboratory Analytes
Hematology: hematocrit, hemoglobin (Hb), platelet count, red blood cell count (RBC), white 
blood cell count (WBC) with differential (absolute and percentage) including lymphocytes, 
monocytes, neutrophils, eosinophils, basophils, reticulocyte count and 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, creatinine, total Bilirubin (reflex to direct 
bilirubin), glucose, lipase, potassium, sodium; Fibrotest/APRI calculation and direct bilirubin at 
Screening only.
Urinalysis: appearance, blood, color, glucose, leukocyte esterase, pH, protein, urobilinogen. 
Reflex to microscopic urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HCV, HBV and HIV. HCV RNA will be measured using the 
COBAS TaqMan HCV Test, v2.0 for Use with Ampliprep. HCV genotype and subtype will be 
determined using the Siemens VERSANT® HCV Genotype INNO-LiPA 2.0 Assay (reflex to 
Trugene). Gilead reserves the right to use alternate assays for HCV RNA and HCV genotype 
should the above assays become unavailable.
IL28B genotype will be determined by polymerase chain reaction (PCR) amplification of the 
SNP, rs12979860, with sequence specific forward and reverse primers and allele specific 
fluorescently labeled TaqMan MGB probes. Gilead reserves the rights to use an alternate assay 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum β-hCG or Urine β-hCG 
Additional Tests: Urine Drug screen (for amphetamines, cocaine, methadone, opiates) and
hemoglobin A1c (HbA1c)


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6.6.2.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history, including prior HCV treatment history 
(only applicable for treatment experienced subjects), will be collected on all subjects during 
screening.
If treatment experienced, record the duration of the prior treatment and the type of interferon 
and/or ribavirin and, if applicable, protease inhibitor administered
6.6.3.
Complete Physical Examination
A complete physical examination should be in keeping with a complete physical examination 
performed as part a new patient evaluation and must include source documentation of general 
appearance, and the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, 
mouth and tongue; chest (excluding breasts); respiratory; cardiovascular; lymph nodes, 
abdomen; skin, hair, nails; musculoskeletal; neurological. 
6.6.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
6.6.5.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {2202} 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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6.6.6. 
12-Lead ECGs 
Final 
Amendment 1 
Subjects will be required to rest in a supine position for 2 5 minutes prior to making a recording. 
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abnmmalities. On treatment ECGs should be compared to the subject's 
Day 1 as patt of routine safety monitoring. 
6.6.7. 
Viral RNA Sequencing I Phenotyping Sample 
Plasma samples will be collected at Day 1 and each subsequent visit for viral sequence analysis. 
At any unscheduled visit initiated for the purpose of confnming virologic breakthrough, a viral 
sequence analysis plasma sample must be collected. 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. 
6.6.8. 
PD 
~---------------------------------------A 
PPD 
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6.6.9. 
-p 
~--------------------------------
PD 
6.6.10. 
Pregnancy Testing 
Final 
Amendment 1 
All females of childbearing potential will have mine pregnancy testing evety 4 weeks dming the 
dosing period and 30 days after last dose of study dmg. 
If a positive mine pregnancy test is reported, the subject will be asked to retum to the clinic for a 
confnmat01y senun pregnancy test. 
6.6.11. 
Health Related Quality of Life Survey (HRQoL) 
A Health Related Quality of Life survey (HRQoL) SF-36 will be completed by subjects, 
provided a validated translation in the subject's primmy language is available, at Day 1, 
On-Treatment visits at Week 12 and post treatment Weeks 4 and 12 visits (if applicable), and 
Early Tetmination (if applicable). The subject should read the questionnaire by himself/herself 
and write/mm·k answers directly onto the questionnaire. 
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7.
TOXICITY MANAGEMENT
7.1.
Subject Stopping Rules
Administration of study medication may be discontinued in the event of a clinical or laboratory 
event. The Gilead Medical Monitor must be consulted prior to dose discontinuation of 
SOF/GS-5816 unless the investigator believes that immediate action is warranted to ensure the 
continued safety of the subject.
There is no option for dose reduction of SOF/GS-5816. 
Subjects who meet any of the following laboratory criteria must stop study medication:

Elevation of ALT and/or AST > 5x Baseline/Day 1 or nadir, confirmed by immediate repeat 
testing

Abnormal elevation of ALT > 3x Baseline/Day 1 and total bilirubin > 2x ULN, confirmed by 
immediate repeat testing

Elevation of ALT > 15x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 adverse event or laboratory abnormality assessed (and confirmed by immediate 
repeat testing) as related to SOF/GS-5816


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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 8.5.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
8.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is 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 (e.g., clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 8.1.1 and 8.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia), not the 
laboratory result (i.e., decreased hemoglobin).
8.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy)
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (e.g., venipuncture)
8.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale 
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs associated 
with laboratory abnormalities, the event should be graded on the basis of the clinical severity in 
the context of the underlying conditions; this may or may not be in agreement with the grading 
of the laboratory abnormality.
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, all AEs, regardless of cause or relationship, until 
4 weeks after last administration of study drug must be collected/reported to the CRF/eCRF 
database as instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
Any SAEs and deaths that occur after the post treatment follow-up visit and within 30 days of 
the last dose of study drug, regardless of causality, should also be reported. 


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Investigators are not obligated to actively seek SAEs after the protocol defined follow up period, 
however, if the investigator leams of any SAEs that occm after study participation has concluded 
and the event is deemed relevant to the use of study dmgs, he/she should promptly docmnent and 
rep01i the event to Gilead DSPH. 
• 
All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Rep01iing Process 
• 
Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
inf01mation to Gilead DSPH within24 homs of the investigator's knowledge of the event. 
Detailed instructions can be fmmd in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE i.nf01mation electronically, i.e., the 
eCRF database is not ftmctioning, record the SAE on the paper serious adverse event 
rep01iing f01m and submit as described above. 
-
As soon as it is possible to do so, any SAE rep01ied via paper must be transcribed into the 
eCRF Database according to instmctions in the eCRF completion guidelines. 
-
If an SAE has been rep01ied via a paper f01m because the eCRF database has been 
locked, no fmther action is necessaty. 
Conta.ct i.nfonnation is as follows: 
Gilead DSPH: 
Gilead Sciences 
Medical Monitor: 
Fax: +44 (0) 208 587 2386 
Email: safety _FC@gilead.com 
Name: 
Phone: 
Mobile: 
Anu Osinusi, MD 
PPD 
PPD 
Fax: 
PPD 
E-mail: 
t-'t-'U 
• 
For fatal or life-threatening events, copies of hospital case rep01ts, autopsy rep01is, and other 
documents are also to be subtnitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occm without personal subject identification, 
maintaining the traceability of a document to the subject identifiers. 
• 
Additional i.nfonnation may be requested to ensme the timely completion of accmate safety 
rep01is. 
• 
Any medications necessaty for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject's CRF/eCRF and the event description section of the SAE 
f01m. 
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8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
8.5.
Special Situations Reports
8.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  


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8.5.2.
Instructions for Reporting Special Situations
8.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report 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 Gilead DSPH using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy. 
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 8.1.1 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. 
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. Refer to Appendix 4 for Pregnancy 
Precautions, Definition for Female of Childbearing Potential, and Contraceptive Requirements.
8.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study drug and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 


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Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/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 aTe: 
Final 
Amendment 1 
• 
To evaluate the efficacy of treatment with SOF/GS-5816 for 12 weeks in subjects with 
chronic HCV infection as measured by the prop01tion of subjects with SVR12 
• 
To evaluate the safety and tolerability of treatment with SOF/GS-5816 for 12 weeks 
The secondmy objectives of this study are: 
• 
To detennine the prop01tion of subjects with SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24) 
• 
To evaluate the prop01tion of subjects with virologic failure 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment 
• 
To evaluate the emergence of viral resistance to SOF and GS-5816 during treatment and after 
cessation of treatment 
The explorat01y objectives of this study are: 
~ 
D 
I 
9.1.2. 
Primary Endpoint 
The prima1y efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after cessation of 
therapy) in the Full Analysis Set (F AS) population. 
9.1.3. 
Secondary Endpoint 
Secondary endpoints include the following: 
• 
The prop01tion of subjects with: HCV RNA < LLOQ at 4 and 24 weeks after cessation of 
therapy (SVR4 and SVR24) 
• 
The proportion of subjects with HCV RNA < LLOQ on treatment 
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• 
HCV RNA change from Day 1 
• 
The proportion of subjects with virologic failure 
9.1.4. 
Safety Endpoints 
Final 
Amendment 1 
The prima1y safety endpoint is any AE leading to pe1manent discontinuation of study dmg(s). 
9.1.5. 
Other Endpoints of Interest 
PPD 
9.2. 
Analysis Conventions 
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be perf01med using SAS® software (SAS Institute, Cruy, North Cru·olina, USA). 
The study dmg in this study includes SOF/GS-5816. Last dose of study dmg refers to the last 
dose of SOF/GS-5816 and will be used in the defmition oftreatment-emergent AEs and 
laborat01y abn01malities as well as the efficacy endpoints of SVR at various post treatment time 
points. 
9.2.1. 
Analysis Sets 
9.2.1.1. 
Efficacy 
The analysis set for antiviral activity analyses will be the Full Analysis Set (F AS) which includes 
subjects who were enrolled into the study and received at least one dose of study dmgs. 
9.2.1.2. 
Safety 
The prima1y analysis set for safety analyses will include subjects who received at least one dose 
of study dmg. 
Treatment-emergent data will be analyzed and defmed as data collected from the fn·st dose of 
study dmg through the date of last dose of study dmg plus 30 days. 
9.2.2. 
Data Handling Conventions 
Missing data can have an impact upon the interpretation of the trial data. Other than the 
endpoints discussed below, values for missing data will not be imputed. 
For the analysis of post-baseline categorical efficacy endpoints, if a data point is missing and is 
preceded and followed in time by values that are deemed successes, then the missing data point 
will be tenned a success; othe1wise the data point will be te1med a failure. 
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Any subject with missing data due to premature discontinuation of the study medication will be 
considered a failure at the date of premature discontinuation and all time points subsequent to the 
date of premature discontinuation.  If no HCV RNA values are obtained after the last dose of 
study medication, the subject will be considered a treatment failure for the SVR endpoints. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject received study medication, the subject will be included in a summary of adverse 
events according to the treatment received; otherwise, if the subject is not dosed then they 
will be excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the pre-dose value and the change from pre-dose values.
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.
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).
9.2.3.
Interim Analysis
An interim analysis may be performed as appropriate for Region 2 or a specific country in 
Region 2 after all subjects enrolled in the relevant countries have been followed through 
12 weeks post treatment or discontinued from the study.
9.3.
Demographic Data and Baseline Characteristics
Demographic and baseline characteristics will be summarized using standard descriptive 
methods by region and overall.
Demographic data will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include body mass index, HCV RNA level (log10 IU/mL), 
genotype of HCV infection, IL28B genotype, and additional endpoints as necessary.


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9.4.
Efficacy Analysis
9.4.1.
Primary Analysis
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after discontinuation of 
therapy) in the FAS population. The primary analysis will be performed after all enrolled 
subjects have been followed through post treatment Week 12 or discontinued from study.
In the primary efficacy analysis, the SVR12 rate in Region 1 will be compared to the 
pre-specified performance goal of 85% by using a two-sided exact one-sample binomial test at 
the 0.05 significance level. The null (H0) and alternative (H1) hypotheses used to assess 
superiority of SOF/5816 in Region 1 relative to the performance goal of 85% are:

H0: SVR12 rate = 85%

H1: SVR12 rate ≠ 85%
It is difficult to characterize a single historical control rate for all genotypes included in this 
study given the different standards of care of each genotype (some of which include interferon), 
and the lack of historical data for genotype 4, 5, and 6 participants. Given these difficulties, 
rather than use a historical control rate as the basis for assessing the primary endpoint, a 
pre-specified performance goal is defined as a benchmark against which the efficacy of 
SOF/GS-5816 will be tested. The benchmark sets a high bar of 85%.  The basis for this 
benchmark includes the overall trend toward increasing SVR rates in recent years, the higher 
SVR rates observed with Peg-IFN + RBV treatment in Chinese and other Asian subjects {24218}
compared with other races, and the general appeal of using a fixed clinically relevant threshold 
as a measure of treatment benefit {28509} of SOF/GS-5816.
A confidence interval approach will be used to estimate the SVR12 rates for Region 2 and for the 
overall population (ie, combined Region 1 and Region 2).
The point-estimate with the 2-sided 95% exact confidence interval (CI) using the binomial 
distribution (Clopper-Pearson method) will be constructed for the SVR12 rates by region and the 
overall population, and may be for individual countries as appropriate.
9.4.2.
Secondary Analysis
The proportion of subjects with HCV RNA below the LLOQ over time (including SVR 
endpoints) will be presented by region in tabular and graphical form.
Descriptive summaries and listings will be provided for additional efficacy evaluations of the 
proportion of subjects who experience virologic failure, serum HCV RNA actual values and 
change from baseline, other endpoints of interest including ALT normalization and Health 
Related Quality of Life (HRQoL) endpoints.


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Details on efficacy analyses will be described in the statistical analysis plan. 
9.5. 
Safety Analysis 
Final 
Amendment 1 
Safety will be evaluated by assessment of clinicallaborat01y tests, physical examinations, vital 
signs measurements at various time points during the study, and by the documentation of AEs. 
All safety data collected on or after the first dose of study dmg administration up to 30 days after 
the last dose of study dmg will be smnma1·ized by region and overall according to the study dmg 
received. 
9.5.1. 
Extent of Exposure 
A subject's extent of exposure to study dmg will be generated from the study dmg 
administration page of the CRF. Exposure data will be smnmarized by region and overall. 
9.5.2. 
Adverse Events 
Clinical and laborat01y AEs will be coded using the Medical Dictionmy for Regulat01y 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Tetm (HLGT), 
High-Level Tetm (HLT), Prefened Tenn (PT), and Lower-Level Tetm (LLT) will be attached to 
the clinical database. 
Events will be smnmarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any adverse event with onset date of on or after the study dmg 
start date and no later than 30 days after petmanent discontinuation of study drug or any adverse 
event leading to prematme discontinuation of study. 
Smnmaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC 
and prefened tetm) will be provided by region and overall: 
• 
All AEs, 
• 
All study dmg-related AEs, 
• 
Combined Grade 2, 3 and 4 AEs, 
• 
Combined Grade 3 and 4 AEs, 
• 
Combined Grade 2, 3 and 4 study dmg-related AEs, 
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
Combined Grade 3 and 4 study drug-related AEs,

All AEs that caused permanent discontinuation from study drug,

All SAEs (including death), and

All study drug-related SAEs
All AEs collected during the course of the study will be presented in data listings.
9.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by region, overall, and study visit along with corresponding change from Day 1.
Graded laboratory abnormalities will be defined using the laboratory toxicity grading defined in 
Appendix 3 of this protocol. The incidence of treatment-emergent laboratory abnormalities, 
defined as values that increase by at least one toxicity grade from Day 1 at any time 
post-baseline up to the date of last dose of study drug plus 30 days will be summarized by region 
and overall.
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.
All laboratory abnormalities will be included in the listings of laboratory data.
9.5.4.
Other Safety Evaluations
Individual data for 12-lead ECG, vital signs measurements will be listed by subject and 
summarized by region and overall by incidence of events/abnormalities or descriptive statistical 
summaries (n, mean, SD, median, Q1, Q3, minimum, and maximum), as appropriate. In 
comparison to pre-treatment (either Screening or pre-dose on Day 1) values, vital signs 
measurements and 12-lead ECG findings will additionally be summarized using pre-determined, 
clinically relevant thresholds. 
9.6.
Sample Size
The sample size justification is based on the Region 1 population. A sample size of 260 subjects 
in Region 1 will provide more than 80% power to detect an improvement of at least 6 percentage 
points in SVR12 rate from the performance goal of 85% by using a two-sided exact one-sample 
binomial test at the significance level of 0.05. 


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In addition, a confidence interval approach will be used to estimate the SVR12 rates for Region 2 
and for the overall population (ie, combined Region 1 and Region 2). With 100 subjects from 
Region 2, and 360 subjects from the overall population, the 2-sided 95% exact CIs for different 
observed SVR12 rates are presented in the table below.
Region
Observed SVR12 rate
2-sided 95% exact CI
Region 2 (n=100)
80% (80 out of 100)
71% - 87%
90% (90 out of 100)
82% - 95%
Overall (n=360)
80% (288 out of 360)
75% - 84%
90% (324 out of 360)
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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. For studies conducted under a United States IND, the investigator 
will ensure that the basic principles of “Good Clinical Practice,” as outlined in 21 CFR 312, 
subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 1998, and 
21 CFR, part 56, 1998, are adhered to.  These standards are consistent with the requirements of 
the European Community Directive 2001/20/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.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.”
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB or IEC. Approval from the IRB or IEC 
must be obtained before starting the study and should be documented in a letter to the 
investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation.
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 


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investigator must utilize an IRB or IEC-approved consent form for documenting written 
informed consent. Each informed consent will be appropriately signed and dated by the subject 
or the subject’s legally authorized representative and the person obtaining consent.
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, (where 
local regulations allow) and an identification code (i.e., not names) should be recorded on any 
form or biological sample submitted to the Sponsor, IRB or IEC, or laboratory. The investigator 
must keep a screening log showing codes, names, and addresses for all subjects screened and for 
all subjects enrolled in the trial.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the Investigator Brochure, this protocol, CRFs, the investigational new drug, and any 
other study information, remain the sole and exclusive property of Gilead Sciences during the 
conduct of the study and thereafter. This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from Gilead Sciences. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain.
10.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB 
or IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data are listed in the Source Data verification Plan, and should include 
sequential notes containing at least the following information for each subject:

subject identification (name, date of birth, gender);

documentation that subject meets eligibility criteria, i.e., history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

participation in trial (including trial number);

trial discussed and date of informed consent;

dates of all visits;


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
documentation that protocol specific procedures were performed;

results of efficacy parameters, as required by the protocol;

start and end date (including dose regimen) of trial medication (preferably drug dispensing 
and return should be documented as well);

record of all adverse events and other safety parameters (start and end date, and preferably 
including causality and intensity);

concomitant medication (including start and end date, dose if relevant; dose changes should 
be motivated);

date of trial completion and reason for early discontinuation, if applicable.
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (i.e., United States, Europe, or Japan) 
and until there are no pending or contemplated marketing applications in an ICH region; or, if no 
application is filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and regulatory authorities have been notified. Investigators may be 
required to retain documents longer if required by applicable regulatory requirements, by local 
regulations, or by an agreement with Gilead Sciences. The investigator must notify 
Gilead Sciences before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead Sciences must be notified in advance.
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences 
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples at the conclusion of this study may be retained in storage by the Sponsor for 
a period up to 10 years for purposes of this study.
10.1.6.
Electronic Case Report Forms (eCRF)
For each subject enrolled, an eCRF must be completed and signed by the principal investigator 
or sub-investigator (as appropriate) within a reasonable time period after data collection. This 
also applies to records for those subjects who fail to complete the study (even during a 
pre-randomization screening period if an eCRF was initiated). If a subject withdraws from the 
study, the reason must be noted on the eCRF. If a subject is withdrawn from the study because of 
a treatment-limiting adverse event, thorough efforts should be made to clearly document the 
outcome.


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10.1.7.
Drug Accountability
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational medicinal product. This includes acknowledgment of 
receipt of each shipment of study product (quantity and condition), subject dispensing records, 
and returned or destroyed study product. Dispensing records will document quantities received 
from Gilead Sciences and quantities dispensed to subjects, including lot number, date dispensed, 
subject identifier number, subject initials, and the initials of the person dispensing the 
medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRBs or IECs, 
or to regulatory authority or health authority inspectors.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB or IEC 
in accordance with local requirements. Approval must be obtained before changes can be 
implemented.
10.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency(ies). 
Gilead Sciences will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may 
be prepared in certain cases.


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After conclusion of the study and without prior written approval from Gilead Sciences, 
investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

the results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead Sciences in an abstract, manuscript, or presentation form; or

the study has been completed at all study sites for at least 2 years.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 10.1.4).
The investigator will submit any proposed publication or presentation along with the respective 
scientific journal or presentation forum at least 30 days before submission of the publication or 
presentation. The investigator will comply with Gilead Sciences’ request to delete references to 
its confidential information (other than the study results) in any paper or presentation and agrees 
to withhold publication or presentation for an additional 60 days in order to obtain patent 
protection if deemed necessary.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the CRFs for consistency.
The monitor is responsible for routine review of the CRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences may conduct inspections or audits 
of the clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.
10.3.3.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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Final
Gilead Sciences, Inc.
Amendment 1
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hyperendemicity of hepatitis C virus infection in Taiwan: the important role of 
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Yu ML, Dai CY, Lin ZY, Lee LP, Hou NJ, Hsieh MY, et al. A randomized trial 
of 24- vs. 48-week courses of PEG interferon alpha-2b plus ribavirin for 
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Tsang OT, Zee JS, Chan JM, Li RS, Kan YM, Li FT, et al. Chronic hepatitis C 
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Final
Gilead Sciences, Inc.
Amendment 1
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clinical management of interferon-alpha-associated psychiatric side effects. 
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Final
Gilead Sciences, Inc.
Amendment 1
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Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N 
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virus in Vietnam: high prevalence of infection in dialysis and multi-transfused 
patients involving diverse and novel virus variants. PLoS ONE 2012;7 
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SOF/GS-5816 FDC
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Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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12.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table Study Visits
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


SOF/GS-5816 FDC 
Protocol GS-US-342-1518 
Final 
Gilead Sciences, Inc. 
Amendment 1 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Multicenter, Open-Label Study to Investigate the Efficacy and Safety of 
Sofosbuvir/GS-5816 Fixed Dose Combination for 12 Weeks in Subjects with Chronic HCV 
GS-US-342-1518, Amendment 1, 21 Apri12015 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Anu Osinusi, MD (Printed) 
Medical Monitor 
PPD 
Signature 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
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Gilead Sciences, Inc.
Amendment 1
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Appendix 2.
Study Procedures Table
Study Visits
Screening
Day 1
On-treatment Study Week (± 3 days)
Post treatment 
Study Week (± 5 days)i
1
2
4
6
8
10
12/ET
4
12
24
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
Height
X
Weight
X
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGc
X
X
X
X
AEs 
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention 
Counseling
X
X
X
Health Related Quality of 
Life Survey, SF-36
X
X
X
X
Review of Study 
Medication Complianceg
X
X
X
X
X
X
X
Study Drug Dispensinga
X
X
X


SOF/GS-5816 FDC 
Protocol GS-US-342-1518 
Gilead Sciences, Inc. 
Laboratory Assessments 
Hematology, Chemistry 
Coagulation Tests 
HCVRNA 
Viral RNA Sequencing I 
Phenotyping Sample! 
Pregnancy Testingd 
Urinalysis, 
Urine Drug Screen 
HCV Genotyping, IL28B 
HCV, HIV, HBV Serology 
HbA 1 c, Fibrotest® 
Screening 
Dayl 
1 I 
2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
On-treatment Study Week(± 3 days) 
I 
4 I 
6 I 
8 I 10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
I 12/ET 
X 
X 
X 
X 
X 
Final 
Amendment 1 
Post treatment 
Study Week(± 5 days)i 
4 I 12 I 24 
X 
X 
X 
X 
X 
X 
X 
X 
PPD 
i 
Pharmacogenomic Samplee 
X 
Imaging for Hepatocellular 
Carcinoma (Heel 
X 
a 
Day 1 assessments must be performed prior to dosing. 
b 
Vital signs include resting blood pressure, pulse, respiratory rate, and temperature. 
c 
Subjects will be required to rest in a supine position for 2: 5 minutes prior to making a recording. The investigator (or qualified designee) should review the ECG traces 
recorded in real time for gross abnormalities. 
d 
Females of childbearing potential only. Serum P-hCG pregnancy test performed at screening and confirmation of positive urine pregnancy test. All females of childbearing 
potential will have urine pregnancy testing every 4 weeks during the dosing period. If urine is positive, confirm immediately with serum P-hCG. 
e 
Only for subjects who have provided consent for this sample and testing. This sample can be obtained at a subsequent visit if not obtained at Day 1. 
CONFIDENTIAL 
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21 April 2015 
J 


SOF/GS-5816 FDC 
Protocol GS-US-342-1518 
Gilead Sciences, Inc. 
Final 
Amendment 1 
f 
If presence of cirrhosis is determined, then appropriate diagnostic imaging (e.g., cr or ultrasound) should be performed to exclude the presence of hepatocellular carcinoma 
(HCC) 
g 
Subjects must be instructed to bring back all medication in the original container at every post-Day 1 study visit through the end of treatment. Study medication will be 
reconciled at every post-Day 1 visit by the investigator in order to monitor the subject's adherence with the medication regimen. 
h 
PPD 
All subjects will complete Post treatment Week 4. Subjects with HCV RNA < LLOQ at the post treatment Week 4 and/or Week 12 visits will complete the subsequent post 
treatment visits, unless viral relapse is determined. 
Plasma samples will be collected for possible viral resistance and other Virology studies 
CONFIDENTIAL 
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Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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21 April 2015
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18June2012
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR 
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR 
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV positive or negative)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L


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Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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21 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Infant, 2 – 7 Days
1250 to 1500/mm3
1.25 to 1.50 GI/L
1000 to 1250/mm3
1.00 to < 1.25 GI/L
750 to 1000/mm3
0.75 to < 1.00 GI/L
750/mm3
< 0.75 GI/L
Infant, 1 Day
4000 to 5000/mm3
4.00 to 5.00 GI/L
3000 to 4000/mm3
3.00 to < 4.00 GI/L
1500 to 3000/mm3
1.50 to < 3.00 GI/L
1500/mm3
< 1.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 76
21 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0% 


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 77
21 April 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
146  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 78
21 April 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4  mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*) 
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63  to LLN mmol/L
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.14 mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol/L to LLN
57 to 87 μmol/L
27 to 57 μmol/L
27 μmol/L
Creatinine 
1.50 to 2.00 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol/L
177 to 265 μmol/L
265 to 530 μmol/L
530 μmol/L
Bicarbonate
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L
LDL
(Fasting)
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL


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


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


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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


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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
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
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) 


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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
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


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


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


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


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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)
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


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 94
21 April 2015
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


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 95
21 April 2015
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]


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 96
21 April 2015
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


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 97
21 April 2015
ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, back 
of neck, breasts, 
abdomen)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current meds to regain glucose 
control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences 
(eg, ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, myxedema coma)
Lipoatrophy (eg, fat loss 
from the face, extremities, 
buttocks)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 98
21 April 2015
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


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 99
21 April 2015
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1.
Background
Non-clinical toxicity studies of SOF demonstrated no adverse effects on fertility or embryo-fetal 
development. Clinical data available at this time suggest that this drug does not have a drug-drug 
interaction (DDI) with hormones used for contraception.
Non-clinical toxicity studies of GS-5816 demonstrated no effects on fertility or embryo-fetal 
development. Preliminary clinical pharmacological data available at this time suggest that 
GS-5816 does not have a drug-drug interaction (DDI) with hormones used for contraception. 
Therefore SOF/GS-5816 can be administered with hormonal contraceptives. 
However, the risks of treatment with SOF/GS-5816 during pregnancy in human have not been 
evaluated. Please refer to the latest version of the investigator’s brochure for additional 
information. 
2. Definition of Female of Childbearing Potential and Contraceptive Requirements for 
Female Subjects (and their male partners)
Women ≥ 54 years of age with cessation for ≥ 12 months of previously occurring menses, or 
women of any age who have had a hysterectomy, or have had both ovaries removed, or have had 
medically documented ovarian failure will be considered to be of non-childbearing potential. 
Women < 54 years of age (including those with amenorrhea of any duration) who have not had a 
hysterectomy, and have not had both ovaries removed, and have not had medically documented 
ovarian failure will be considered to be of childbearing potential. 
Women of childbearing potential must have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test on the Day 1 visit prior to enrollment. They must also agree to one 
of the following from 3 weeks prior to Day 1 until 30 days after the last dose of SOF/GS-5816.

Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) is not permitted.
Or

Consistent and correct use of 1 of the following methods of birth control listed below, in 
addition to a male partner who correctly uses a condom from the date of Screening until 
30 days after the last dose of SOF/GS-5816: 
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent (where 
available)


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 100
21 April 2015
tubal sterilization
vasectomy in male partner
hormone-containing contraceptive:
■
implants of levonorgestrel
■
injectable progesterone
■
oral contraceptives (either combined or progesterone only)
■
contraceptive vaginal ring 
■
transdermal contraceptive patch
3. Contraceptive Requirements for Male Subjects (and their female partners)
All male study participants must agree to consistently and correctly use a condom from Baseline 
until 90 days after the last dose of SOF/GS-5816. 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 90 days after the last dose of SOF/GS-5816.
Male subjects must agree to refrain from sperm donation for at least 90 days after the last dose of 
SOF/GS-5816.
4. Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days (or 90 days for partners of male subjects) of 
the last dose of SOF/GS-5816. Subjects who become pregnant or who suspect that they are 
pregnant must report the information to the investigator and discontinue study drug immediately. 
Subjects whose partner has become pregnant or suspects she is pregnant must report the 
information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 8.5.2.1.

Prot_000.pdf: 
Study Title: 
Sponsor: 
ClinicalTrials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Sciences Study 
Director 
Protocol Version/Date: 
(r') GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3, Multicenter, Open-Label Study to Investigate the 
Efficacy and Safety ofSofosbuvir/GS-5816 Fixed Dose 
Combination for 12 Weeks in Subjects with Chronic HCV 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 USA 
Not Available 
Hepatitis C Virus Infection 
GS-US-342-1518 
Name: 
Telephone: 
Fax: 
Email: 
I"'I"'U 
Original: 
16 Janumy 2015 
CONFIDENTIALITY STATEMENT 
The infmmation contained in this document, pat1iculm·ly tmpublished data, is the property or 
Ullder 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 infonnation is only to be used by you in 
com1ection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infmmation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaty to obtain infmmed consent from those 
persons to whom the dmg may be administered. 


SOF/GS-5816 FDC 
Protocol GS-US-342-1518 
Gilead Sciences, Inc. 
TABLE OF CONTENTS .... 
LIST OF IN-TEXT TABLES 
PROTOCOL SYNOPSIS 
TABLE OF CONTENTS 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS. 
Final 
Original 
. ..... 2 
.4 
.5 
. .............. ............... ................... .. .. 10 
1. 
INTRODUCTION .................................... ............... ............... ............... ............... ............... ................... .. .. 13 
2. 
3. 
4. 
1.1. 
1.2. 
1.3. 
1.4. 
1.5. 
1.6. 
1.7. 
Background ... ................ ................ ............. . 
HCV in China and Southeast Asia ................ .......... . 
Sofosbuvir/GS-5816 Fixed Dose Combination 
Additional Clinical Study Experience ........... .......... . 
1.4.1. 
Study GS-US-281-1 058 
Rationale for the Current Study ..... .......... . 
Rationale for Dose Selection ......... ..... . 
Overall Risk/Benefit Assessment 
OBJECTIVES .. .......... ................ .......... . 
STUDY DESIGN .................................... . 
3.1. 
3.2. 
3.3. 
3.4. 
3.5. 
3.6. 
Treatment Plan and Regimen 
Visit Schedule ..................................................... . 
Virologic Response-Based Stopping Criteria 
Treatment Discontinuation Criteria .................... . 
Discontinuations .. .................................... . 
Substudies ................................... . 
3.6.1. 
PPD 
~--------------------------~ 
SUBJECT POPULATION ............................................... . 
4.1. 
4.2. 
4.3. 
Number of Subjects and Subject Selection 
Inclusion Criteria ................................................. . 
Exclusion Criteria ................................................ . 
5. 
INVESTIGATIONAL :MEDICINAL PRODUCTS 
5.1. 
5.2. 
5.3. 
5.4. 
5.5. 
Emollment ..... . 
Description and Handling of SOF /GS-5816 FDC .. 
5. 2. 1. 
Formulation .. 
5.2.2. 
Packaging and Labeling ...................... . 
5.2.3. 
Storage and Handling ... 
5.2.4. 
Dosage and Administration of Sofosbuvir/GS-5816 FDC ... 
Study Drug Adherence and Drug Accountability ... 
Concomitant Medications 
Investigational Medicinal Product Return or Disposal 
6. 
STUDY PROCEDURES .......... . 
6.1. 
6.2. 
6.3. 
6.4. 
Subject Emollment ....... . 
Screening Assessments 
6.2.1. 
Screening Visit . 
Treatment Assessments 
6.3.1. 
Day 1 Visit ...... . 
6.3.2. 
Week 1, 2, 4, 6, 8, and 12 Visits(± 3 days) 
Early Termination (ET)/Unscheduled Visit ................. . 
CONFIDENTIAL 
Page 2 
. ... 13 
. ... 14 
.. .. 16 
. ... 16 
.. .. 16 
. ... 19 
. ... 20 
.. .. 21 
. ... 22 
. ... 23 
.. .. 23 
. ... 23 
.. .. 24 
. ... 24 
. ... 25 
. ... 25 
.. .. 25 
. ... 26 
.... 26 
. ... 26 
. ... 28 
. ... 30 
.... 30 
. ... 30 
. ... 30 
. ... 30 
. ... 30 
. ... 31 
. ... 31 
. ... 31 
. ... 32 
. ....... 33 
........ 33 
........ 33 
. ....... 33 
........ 35 
. ....... 35 
........ 36 
. ....... 37 
16 January 2015 


SOF/GS-5816 FDC 
Protocol GS-US-342-1518 
Gilead Sciences, Inc. 
Final 
Original 
6.5. 
Post Treatment Assesstnents .................................................................................................................. 38 
6.5.1. 
Post Treatment Week 4 (± 5 days) ....................................................................................... 38 
6.5.2. 
Post Treatment Weeks 12 and 24, if applicable(± 5 days) .................................................. 38 
6.6. 
Procedtu·es and Specifications ................................................................................................................ 39 
6.6.1. 
Clinical Laboratoty Analytes ............................................................................................... 39 
6.6.2. 
Medical Histoty .................................................................................................................... 40 
6.6.3. 
Complete Physical Examination ........................................................................................... 40 
6.6.4. 
Vital Signs ............................................................................................................................ 40 
6.6.5. 
Creatinine Clearance ............................................................................................................ 40 
6.6.6. 
12-Lead ECGs ...................................................................................................................... 41 
6.6. 7. 
Viral RNA Sequencing I Phenotyping Sample .................................................................... .41 
~ :~ :!: 
~~g 
............ : : : ::: : : ::: ::: :::: : : : : : : : : : : : : ::::::::: :: : : :::: : : : : : : : : : : : : :~ 
6.6.10. 
6.6.11. 
Pregnancy Testing ................................................................................................................ 42 
Health Related Quality of Life Sm-vey (HRQoL) ................................................................ .42 
7. 
TOXICITYMANAGEMENT ............................................................................................................................ 43 
7 .1. 
Subject Stopping Rules .......................................................................................................................... 43 
8. 
ADVERSE EVENTS MANAGEMENT ............................................................................................................ 44 
8.1. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events ................................. 44 
8.1.1. 
Adverse Events ..................................................................................................................... 44 
8.1.2. 
Serious Adverse Events ........................................................................................................ 44 
8.1.3. 
Clinical Laboratory Abnonnalities and Other Abnonnal Assessments as 
Adverse Events or Serious Adverse Events ........................................................................ .45 
8.2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................ .45 
8.2.1. 
Assessment of Causality for Study Dmgs and Procedm-es .................................................. .45 
8. 2 .2. 
Assesstnent of Severity ........................................................................................................ 46 
8.3. 
Investigator Requirements and Instructions for Repmti.ng Adverse Events and Serious 
Adverse Events to Gilead ....................................................................................................................... 46 
8.4. 
Gilead Repmting Requirements ............................................................................................................. 48 
8.5. 
Special Situations Reports ...................................................................................................................... 48 
8.5 .1. 
Definitions of Special Situations .......................................................................................... 48 
8.5.2. 
Instmctions for Reporting Special Situations ...................................................................... .49 
9. 
STATISTICALCONSIDERATIONS ................................................................................................................ 51 
9.1. 
Analysis Objectives and Endpoints ........................................................................................................ 51 
9 .1.1. 
Analysis Objectives .............................................................................................................. 51 
9 .1.2. 
Pritnary Endpoint ................................................................................................................. 51 
9 .1.3. 
Secondary Endpoint ............................................................................................................. 51 
9.1.4. 
Safety Endpoints .................................................................................................................. 51 
9.1.5. 
Other Endpoints of Interest .................................................................................................. 52 
9.2. 
Analysis Conventions ............................................................................................................................. 52 
9.2.1. 
Analysis Sets ........................................................................................................................ 51 
9 .2.2. 
Data Handling Conventions ................................................................................................. 52 
9.2 .3. 
Interim Analysis ................................................................................................................... 53 
9.3. 
Demographic Data and Baseline Characteristics ................................................................................... 53 
9.4. 
Efficacy Analysis ................................................................................................................................... 54 
9.4 .1. 
Pritnary Analysis .................................................................................................................. 54 
9.4.2. 
Secondaty Analysis .............................................................................................................. 54 
9.5. 
Safety Analysis ....................................................................................................................................... 55 
9.5.1. 
Extent ofExposm-e ............................................................................................................... 55 
9.5.2. 
Adverse Events ..................................................................................................................... 55 
9.5.3. 
Laboratoty Evaluations ........................................................................................................ 56 
CONFIDENTIAL 
Page 3 
16 Januruy 2015 


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 4
16 January 2015
9.5.4.
Other Safety Evaluations......................................................................................................56
9.6.
Sample Size............................................................................................................................................56
10.
RESPONSIBILITIES..........................................................................................................................................58
10.1.
Investigator Responsibilities ..................................................................................................................58
10.1.1.
Good Clinical Practice..........................................................................................................58
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval...............................................................................................................................58
10.1.3.
Informed Consent.................................................................................................................58
10.1.4.
Confidentiality......................................................................................................................59
10.1.5.
Study Files and Retention of Records ..................................................................................59
10.1.6.
Electronic Case Report Forms (eCRF).................................................................................60
10.1.7.
Drug Accountability.............................................................................................................61
10.1.8.
Inspections............................................................................................................................61
10.1.9.
Protocol Compliance............................................................................................................61
10.2.
Sponsor Responsibilities ........................................................................................................................61
10.2.1.
Protocol Modifications.........................................................................................................61
10.2.2.
Study Report and Publications .............................................................................................61
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................62
10.3.1.
Access to Information for Monitoring..................................................................................62
10.3.2.
Access to Information for Auditing or Inspections ..............................................................62
10.3.3.
Study Discontinuation..........................................................................................................62
11.
REFERENCES ...................................................................................................................................................63
12.
APPENDICES ....................................................................................................................................................69
Appendix 1.
Investigator Signature Page....................................................................................................70
Appendix 2.
Study Procedures Table Study Visits .....................................................................................71
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............74
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................98
LIST OF IN-TEXT TABLES
Table 1-1.
Summary Characteristics by Country.....................................................................................14
Table 1-2.
Preliminary NGMN, NG, EE, and GS-5816 Plasma PK Parameters Following 
Administration of NGM/EE alone or with GS-5816..............................................................18
Table 1-3.
Preliminary Summary of LH, FSH, and Progesterone Concentrations Following 
Administration of NGM/EE alone or with GS-5816..............................................................19
Table 5-1.
List of Disallowed Medications..............................................................................................32


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 5
16 January 2015
PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 3, Multicenter, Open-Label Study to Investigate the Efficacy 
and Safety of Sofosbuvir/GS-5816 Fixed Dose Combination for 
12 Weeks in Subjects with Chronic HCV
ClinicalTrials.gov 
Identifier:
Not Available
Study Centers:
Approximately 32 sites in China, Malaysia, Singapore, Thailand, and 
Vietnam
Number of Subjects:
Approximately 360 subjects
Target Population:
Adults with chronic hepatitis C virus (HCV) infection 
Treatment Duration:
Subjects will be treated for 12 weeks
Objectives:
The primary objectives of this study are:

To evaluate the efficacy of treatment with sofosbuvir 
(SOF)/GS-5816 fixed dose combination (FDC) for 12 weeks in 
subjects with chronic HCV infection as measured by the 
proportion of subjects with sustained viral response 12 weeks 
after cessation of treatment (SVR12)

To evaluate the safety and tolerability of treatment with 
SOF/GS-5816 for 12 weeks
The secondary objectives of this study are:

To determine the proportion of subjects with SVR at 4 and 
24 weeks after cessation of treatment (SVR4 and SVR24)

To evaluate the proportion of subjects with virologic failure

To evaluate the kinetics of circulating HCV RNA during 
treatment and after cessation of treatment

To evaluate the emergence of viral resistance to SOF and 
GS-5816 during treatment and after cessation of treatment


SOF/GS-5816 FDC 
Protocol GS-US-342-1518 
Gilead Sciences, Inc. 
Study Design: 
CONFIDENTIAL 
The exploratoty objectives of this study are: 
~ 
D 
I 
Final 
Original 
Intemational, multicenter, open-label study in treatment-naive and 
treatment-experienced adults with chronic HCV infection. Subjects 
with or without cinhosis will be enrolled. 
Approximately 20% of subjects may be treatment experienced and 
approximately 20% of subjects may have compensated cinhosis at 
screerung. 
Subjects with chronic HCV infection will be enrolled to receive 
SOF/GS-5816 once daily for 12 weeks. 
This multi-regional clinical trial (MRCT) is planned to be conducted 
in China, Malaysia, Singapore, Thailand, and Vietnam. China will be 
considered Region I. Malaysia, Singapore, Thailand, and Vietnam, 
which are all located in Southeast Asia, will be considered Region2. 
Approximately 360 subjects will be enrolled in the sh1dy in total. The 
approximate number of subjects to be enrolled in each region 
according to HCV genotype is represented in the table below: 
HCVGT 
(Previous 
Rx History) 
Region 1 
(China) 
Region2 
(Malaysia, 
Singapore, 
Thailand, 
Vietnam) 
GT =Genotype 
Rx =Treatment 
GT-1 
GT-2 
(TN, TE) 
(TN, TE) 
80 
60 
100 
TN= Treatment Naive, TE = Treatment Experienced 
GT-3 
GT-4,5,6 
(TN, TE) 
(TN, TE) 
Total 
60 
60 
260 
100 
It is expected that a small number of subjects whose HCV genotype 
camwt be determined by the centrallaboratoty (HCV genotype 
indeterminate) may also be enrolled. 
Page 6 
16 Janruuy 2015 


SOF/GS-5816 FDC 
Protocol GS-US-342-1518 
Gilead Sciences, Inc. 
Sub-Study: 
Diagnosis and Main 
Eligibility Criteria: 
Study Procedmes/ 
Frequency: 
CONFIDENTIAL 
Final 
Original 
Chronic HCV-infected, male and non-pregnant/non-lactating female 
subjects, ages 18 years or older. 
Refer to Sections 4.2 and 4.3 for detailed Inclusion and Exclusion 
Criteria. 
Screening assessments will be completed within 28 days of the Day 1 
visit. The screening window can be extended to 42 days for subjects 
requiring liver biopsy or additional HCV genotyping. 
All subjects will complete the following study visits: Screening, 
Day 1, on-treatment visits at the end of Weeks 1, 2, 4, 6, 8, 10, 
and 12. Following the last dose of study dmg, all subjects will 
complete post treatment Week 4, including those subjects who 
tetminate study dmg treatment early. Subjects who achieve SVR4 
(HCV RNA < LLOQ at the post treatment Week 4 visit) will attend 
the post treatment Week 12 visit and those who achieve SVR12 
(HCV RNA < LLOQ) will complete the post treatment Week 24 
visit. Viral breakthrough or relapse must be confmned. 
Screening assessments will include physical examination, medical 
histmy, height, weight, vital signs, 12-lead ECG, adverse events 
related to screening procedmes, concmnitant medications, safety 
laboratmy tests (including hematology, chemistry and coagulation), 
HCV RNA, serology (HIV, HCV, HBV), hemoglobin Ale (HbAl c), 
assessment of the presence or absence of cinhosis, screening for 
hepatocellular carcinoma (HCC) for subjects with cinhosis, serum 
~-hCG (females of child bearing potential only), IL28B and HCV 
genotyping, urinalysis and mine dmg screen. 
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SOF/GS-5816 FDC 
Protocol GS-US-342-1518 
Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
Evaluation Criteria: 
Safety: 
Efficacy: 
CONFIDENTIAL 
Final 
Original 
Based on the study visit, on-treatment assessments include physical 
examination, adverse events (AEs), concomitant medications, weight, 
vital signs, safety laborat01y tests, HCV RNA, viral sequencing 
samples, 12-lead ECG, Health Related Quality of Life (HRQoL) 
Survey SF-36, study medication dispensing and pill count, and urine 
pregnancy tests and pregnancy prevention cmmseling (females of 
child bearing potential only) as applicable. 
At the time of ECG collection, Day 1 (prior to study drug 
administration) and at Week 1 and Week 12 or Early Tennination, 
printed copies (paper) will be reviewed by qualified study staff (as 
detennined by the Investigator) and compared to the subject's Day 1 
ECG as part of routine safety monitoring. 
Post treatment assessments include weight, vital signs, AEs, 
concomitant medications, HRQoL SF-36, safety laboratory tests, 
HCV RNA, viral sequencing samples, and urine pregnancy tests 
(females of child bearing potential only). 
PPD 
I 
PPD 
I 
SOF/GS-5816 fixed dose combination (FDC) is manufactured as a 
400 mg/1 00 mg FDC tablet for oral administration. Subjects will take 
1 tablet daily with or without food. 
AEs and laborat01y tests will be collected throughout the study. 
Efficacy will be evaluated using scheduled assessments ofHCV RNA 
perf01med using COBAS® TaqMan® HCV Test, v2.0 for use with 
Ampliprep. 
Page 8 
16 Janruuy 2015 


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Statistical Methods:
The primary efficacy endpoint for the study is SVR12 in all enrolled
and treated subjects. 
The hypothesis to be tested will be that the SVR12 rate in Region 1 is 
superior to the pre-specified performance goal of 85%. A confidence 
interval approach will be used to estimate the SVR12 rates for Region 
2 and for the overall population (ie, combined Region 1 and Region 
2).
In the primary efficacy analysis, the SVR12 rate I Region 1 will be 
compared to 85% by using a two-sided exact one-sample binomial 
test at the 0.05 significance level. In addition, the point-estimate with 
the 2-sided 95% exact confidence interval (CI) using the binomial 
distribution (Clopper-Pearson method) will be constructed for the 
SVR12 rates by region and the overall population.
The sample size justification is based on the Region 1 population. A 
sample size of 260 subjects in Region 1 will provide more than 80% 
power to detect an improvement of at least 6 percentage points in 
SVR12 rate from the performance goal of 85% by using a two-sided 
exact one-sample binomial test at significance level of 0.05.
The point-estimate with the 2-sided 95% exact confidence interval 
(CI) using the binomial distribution (Clopper-Pearson method) will be 
constructed for the SVR12 rates by region and the overall study 
population. 
Secondary efficacy endpoints include SVR4 and SVR24.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
β-hCG
β-human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
APRI
AST:platelet ratio index
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase  (also SGOT)
AUC
area under the curve
AUCtau
area under the plasma concentration versus time curve over the dosing interval 
(tau)
BW
body weight
CI
confidence interval
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Ctau
observed drug concentration at the end of the dosing interval (tau)
CRF
case report form(s)
CRO
Contract (or clinical) research organization 
DAA
Direct acting antiviral
DCV
Daclatasvir (HCV NS5A Inhibitor)
dL
Deciliter
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
ESA
Erythropoiesis stimulating agent
Emax
maximal effect
ESLD
End Stage Liver Disease
ET
Early Termination
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
Fixed dose combination
g
grams
GBD
Global Burden of Disease
GCP
Good Clinical Practice (Guidelines)
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
HbA1c
Hemoglobin A1c
HBV
Hepatitis B virus


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HDPE
High-density polyethylene
HIV
Human immunodeficiency virus
HLGT
High-Level Group Term
HLT
High-Level Term
IB
Investigator Brochure
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IFN
Interferon
IL28B
IL28B gene
IND
Investigational New Drug (Application)
INR
International Normalized Ratio of prothrombin time
IRB
institutional review board
IUD
intrauterine device
IV
Intravenous
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDL
low-density lipoprotein
LDV
ledipasvir
LLN
lower limit of the normal range
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MCV 
mean corpuscular volume or mean cell volume
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PCR
Polymerase Chain Reaction
Peg-IFN
pegylated interferon
P-gp
P-glycoprotein 
PG
Pharmacogenomic
PT
preferred term or prothrombin time 
RBC
Red blood cell count 
RBV
Ribavirin


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
RNA
ribonucleic acid
SADR
Serious adverse drug reaction
Scr
serum creatinine (mg/dL)
SAE
serious adverse event
SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
SOC
System Organ Class
SOF
Sofosbuvir, formerly GS-7977
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
ULN
upper limit of the normal range
US
United States
WBC
white blood cell count
WHO
World Health Organization


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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 {28346}. In the United States (US), approximately 
2.7 million people have chronic HCV infection {28338} and HCV infection causes over 
15,000 deaths each year {20446}, 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 
{28339}. Successful treatment of chronic HCV infection reduces the need for liver transplant, the 
incidence of HCC and overall mortality {25891}. 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 with different 
regimens and durations dependent on the HCV genotype {27503}.The next wave of therapies for 
the treatment of HCV includes combinations of direct acting antivirals (DAAs) including SOF 
that will obviate the need for administration of Peg-IFN and RBV. 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 or 12 weeks resulted in 
high SVR12 rates in subjects with GT1 HCV infection {28583}, {28585}, {28587}.
Most current HCV drug development effort focuses on GT1 HCV infection as this is the most 
prevalent HCV genotype worldwide, including in developing countries {32174}, {31525}. 
However, over half of all HCV infections are non-GT1: estimates from 2 recent meta-analyses 
indicate GT3 HCV is the next most common accounting for 22-30% of infections, while GT2 
and GT4 each account for approximately 8 to 13%, GT6 for approximately 2 to 5%, and GT5 for 
approximately 1% of HCV infections worldwide. The availability of a well-tolerated, all oral, 
short duration therapy that is effective across all HCV genotypes would be a major advance for 
the treatment of HCV infection globally, particularly in regions where HCV genotyping is not 
part of routine medical care.
Although some individualization of care will be necessary, particularly for patients with 
advanced disease, the development of a pangenotypic regimen of short-duration that may not 
require HCV genotyping, response guided therapy, or intensive safety monitoring due to use of 
Peg-IFN or RBV will enable more patients to be treated.


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1.2.
HCV in China and Southeast Asia
The prevalence of HCV infection in East and Southeast Asia is difficult to quantify due to 
differences in the level of public health surveillance systems and access to general medical care. 
A recent literature review estimated the prevalence of anti-HCV antibodies in the Global Burden 
of Disease (GBD) regions as defined by the World Health Organization (WHO). In East Asia, 
which includes China, the prevalence was estimated to be 3.7% while in Southeast Asia, which 
includes Vietnam, Thailand, and Malaysia, the prevalence was estimated to be 2.0% {29744}. 
Although geographically Singapore is in Southeast Asia, it is classified by WHO as part of “High 
income Asia-Pacific” GBD and HCV prevalence in this region is 1.4% {29744}. 
Genotype diversity is high in both these regions {31525}. Although there are inter- and 
intra-country differences, the most frequently observed HCV genotypes in both regions are GT1, 
2, 3 and 6 (Table 1-1). In China, GT1, GT2 and GT6 are generally the most common, although 
regional differences in genotype distribution, such as GT3 in the South, are apparent {24217}. 
GT6 is also common in Vietnam and Thailand while GT3 is the most common genotype in 
Thailand and Malaysia, and GT2 is found in both countries. Although GT1 is the predominant 
genotype in Singapore, approximately 20% of infections are GT2 or GT3.
Table 1-1.
Summary Characteristics by Country
China
Vietnam
Thailand
Malaysia
Singapore
Estimated HCV Ab 
Seroprevalence
1.3n,p-3.2%a
2.5%b
2.7%n,p
1.5%n,p
HCV Genotype 
Distribution
GT-1 – 58.2%c
GT-2 – 15.5%c
GT-3 – 8.7%c
GT-6 – 6.3%c
Other– 11.3%c
GT-1 ~ 47%b
GT3 ~ 6%b
GT-6 ~ 47%b
GT1 ~34%n
GT2 ~ 4%
GT3 ~41%
GT4 <1%
GT6 ~23%
GT1 ~39%n
GT2 ~4%
GT3 ~56%
GT4 ~1%
GT1 ~81%n
GT2 ~ 7%
GT3 ~ 12%
Estimated % IL28B-
CC Genotype
~85%-88%c,g
~90%d
77%o
Estimated Peg-IFN 
+RBV SVR rates
    GT-1
~44-70%h,j,k,m
~53%f
74%
    GT-2
75%j
-
    GT-3
-
80%
    GT-6
~65-86%h,i,l,m
~74%f
65%r
References: a{24428}; {24397}; {24800}; {24799}; {24798};{24235}; b{19682}; c{24217};{24212}; {24211}; {24388};  
{24242};  {24382}; {24410}; {24209};  d{22075};f{24413}; g{24383}; h{24797}; i{24395}; j{13261}; k{24391}; l{24393}; 
m{24411}, 
In these Asian countries the predominant modes of HCV transmission have been iatrogenic in 
nature with large proportions of infected patients being exposed prior to the implementation of 
routine HCV antibody screening at blood banks, improved sterilization techniques for 
medical/dental equipment, and the widespread availability of disposable medical supplies 


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{24216}, {24239}, {24396}, {32905}, {32906}, {32907}. Transmission of HCV infection through 
traditional medical approaches including acupuncture is also common {24239}, {24428}. Due to 
the timing of introduction of practices aimed at reducing HCV transmission, the seroprevalence 
of HCV antibodies is seen to increase with age and is generally highest in those over 60 years of 
age in China {24384}.  Elderly patients are more likely to be treatment-experienced and may be
at higher risk of developing progressive liver disease. Comorbid conditions such as 
cardiovascular disease and diabetes are common with increasing age, which pose additional 
challenges to patient management {24398}, {22156}. The use of IFN is particularly challenging in 
elderly patients who generally report a higher frequency of adverse events and of greater severity 
compared to younger patients. Lower levels of treatment adherence are also observed. These 
factors likely contribute to the overall lower SVR rates generally observed in the elderly {24390}. 
As these patients continue to age, the number who will develop hepatic complications including 
cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver disease (ESLD) is significant 
{22077}, which will pose a significant burden on the healthcare systems in the region.
In addition to blood transfusions and medical procedures, intravenous drug abuse (IVDA) is a 
significant risk factor in Malaysia, Thailand and Vietnam, as well as parts of China {19682}, 
{32762}. The use of interferon (IFN)-based therapy is also problematic in the IVDA population. 
The risk for developing severe IFN-related psychiatric events including depression, suicidal 
ideation, cognitive disturbances, psychotic symptoms, fatigue, and habit relapse is high. 
Adherence to therapy may be low and effective treatment requires multidisciplinary support 
{25091}.
Treatment of chronic infection in many countries in Asia is currently based upon weekly 
subcutaneous administration of pegylated interferon (Peg-IFN) with orally administered ribavirin 
(RBV) for 24 to 48 weeks dependent upon genotype and virologic response. In Caucasians, this 
treatment regimen affords sustained virologic response rates (SVR) on the order of 42-46% in 
treatment-naïve patients with GT1 and 76-82% in patients with GT2/3 infection {23342}, 
{23351}. Observed SVR rates using the same interferon (IFN) based treatment regimens are 
generally higher in Asian patients: Yu and Chuang {24218} summarize SVR rates in Asian 
patients in general as approximately 70% for those with HCV GT1 infection, 90% for GT2/3 
infection, and 80% for GT6 infection. Although data are limited, published SVR rates for the 
countries included in this study are included in Table 1-1. The higher SVR rates have been 
largely attributed to a higher proportion of Asian patients (>85%) possessing the host IL28B-CC 
genotype which confers a favorable virologic outcome following treatment with IFN-containing 
regimens {22075}, {24243}, {22156}, {21337}, {22098}. Although relatively high SVR rates can 
be achieved in Asian patients with IFN+RBV, the safety and tolerability of IFN-containing 
regimens is sub-optimal. Contraindications to IFN preclude its use by a significant number of 
patients {22156} while management of adverse effects commonly result in dose reductions and 
may lead to treatment discontinuation. Safety and tolerability are particularly problematic in an 
aging population with chronic hepatitis C. Moreover, lower SVR rates are also observed in older 
patients {24406}.


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Recently, first generation protease inhibitors (PI) (i.e., telaprevir [TVR] and boceprevir [BCV]) 
have been approved in some countries for use in patients with GT1 infection when combined 
with Peg-IFN+RBV. The Peg-IFN+RBV+PI regimens have incrementally improved SVR rates 
in GT1 treatment-naïve patients to approximately 70%; however, they are associated with 
significant safety and tolerability concerns {17996}, {17492} and their use is limited to GT1 
HCV.
1.3.
Sofosbuvir/GS-5816 Fixed Dose Combination
SOF/GS-5816 fixed-dose combination (SOF/GS-5816 FDC) combines two HCV specific direct 
acting antivirals (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 a component of an antiviral treatment 
regimen. GS-5816 is a HCV NS5A inhibitor that has demonstrated activity against HCV 
genotypes 1, 2, 3 and 4 HCV in a 3-day monotherapy study. Phase 2 studies of SOF +GS-5816 
administered as single agents have demonstrated that the combination of SOF 400 mg and 
GS-5816 100 mg administered for 12 weeks is well tolerated and results in high SVR rates 
across a broad range of HCV genotypes. The SOF/GS-5816 FDC (400 mg/100 mg) is a 
co-formulation of SOF 400 mg and GS-5816 100 mg for Phase 3 evaluation that has 
demonstrated similar exposure of each component compared to co-administration of the single 
agents.  
The development of SOF/GS-5816 may have a major impact of the global prevalence and burden 
of HCV as it may represent a simple, well tolerated, highly efficacious pangenotypic treatment 
for all HCV infected patients.
Please refer to the Investigator’s Brochure (IB) for additional information on SOF/GS-5816, and 
the individual components, including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.4.
Additional Clinical Study Experience
1.4.1.
Study GS-US-281-1058
GS-US-281-1058 is an open-label, Phase 1, multiple-dose drug-drug interaction study in healthy 
female subjects of childbearing age evaluating the effect of GS-5816 on the pharmacokinetics of 
a representative hormonal contraceptive medication, norgestimate/ethinyl estradiol (NGM/EE, 
OC). The study is summarized herein, as the data are relevant to the current study. Following 


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screening, eligible subjects were enrolled in a lead-in period (Part A) of 28 days during which 
they completed dosing with the hormonal 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 + GS-5816 were assessed in Part B of the study, which consisted of 2 cycles: subjects 
received OC alone during Cycle 1, and OC plus GS-5816 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+GS-5816) 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 GS-5816. Steady-state GS-5816 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 GS-5816 relative to 
administration of NGM/EE alone. A modest increase in EE Cmax was observed when 
administered with GS-5816 with no change in overall exposure (AUC) or Ctau. The magnitude of 
increase in EE Cmax when administered with GS-5816 is similar to that observed with the 
concomitant administration of other drugs such as voriconazole and etravirine, which did not 
warrant dose adjustment {13886}, {24911}. GS-5816 exposures were consistent with historical 
data (Studies GS-US-281-0115, GS-US-342-0104).


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Table 1-2.
Preliminary NGMN, NG, EE, and GS-5816 Plasma PK Parameters 
Following Administration of NGM/EE alone or with GS-5816
PK Parameter
Mean (%CV)
GLSM Ratio 
(90% CI) NGM/EE +
GS-5816 vs. NGM/EE
NGM/EE Alone 
(N = 15)
NGM/EE + GS-5816 
(N = 13)
Norelgestromin
AUCtau (pg•h/mL)
17,700 (16.7)
15,700 (11.2)
0.89 (0.85, 0.94)
Cmax (pg/mL)
1650 (16.8)
1600 (13.7)
0.97 (0.90, 1.04)
Ctau (pg/mL)
454 (18.5)
416 (14.3)
0.92 (0.86, 0.98)
Norgestrel
AUCtau (pg•h/mL)
47,000 (34.4)
43,000 (32.4)
0.91 (0.73, 1.14)
Cmax (pg/mL)
2410 (30.6)
2330 (31.5)
0.96 (0.80, 1.17)
Ctau (pg/mL)
1760 (34.4)
1640 (35.7)
0.92 (0.74, 1.15)
Ethinyl Estradiol
AUCtau (pg•h/mL)
666 (30.7)
686 (27.3)a
1.06 (0.98, 1.14)
Cmax (pg/mL)
57.5 (27.3)
80.0 (28.4)a
1.42 (1.28, 1.58)
Ctau (pg/mL)
14.8 (39.3)
12.4 (43.9)a
0.84 (0.77, 0.92)
GS-5816
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
Preliminary 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 {25217}, {25218}, {25219}. Follicle stimulating hormone was lower or 
within the expected range for the ovulatory phase {25218}. 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.


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Table 1-3.
Preliminary Summary of LH, FSH, and Progesterone Concentrations 
Following Administration of NGM/EE alone or with GS-5816
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)
Based on these results, no loss in contraceptive efficacy is expected upon administration of 
combined oral contraceptives containing norgestimate/ethinyl estradiol with GS-5816. 
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 GS-5816 as a single agent or as part of SOF/GS-5816 FDC is permitted. 
1.5.
Rationale for the Current Study
This Phase 3 study has been designed as a multicenter, open-label, non-randomized study 
evaluating SOF/GS-5816 for 12 weeks. Approximately 360 subjects will be enrolled. 
The population of the study will be subjects with chronic HCV infection of any genotype, with 
approximately 20% having prior treatment failure and approximately 20% having evidence of 
compensated cirrhosis at screening.  
Although favorable virologic response rates can be achieved in Asian patients with currently 
available therapy, there are significant advantages to the development of novel, all-oral, safe and 
effective IFN-free regimens. The NEUTRINO study (GS-US-334-0110) demonstrated that SOF 
+ Peg-INF/RBV treatment for 12 weeks results in high SVR rates in subjects with genotype 1 
and 4 HCV infection and in the small number of subjects with genotype 5 and 6 HCV infection 
{24715}. However, the side effects of SOF + Peg-INF/RBV occurred across multiple organ 
systems and the availability of a Peg-INF-and RBV-free regimen would be an advancement for 
patients with genotype 1, 4, 5, and 6 HCV infection. Although SOF +RBV for 12 or 24 weeks 
resulted in high SVR rates in subjects with genotype 2 or 3 HCV infections, respectively, the 
availability of a RBV-free regimen would be an advancement in treatment as well. 
Therapies which are not administered by injection nor associated with IFN-related adverse 
events are likely to improve patient treatment adherence and support high rates of viral cure. It is 
also likely that agents with favorable safety profiles which do not require frequent dose 
modification nor intensive monitoring of clinical adverse events and laboratory abnormalities 
will facilitate patient management particularly in rural areas.
Phase 2 evaluation of SOF + GS-5816 demonstrated that co-administration of the single agents 
for 8 or 12 weeks was well tolerated and resulted in high SVR rates across a broad range of HCV 
genotypes. In the Phase 2 study GS-US-342-0102 , administration of SOF 400mg + GS-5816 


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100mg for 12 weeks to treatment-naïve subjects without cirrhosis with genotype 1, 2, 3, 4, or 6 
HCV infection resulted in SVR12 rate of 100% (28/28), 100% (10/10), 93% (25/27), 86% (6/7), 
and 100% (5/5), respectively. In addition, one treatment naïve subject with genotype 5 HCV 
infection administered SOF +GS-5816 25mg for 12 weeks achieved SVR12. The 
GS-US-342-0109 study evaluated SOF + GS-5816 with and without RBV in populations of 
patients considered more difficult to cure, including subjects who had failed a prior interferon 
based regimen and those with cirrhosis. Administration of SOF 400mg + GS-5816 100 mg for 
12 weeks resulted in SVR12 rates of 88% (23/26) and 100% (27/27) in treatment experienced 
subjects with genotype 3 HCV infection with and without cirrhosis, respectively. Administration 
of SOF 400mg + GS-5816 100mg for 12 weeks resulted in an SVR12 rates of 100% (27/27) in 
subjects with genotype 1 HCV infection who had failed prior treatment with  a protease inhibitor 
with Peg-IFN/RBV. Seven of these 27 subjects had cirrhosis. 
The Phase 2 data suggest that SOF 400 mg +GS-5816 100mg has the potential to cure HCV 
infected patients across a broad range of HCV genotypes, when administered for 12 weeks 
without RBV and regardless of prior treatment experience or cirrhosis status. The co-formulation 
of SOF/GS-5816 (400 mg/100 mg) adds to the simplicity of the regimen in allowing for a once 
daily pill. Data from this study will support the development of a well-tolerated, short duration, 
RBV-free regimen for all genotypes of HCV infection that has the potential to make an impact 
on the global prevalence and burden of HCV infection. 
This study will assess the safety and efficacy of GS-5816/SOF in Asian patients. Each of the 
countries selected for inclusion in the study has a high burden of disease associated due to HCV 
infection. In China, estimates of the seroprevalence of HCV range from 1.3 to 3.2% which 
corresponds to approximately 15 to 30 million people. Seroprevalence estimates are similar in 
Malaysia, Thailand, and Vietnam although data is limited. The genotype distribution in the 
selected countries will facilitate enrollment of subjects with genotypes 1, 2, 3 and 6 HCV 
infection—the most common HCV genotypes across East and Southeast Asia.    
In particular, the availability of a single, pangenotypic regimen is anticipated to be especially 
beneficial in Asia where genotype diversity is high and genotyping may not be available or 
routinely done. Access to treatment for patients with HCV infection would be expanded as a 
result.  
1.6.
Rationale for Dose Selection
Sofosbuvir 400 mg, once daily, when dosed in combination with RBV with or without Peg-IFN
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 marketed dose of sofosbuvir for the treatment of HCV-infection and as 
such, has been selected for co-formulation with GS-5816 into a fixed-dose combination tablet.
GS-5816 100 mg has been administered in combination with SOF 400 mg for 12 weeks to 
237 HCV-infected subjects in Phase 2 studies. GS-5816 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 


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study GS-US-281-0102 established the anti-HCV activity of GS-5816 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 GS-5816 100 mg support further 
evaluation of this combination in clinical development.
1.7.
Overall Risk/Benefit Assessment
This study will provide information on the safety and efficacy of SOF/GS-5816, which combines 
a potent HCV nucleotide inhibitor and a potent HCV NS5A inhibitor. This combination has the 
potential to be a once-daily pangenotypic regimen for the treatment of chronic HCV infection. 
The potential benefits of SOF/GS-5816 over the current standard of care for the treatment of 
chronic HCV are:

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-IFN 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/GS-5816 has not been established. The safety profile of SOF + 
GS-5816 25mg or GS-5816 100mg administered for 8 or 12 weeks has been established in over 
800 subjects in Phase 2 studies. The safety profile of the proposed therapeutic regimen of SOF 
400mg and GS-5816 100mg administered for 12 weeks has been established in 237 subjects 
enrolled in Phase 2 studies. No clinical safety issues specifically related to GS-5816 or SOF + 
GS-5816 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 {28583}, 
{28585}, {28587}.
During the conduct of the study, the sponsor will perform ongoing safety review.
In summary, if high rates of SVR can be obtained with a short, IFN-free, RBV-free, 
pangenotypic regimen, the anticipated improvements in safety and tolerability would offer a 
favourable risk-benefit determination for patients with chronic HCV infection and enhance 
access to treatment.


SOF/GS-5816 FDC 
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Gilead Sciences, Inc. 
2. 
OBJECTIVES 
The primaty objectives of this study are: 
Final 
Original 
• 
To evaluate the efficacy of treatment with SOF/GS-5816 for 12 weeks in subjects with 
chronic HCV infection as measmed by the proportion of subjects with SVR12 
• 
To evaluate the safety and tolerability of treatment with SOF/GS-5816 for 12 weeks 
The secondruy objectives of this study ru·e: 
• 
To detennine the prop01tion of subjects with SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24) 
• 
To evaluate the prop01tion of subjects with virologic failme 
• 
To evaluate the kinetics of circulating HCV RNA dming treatment and after cessation of 
treatment 
• 
To evaluate the emergence of viral resistance to SOF and GS-5816 dming treatment and after 
cessation of treatment 
The explorat01y objectives of this study are: 
~ 
0 
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3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is an international, multicenter, open-label study that will evaluate the safety, tolerability 
and antiviral efficacy of SOF/GS-5816 for 12 weeks in treatment-naïve and 
treatment-experienced adults with chronic HCV infection. Subjects with or without cirrhosis will 
be enrolled. 
Approximately 20% of subjects may be treatment experienced and approximately 20% of 
subjects may have compensated cirrhosis at screening. 
Subjects with chronic HCV infection will be enrolled to receive SOF/GS-5816 once daily for 
12 weeks.
This multi-regional clinical trial (MRCT) is planned to be conducted in China, Malaysia, 
Singapore, Thailand, and Vietnam. China will be considered Region 1. Malaysia, Singapore, 
Thailand, and Vietnam, which are all located in Southeast Asia, will be considered Region 2.
Approximately 360 subjects will be enrolled in the study in total. The approximate number of 
subjects to be enrolled in each region according to HCV genotype is represented in the table 
below: 
HCV GT
(Prior Rx History)
GT-1
(TN, TE)
GT-2
(TN, TE)
GT-3
(TN, TE)
GT-4,5,6
(TN, TE)
Total
Region 1 (China)
80
60
60
60
260
Region 2 
(Malaysia, 
Singapore, 
Thailand, Vietnam)
100
100
Rx = Treatment
TN = Treatment Naïve, TE = Treatment Experienced
It is expected that a small number of subjects whose HCV genotype cannot be determined by the 
central laboratory (HCV genotype indeterminate) may also be enrolled.
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 or additional HCV 
genotyping. 


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All subjects will complete the following study visits: Screening, Day 1, on-treatment visits at the 
end of Weeks 1, 2, 4, 6, 8, 10, and 12. Following the last dose of study drug, all subjects will 
complete post treatment Week 4, including those subjects who terminate study drug treatment 
early. Subjects who achieve SVR4 (HCV RNA < LLOQ) will attend the post treatment Week 12 
visit and those who achieve SVR12 (HCV RNA < LLOQ) will complete the post treatment 
Week 24 visit. Viral breakthrough or relapse must be confirmed.  
The assessments performed at each visit are described in Section 6 and shown in Appendix 2.
3.3.
Virologic Response-Based Stopping Criteria
The following on-treatment virologic response-based treatment stopping criteria will be utilized:

Confirmed HCV RNA ≥ LLOQ after 2 consecutive HCV RNA < LLOQ

Confirmed > 1 log10 increase from on-treatment nadir

HCV RNA ≥ LLOQ through 8 weeks of treatment 
Confirmation should be performed as soon as possible and must occur no later than 2 weeks after 
an initial observation indicating virologic failure during the on-treatment phase. 
All subjects who terminate treatment early will complete the early termination (ET) and post
treatment Week 4 visit. Subjects who achieve SVR4 will attend the post treatment Week 12 visit 
and those who achieve SVR12 will complete the post treatment Week 24 visit.
3.4.
Treatment Discontinuation Criteria
When medically feasible, the Medical Monitor must be consulted prior to subject 
discontinuation. 
Study drug(s) must be discontinued in the following instances:

Unacceptable toxicity, as defined in Section 7 of the protocol, or toxicity that, in the 
judgment of the investigator, compromises the ability to continue study-specific procedures 
or is considered not to be in the subject’s best interest

Pregnancy of female subject

Efficacy failure as defined in Section 3.3

Significant protocol violation

Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy or other reason

Discontinuation of the study at the request of Gilead, regulatory agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC)


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3.5. 
Discontinuations 
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Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an early termination visit (see Section 6.4). All subjects who terminate treatment early 
will complete the early tennina.tion (ET) visit and post treatment Week 4 and Week 12 visits. 
3.6. 
Substudies 
3.6.1. 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 360 subjects will be enrolled in this study.  A detailed breakdown of the number 
of subjects to be enrolled in each region according to HCV genotype is presented in Section 3.1. 
Approximately 20% of subjects may be treatment experienced and approximately 20% of 
subjects may have compensated cirrhosis at screening. 
In order to manage the total study enrollment, Gilead Sciences, Inc., at its sole 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) Bodyweight 40 kg
4) HCV RNA 104 IU/mL at Screening
5) HCV genotype 1, 2, 3, 4, 5, 6, or indeterminate as assessed at Screening by the Central 
Laboratory 
6) Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy
7) Classification as treatment naïve or treatment experienced (approximately 20% of subjects 
may be treatment experienced):
a) Treatment naïve is defined as having never been exposed to approved or experimental 
HCV-specific direct-acting antiviral agents or prior treatment of HCV with interferon or 
ribavirin
b) Treatment experienced is defined as prior treatment failure to a regimen containing 
interferon either with or without RBV that was completed at least 8 weeks prior to Day 1.  
Subject must not have discontinued the prior regimen that resulted in virologic 
failure due to an adverse event.
i)
The subject’s medical records must include sufficient detail of prior virologic failure 
to allow for categorization of prior response (Reference Section 6.2.1), as either:
(1) Non-Responder: Subject did not achieve undetectable HCV RNA levels while on 
treatment, or 
(2) Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels during 
treatment or within 4 weeks of the end of treatment but did not achieve SVR


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8) Cirrhosis Determination (approximately 20% of subjects may have cirrhosis)
a) Cirrhosis is defined as any one of the following:
i)
Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥5)
ii) FibroTest® score > 0.75 AND an AST:platelet ratio index (APRI) > 2 during 
Screening
iii) Fibroscan® with a result of >12.5 kPa 
b)
Absence of cirrhosis is defined as any one of the following:
i)
A liver biopsy performed within 2 years of Day 1 showing absence of cirrhosis
ii) FibroTest score ≤ 0.48 AND APRI ≤ 1 performed during Screening
iii) Fibroscan with a result of ≤ 12.5 kPa within ≤ 6 months of Day 1
In the absence of a definitive diagnosis of presence or absence of cirrhosis by Fibrotest/APRI
using the above criteria, a liver biopsy or Fibroscan is required. Liver biopsy results will 
supersede Fibrotest/APRI or Fibroscan results and be considered definitive.
9) Liver imaging within 6 months of Day 1 is required in cirrhotic patients only to exclude 
hepatocellular carcinoma (HCC)
10) Females of childbearing potential (as defined in Appendix 4) must have a negative serum 
pregnancy test at Screening and a negative urine pregnancy test on Day 1 prior to enrollment
11) 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 4
12) Lactating females must agree to discontinue nursing before the study drug is administered
13) Subject must be of generally good health, with the exception of chronic HCV infection, as 
determined by the Investigator 
14) Subject must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Current or prior history of any of the following:
a) Clinically-significant illness (other than HCV) 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) are also excluded.  
b) Gastrointestinal disorder or post-operative 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) Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage).
e) Solid organ transplantation.
f)
Significant pulmonary disease, significant cardiac disease or porphyria.
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 6 months prior to Day 1 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)
Significant drug allergy (such as anaphylaxis or hepatotoxicity). 
2) Screening ECG with clinically significant abnormalities
3) Subjects has the following laboratory parameters at screening: 
a) ALT > 10 the upper limit of normal  (ULN)
b) AST > 10 ULN
c) Direct bilirubin > 1.5 ULN
d) Platelets < 50,000/L


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e) HbA1c > 8.5% 
f)
Creatinine clearance (CLcr) < 60 mL /min as calculated by the Cockcroft-Gault equation 
{2202}
g) Hemoglobin < 11 g/dL for female subjects; < 12 g/dL for male subjects.
h) Albumin < 3 g/dL 
i)
INR > 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR
4) Prior exposure to SOF or other nucleotide analogue HCV NS5B inhibitor or any HCV NS5A 
inhibitor.
5) Pregnant or nursing female or male with pregnant female partner. 
6) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alfa-1 antitrypsin deficiency, cholangitis).
7) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV).
8) Clinically-relevant alcohol or drug abuse within 12 months of screening. A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator.
9) Use of any prohibited concomitant medications as described in Section 5.4
10) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone 
equivalent > 10 mg/day).
11) Known hypersensitivity to GS-5816, SOF, or formulation excipients.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Enrollment
An Interactive Web Response System (IWRS) will be employed to manage subject enrollment
and study drug re-supply.  Eligible subjects will be enrolled and assigned to the open-label 
treatment. Every subject will receive SOF/GS-5816 tablet for 12 weeks.
5.2.
Description and Handling of SOF/GS-5816 FDC
5.2.1.
Formulation
The SOF/GS-5816 (400 mg/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/GS-5816 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/GS-5816 (400 mg/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/GS-5816 bottles to be distributed to study centers shall be labeled to meet applicable 
requirements of the US Food and Drug Administration (FDA) and/or other local regulations as 
applicable.
5.2.3.
Storage and Handling
SOF/GS-5816 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 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling SOF/GS-5816.
Sufficient quantities of SOF/GS-5816 tablets to complete the entire study will be shipped to the 
investigator or qualified designee from Gilead Sciences Clinical Supply Management (or its 
designee).


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5.2.4.
Dosage and Administration of Sofosbuvir/GS-5816 FDC
SOF/GS-5816 (400 mg/100 mg) 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(s) 
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.
5.3.
Study Drug Adherence and Drug Accountability
Subjects must be instructed to bring back all bottles of study medication(s) in the original 
container at every post-Day 1 study visit through the end of treatment.
Study medication will be reconciled using medication pill count at all on treatment visits by the 
investigator or designee (i.e. pharmacist) in order to monitor the subject’s adherence with the 
medication regimen.
5.4.
Concomitant Medications
Concomitant medications taken within 30 days prior to Screening, approximately and including 
30 days after the last dose of study drug need to be recorded in the source documents and 
electronic case report forms (eCRFs).
The following medications are prohibited from 28 days prior to the Day 1 visit through the end 
of treatment:

Hematologic stimulating agents (e.g. erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)

Chronic systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (e.g., infliximab)

Investigational agents or devices for any indication
Concomitant use of certain medications or herbal/natural supplements (e.g., substrates, inhibitors 
or inducers of drug transporters or metabolizing enzymes [e.g., P-gp or CYP3A]) with study 
drug(s) may result in pharmacokinetic interactions resulting in increases or decreases in exposure 
of study drug(s) or these medications. The use of the following agents is prohibited from 21 days 
prior to Day 1 through the end of treatment.  
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 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
Diltiazem, Verapamil, Amiodarone, 
Dronedarone, Quinidine, Ranolazine, 
Bosentan, Olmesartan, Valsartan, 
Digoxind
Herbal/Natural 
Supplementsb
St. John’s Wort, Echinaccea. Milk thistle 
(i.e. silymarin), Chinese herb sho-saiko-
to (or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorse
Rosuvastatin (≤10 mg/day), Atorvastatin, 
Simvastatin, Pravastatin, Pitavastatin, 
Fluvastatin, Lovastatin
Other
Modafinil b, Sulfasalazinec, Methotrexatec
a
The 21 day washout period does not apply to PPIs, which can be taken up to 7 days before baseline Day 1. H2-receptor 
antagonists must not exceed a dose of 20 mg famotidine or equivalent and can be taken simultaneously with SOF/GS-5816 
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) of 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 symptoms of digoxin toxicity. 
e
Use with SOF/GS-5816 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.
Medications for disease conditions excluded from the protocol (e.g., HIV-1 infection, active 
cancer, transplantation) are not listed under this Concomitant Medication section and are 
disallowed in the study.
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.
5.5.
Investigational Medicinal Product Return or Disposal
Please refer to Section 10.1.7 for Investigational Medicinal Product Accountability and Return.


SOF/GS-5816 FDC 
Protocol GS-US-342-1518 
Gilead Sciences, Inc. 
6. 
STUDY PROCEDURES 
Final 
Original 
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. 
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO). 
6.1. 
Subject Enrollment 
Study visits will occur at Screening, Day 1, and on-treatment at the end of Weeks 1, 2, 4, 6, 8, 
10, and 12. Post treatment Visits will occur at Weeks 4, 12, and 24 (if applicable) following the 
last dose of study medications. 
All subjects will complete post treatment Week 4 regardless of treatment duration. Subjects with 
HCV RNA < LLOQ at the post treatment Week 4 and/or Week 12 visits will complete the 
subsequent post treatment visits, tmless viral relapse is detennined. The end of study will occur 
at the post treatment Week 24 visit. 
Inf01mation on the specific laboratory paTameters to be measured and clinical assessments to be 
perf01med are provided in (Section 6.6.1). 
6.2. 
Screening Assessments 
6.2.1. 
Screening Visit 
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 or additional HCV 
genotyping. 
The following will be perf01med and documented at screening: 
• 
Obtain signed informed consent 
_ 
PPD 
• 
Dete1mine inclusion eligibility (Reference Section 4.2 and 4.3) 
-
If the presence of cinhosis is determined, then appropriate diagnostic imaging (CT or 
Ultrasound) should be perf01med to exclude the presence of hepatocellular carcinoma 
(HCC) 
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
Obtain medical history 
If treatment experienced, record the duration of the prior treatment and the type of 
interferon and/or ribavirin or DAA administered
Record whether the subject had a Non-response or Relapse/Breakthrough during prior 
treatment 
■
Non-Response: Subject did not achieve undetectable HCV RNA while on treatment. 
■
Relapse/Breakthrough: Subject achieved undetectable HCV RNA during treatment or 
within 4 weeks of the end of treatment, but did not achieve SVR

Perform complete physical examination

Obtain body height and weight

Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature)

Perform 12-lead ECG

Assessment of adverse events (AEs) and concomitant medications

Obtain blood samples for tests:
— Hematology & Chemistry
— Coagulation tests
— HCV RNA
— Serum -hCG pregnancy test for females of childbearing potential only
— IL28B genotype 
— Determination of genotype of HCV infection
— HCV antibody, HIV 1/2 antibody, and HBV surface antigen (HBsAg)
— HbA1c
— Fibrotest

Obtain urine sample for:
— Urinalysis
— Drug screen


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Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic after screening for the Day 1 visit assessments and enrollment into the study.
A single retest of screening labs are permitted only if there is reason to believe the retest value 
will be within accepted parameters, if the initial exclusionary value was either due to a sample 
processing error or due to extenuating circumstances such as intercurrent infection.
6.3.
Treatment Assessments
Treatment procedures/assessments will occur at Day 1, at the end of Weeks 1, 2, 4, 6, 8, 10, and 
12.
6.3.1.
Day 1 Visit
Day 1 tests and procedures must be completed prior to enrollment and dosing/dispensing of 
study drug.
At the Day 1 visit, the following procedures/assessments are to be completed according to the 
Study Procedures Table in Appendix 2.

Perform complete physical examination

Obtain body weight

Obtain vital signs

Perform 12-lead ECG 

Assessment of AEs and concomitant medications

Subject completes Health Related Quality of Life (HRQoL) Survey, SF-36

Obtain blood samples for tests:
— Hematology & Chemistry
— Coagulation tests 
— HCV RNA
— Viral RNA Sequencing / Phenotyping Sample

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only 

Pregnancy prevention counseling


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• 
PPD 
• 
PPD 
• 
Confirm Eligibility 
• 
Drug Administration 
Dispense study drug as directed by IWRS 
Final 
Original 
Instruct the subject on the packaging, storage, and administration of study drug 
Observe the subject taking the first dose of study drug 
6.3.2. 
Week 1, 2, 4, 6, 8, and 12 Visits(± 3 days) 
The following procedures/assessments are to be completed at the end of Weeks 1, 2, 4, 6, 8, 10, 
and 12 according to the Study Procedures Table in Appendix 2. 
• 
Perform complete physical examination (Week 12 only) 
• 
Obtain body weight (Week 12 only) 
• 
Obtain vital signs 
• 
Perform 12-lead ECG (Weeks 1 and 12 only) 
• 
Assessment of AEs and concomitant medications 
• 
Subject completes Health Related Quality of Life (HRQoL) Survey, SF-36 (Week 12 only) 
• 
Obtain blood samples for tests: 
Hematology & Chemistry 
Coagulation tests (Week 12 only) 
HCVRNA 
Viral RNA Sequencing I Phenotyping Sample 
• 
Obtain urine sample for: 
P-hCG pregnancy test for females of childbearing potential only (Weeks 4, 8, and 12 
only) 
• 
Pregnancy prevention counseling (Week 12 only) 
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• 
PPD 
• 
Complete medication dosage unit counts 
• 
Drug Administration: 
Dispense study drug as directed by IWRS (Weeks 4 and 8 only) 
6.4. 
Early Termination (ET)/Unscheduled Visit 
Final 
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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 virologic failure, a Viral RNA Sequencing I Phenotyping Sample must be 
collected. 
For subjects who have completed an ET visit, the post treatment Week 4, and, if applicable, 
Weeks 12 and 24 follow-up visits will be scheduled after last dose of the study drug. 
If the subject discontinues treatment early, for any reason, the following assessments for the 
early termination (ET) visit must be performed: 
• 
Perform complete physical examination 
• 
Obtain body weight 
• 
Obtain vital signs 
• 
Perform 12-lead ECG 
• 
Assessment of AEs and concomitant medications 
• 
Subject completes Health Related Quality of Life (HRQoL) Survey, SF-36, if available 
• 
Obtain blood samples for tests: 
Hematology & Chemistry 
Coagulation tests 
HCVRNA 
Viral RNA Sequencing I Phenotyping Sample 
• 
Obtain urine sample for: 
P-hCG pregnancy test for females of childbearing potential only (Weeks 4, 8, and 12 
only) 
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• 
Pregnancy prevention counseling 
• 
PPD 
• 
Complete medication dosage unit counts 
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The Sponsor (e.g. Medical Monitor and Clinical Program Manager) and CRO must be informed, 
as soon as possible, when a subject discontinues treatment. 
6.5. 
Post Treatment Assessments 
The post treatment Week 4, 12, and 24 visits should be timed from the date of last administration 
of study drugs. All subjects must complete the post treatment Week 4 visit. Subjects with HCV 
RNA < LLOQ at the post treatment Week 4 and/or Week 12 visits will complete the subsequent 
post treatment visits, unless viral relapse is determined. 
6.5.1. 
Post Treatment Week 4 (± 5 days) 
The following procedures/assessments are to be completed at the post treatment Week 4 visit 
according to the Study Procedures Table in Appendix 2. 
• 
Obtain vital signs 
• 
Assessment of AEs and concomitant medications 
• 
Pregnancy prevention counseling 
• 
Subject completes Health Related Quality of Life (HRQoL) Survey, SF-36 
• 
Obtain blood samples for: 
Hematology & Chemistry 
HCVRNA 
Viral RNA Sequencing I Phenotyping Sample 
• 
Obtain urine sample for: 
P-hCG pregnancy test for females of childbearing potential only 
6.5.2. 
Post Treatment Weeks 12 and 24, if applicable(± 5 days) 
The following procedures/assessments are to be completed at the post treatment Week 12 and 24, 
visits according to the Study Procedures Table in Appendix 2. 
• 
Obtain body weight 
• 
Obtain vital signs 
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
Subject completes Health Related Quality of Life (HRQoL) Survey, SF-36 (Post Treatment 
Week 12 only)

Obtain blood samples for:
— HCV RNA
— Viral RNA Sequencing / Phenotyping Sample 
6.6.
Procedures and Specifications
6.6.1.
Clinical Laboratory Analytes
Hematology: hematocrit, hemoglobin (Hb), platelet count, red blood cell count (RBC), white 
blood cell count (WBC) with differential (absolute and percentage) including lymphocytes, 
monocytes, neutrophils, eosinophils, basophils, reticulocyte count and 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, creatinine, total Bilirubin (reflex to direct 
bilirubin), glucose, lipase, potassium, sodium; Fibrotest/APRI calculation and direct bilirubin at 
Screening only.
Urinalysis: appearance, blood, color, glucose, leukocyte esterase, pH, protein, urobilinogen. 
Reflex to microscopic urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HCV, HBV and HIV. HCV RNA will be measured using the 
COBAS TaqMan HCV Test, v2.0 for Use with Ampliprep. HCV genotype and subtype will be 
determined using the Siemens VERSANT® HCV Genotype INNO-LiPA 2.0 Assay (reflex to 
Trugene). Gilead reserves the right to use alternate assays for HCV RNA and HCV genotype 
should the above assays become unavailable.
IL28B genotype will be determined by polymerase chain reaction (PCR) amplification of the 
SNP, rs12979860, with sequence specific forward and reverse primers and allele specific 
fluorescently labeled TaqMan MGB probes. Gilead reserves the rights to use an alternate assay 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum β-hCG or Urine β-hCG 
Additional Tests: Urine Drug screen (for amphetamines, cocaine, methadone, opiates) and
hemoglobin A1c (HbA1c)


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6.6.2.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history, including prior HCV treatment history 
(only applicable for treatment experienced subjects), will be collected on all subjects during 
screening.
If treatment experienced, record the duration of the prior treatment and the type of interferon 
and/or ribavirin and, if applicable, protease inhibitor administered
6.6.3.
Complete Physical Examination
A complete physical examination should be in keeping with a complete physical examination 
performed as part a new patient evaluation and must include source documentation of general 
appearance, and the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, 
mouth and tongue; chest (excluding breasts); respiratory; cardiovascular; lymph nodes, 
abdomen; skin, hair, nails; musculoskeletal; neurological. 
6.6.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
6.6.5.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {2202} 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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6.6.6. 
12-Lead ECGs 
Final 
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Subjects will be required to rest in a supine position for 2 5 minutes prior to making a recording. 
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abn01malities. On treatment ECGs should be compared to the subject's 
Day 1 as patt of routine safety monitoring. 
6.6.7. 
Viral RNA Sequencing I Phenotyping Sample 
Plasma samples will be collected at Day 1 and each subsequent visit for viral sequence analysis. 
At any unscheduled visit initiated for the purpose of confnming virologic breakthrough, a viral 
sequence analysis plasma sample must be collected. 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. 
6.6.8. 
PD 
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6.6.9. 
p 
6.6.10. 
Pregnancy Testing 
Final 
Original 
All females of childbearing potential will have mine pregnancy testing evety 4 weeks dming the 
dosing period and 30 days after last dose of study drug. 
If a positive mine pregnancy test is reported, the subject will be asked to retum to the clinic for a 
confnmatoty serum pregnancy test. 
6.6.11. 
Health Related Quality of Life Survey (HRQoL) 
A Health Related Quality of Life survey (HRQoL) SF-36 will be completed by subjects, 
provided a validated translation in the subject's primaty language is available, at Day 1, 
On-Treatment visits at Week 12 and post treatment Weeks 4 and 12 visits (if applicable), and 
Early Tetmination (if applicable). The subject should read the questionnaire by himself/herself 
and write/mark answers directly onto the questionnaire. 
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7.
TOXICITY MANAGEMENT
7.1.
Subject Stopping Rules
Administration of study medication may be discontinued in the event of a clinical or laboratory 
event. The Gilead Medical Monitor must be consulted prior to dose discontinuation of 
SOF/GS-5816 unless the investigator believes that immediate action is warranted to ensure the 
continued safety of the subject.
There is no option for dose reduction of SOF/GS-5816. 
Subjects who meet any of the following laboratory criteria must stop study medication:

Elevation of ALT and/or AST > 5x Baseline/Day 1 or nadir, confirmed by immediate repeat 
testing

Abnormal elevation of ALT > 3x Baseline/Day 1 and total bilirubin > 2x ULN, confirmed by 
immediate repeat testing

Elevation of ALT > 15x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 adverse event or laboratory abnormality assessed (and confirmed by immediate 
repeat testing) as related to SOF/GS-5816


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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 8.5.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
8.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is 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 (e.g., clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 8.1.1 and 8.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia), not the 
laboratory result (i.e., decreased hemoglobin).
8.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (e.g., venipuncture)
8.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale 
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs associated 
with laboratory abnormalities, the event should be graded on the basis of the clinical severity in 
the context of the underlying conditions; this may or may not be in agreement with the grading 
of the laboratory abnormality.
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, all AEs, regardless of cause or relationship, until 
4 weeks after last administration of study drug must be collected/reported to the CRF/eCRF 
database as instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
Any SAEs and deaths that occur after the post treatment follow-up visit and within 30 days of 
the last dose of study drug, regardless of causality, should also be reported. 


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Investigators are not obligated to actively seek SAEs after the protocol defined follow up period, 
however, if the investigator leams of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of study dmgs, he/she should promptly document and 
repmi the event to Gilead DSPH. 
• 
All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Repmiing Process 
• 
Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
infmmation to Gilead DSPH within 24 hours of the investigator's knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE infmmation electronically, i.e., the 
eCRF database is not ftmctioning, record the SAE on the paper serious adverse event 
repmiing fmm and submit as described above. 
-
As soon as it is possible to do so, any SAE repmied via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
-
If an SAE has been repmied via a paper fmm because the eCRF database has been 
locked, no fmther action is necessaty. 
Contact infmmation is as follows: 
Gilead DSPH: 
Gilead Sciences 
Medical Monitor: 
Fax: +44 (0) 208 587 2386 
Email: safety _FC@gilead.com 
Name: 
Phone: 
Mobile: 
Anu Osinusi, MD 
PPD 
PPD 
Fax: 
PPD 
E-mail: 
I"'I"'U 
• 
For fatal or life-threatening events, copies of hospital case repotis, autopsy repotis, and other 
documents are also to be subtnitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the fl·aceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensure the timely completion of accurate safety 
repotis. 
• 
Any medications necessaty for fl·eaflnent of the SAE must be recorded onto the concomitant 
medication section of the subject's CRF/eCRF and the event description section of the SAE 
fmm. 
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8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
8.5.
Special Situations Reports
8.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  


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8.5.2.
Instructions for Reporting Special Situations
8.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report 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 Gilead DSPH using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy. 
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 8.1.1 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. 
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. Refer to Appendix 4 for Pregnancy 
Precautions, Definition for Female of Childbearing Potential, and Contraceptive Requirements.
8.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study drug and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 


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Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/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 primaty objectives of this study are: 
• 
To evaluate the efficacy of treatment with SOF/GS-5816 for 12 weeks in subjects with 
chronic HCV infection as measured by the prop01tion of subjects with SVR12 
• 
To evaluate the safety and tolerability of treatment with SOF/GS-5816 for 12 weeks 
The secondaty objectives of this study are: 
• 
To detennine the prop01tion of subjects with SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24) 
• 
To evaluate the prop01tion of subjects with virologic failure 
Final 
Original 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment 
• 
To evaluate the emergence of viral resistance to SOF and GS-5816 during treatment and after 
cessation of treatment 
The explorat01y objectives of this study are: 
~ 
D 
I 
9.1.2. 
Primary Endpoint 
The primaty efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after cessation of 
therapy) in the Full Analysis Set (F AS) population. 
9.1.3. 
Secondary Endpoint 
Secondary endpoints include the following: 
• 
The prop01tion of subjects with: HCV RNA < LLOQ at 4 and 24 weeks after cessation of 
therapy (SVR4 and SVR24) 
• 
The prop01tion of subjects with HCV RNA < LLOQ on treatment 
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• 
HCV RNA change from Day 1 
• 
The proportion of subjects with virologic failme 
9.1.4. 
Safety Endpoints 
Final 
Original 
The prima1y safety endpoint is any AE leading to pennanent discontinuation of study drug(s). 
9.1.5. 
Other Endpoints of Interest 
PPD 
9.2. 
Analysis Conventions 
All individual subject data will be listed as measmed. All statistical summaries and analyses will 
be perf01med using SAS® software (SAS Institute, Cruy, North Cru·olina, USA). 
The study dmg in this study includes SOF/GS-5816. Last dose of study dmg refers to the last 
dose of SOF/GS-5816 and will be used in the defmition oftreatment-emergent AEs and 
laborat01y abn01malities as well as the efficacy endpoints of SVR at various post treatment time 
points. 
9.2.1. 
Analysis Sets 
9.2.1.1. 
Efficacy 
The analysis set for antiviral activity analyses will be the Full Analysis Set (F AS) which includes 
subjects who were enrolled into the study and received at least one dose of study dmgs. 
9.2.1.2. 
Safety 
The prima1y analysis set for safety analyses will include subjects who received at least one dose 
of study dmg. 
Treatment-emergent data will be analyzed and defmed as data collected from the first dose of 
study dmg through the date of last dose of study dmg plus 30 days. 
9.2.2. 
Data Handling Conventions 
Missing data can have an impact upon the inte1pretation of the trial data. Other than the 
endpoints discussed below, values for missing data will not be imputed. 
For the analysis of post-baseline categorical efficacy endpoints, if a data point is missing and is 
preceded and followed in time by values that are deemed successes, then the missing data point 
will be tenned a success; othe1w ise the data point will be te1med a failme. 
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Any subject with missing data due to premature discontinuation of the study medication will be 
considered a failure at the date of premature discontinuation and all time points subsequent to the 
date of premature discontinuation.  If no HCV RNA values are obtained after the last dose of 
study medication, the subject will be considered a treatment failure for the SVR endpoints. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject received study medication, the subject will be included in a summary of adverse 
events according to the treatment received; otherwise, if the subject is not dosed then they 
will be excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the pre-dose value and the change from pre-dose values.
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.
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).
9.2.3.
Interim Analysis
An interim analysis may be performed as appropriate for Region 2 or a specific country in 
Region 2 after all subjects enrolled in the relevant countries have been followed through 
12 weeks post treatment or discontinued from the study.
9.3.
Demographic Data and Baseline Characteristics
Demographic and baseline characteristics will be summarized using standard descriptive 
methods by region and overall.
Demographic data will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include body mass index, HCV RNA level (log10 IU/mL), 
genotype of HCV infection, IL28B genotype, and additional endpoints as necessary.


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9.4.
Efficacy Analysis
9.4.1.
Primary Analysis
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after discontinuation of 
therapy) in the FAS population. The primary analysis will be performed after all enrolled 
subjects have been followed through post treatment Week 12 or discontinued from study.
In the primary efficacy analysis, the SVR12 rate in Region 1 will be compared to the 
pre-specified performance goal of 85% by using a two-sided exact one-sample binomial test at 
the 0.05 significance level. The null (H0) and alternative (H1) hypotheses used to assess 
superiority of SOF/5816 in Region 1 relative to the performance goal of 85% are:

H0: SVR12 rate = 85%

H1: SVR12 rate ≠ 85%
It is difficult to characterize a single historical control rate for all genotypes included in this 
study given the different standards of care of each genotype (some of which include interferon), 
and the lack of historical data for genotype 4, 5, and 6 participants. Given these difficulties, 
rather than use a historical control rate as the basis for assessing the primary endpoint, a 
pre-specified performance goal is defined as a benchmark against which the efficacy of 
SOF/GS-5816 will be tested. The benchmark sets a high bar of 85%.  The basis for this 
benchmark includes the overall trend toward increasing SVR rates in recent years, the higher 
SVR rates observed with Peg-IFN + RBV treatment in Chinese and other Asian subjects {24218}
compared with other races, and the general appeal of using a fixed clinically relevant threshold 
as a measure of treatment benefit {28509} of SOF/GS-5816.
A confidence interval approach will be used to estimate the SVR12 rates for Region 2 and for the 
overall population (ie, combined Region 1 and Region 2).
The point-estimate with the 2-sided 95% exact confidence interval (CI) using the binomial 
distribution (Clopper-Pearson method) will be constructed for the SVR12 rates by region and the 
overall population, and may be for individual countries as appropriate.
9.4.2.
Secondary Analysis
The proportion of subjects with HCV RNA below the LLOQ over time (including SVR 
endpoints) will be presented by region in tabular and graphical form.
Descriptive summaries and listings will be provided for additional efficacy evaluations of the 
proportion of subjects who experience virologic failure, serum HCV RNA actual values and 
change from baseline, other endpoints of interest including ALT normalization and Health 
Related Quality of Life (HRQoL) endpoints.


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9.5. 
Safety Analysis 
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Safety will be evaluated by assessment of clinicallaborat01y tests, physical examinations, vital 
signs measurements at various time points during the study, and by the documentation of AEs. 
All safety data collected on or after the first dose of study dmg administration up to 30 days after 
the last dose of study dmg will be stunma1·ized by region and overall according to the study dmg 
received. 
9.5.1. 
Extent of Exposure 
A subject's extent of exposure to study dmg will be generated from the study dmg 
administration page of the CRF. Exposure data will be smnmarized by region and overall. 
9.5.2. 
Adverse Events 
Clinical and laborat01y AEs will be coded using the Medical Dictionmy for Regulat01y 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Tetm (HLGT), 
High-Level Tetm (HLT), Prefened Tetm (PT), and Lower-Level Tetm (LLT) will be attached to 
the clinical database. 
Events will be smmnm·ized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any adverse event with onset date of on or after the study dmg 
start date and no later than 30 days after petmanent discontinuation of study drug or any adverse 
event leading to premature discontinuation of study. 
Smnmaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC 
and prefened tetm) will be provided by region and overall: 
• 
All AEs, 
• 
All study dmg-related AEs, 
• 
Combined Grade 2, 3 and 4 AEs, 
• 
Combined Grade 3 and 4 AEs, 
• 
Combined Grade 2, 3 and 4 study dmg-related AEs, 
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
Combined Grade 3 and 4 study drug-related AEs,

All AEs that caused permanent discontinuation from study drug,

All SAEs (including death), and

All study drug-related SAEs
All AEs collected during the course of the study will be presented in data listings.
9.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by region, overall, and study visit along with corresponding change from Day 1.
Graded laboratory abnormalities will be defined using the laboratory toxicity grading defined in 
Appendix 3 of this protocol. The incidence of treatment-emergent laboratory abnormalities, 
defined as values that increase by at least one toxicity grade from Day 1 at any time 
post-baseline up to the date of last dose of study drug plus 30 days will be summarized by region 
and overall.
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.
All laboratory abnormalities will be included in the listings of laboratory data.
9.5.4.
Other Safety Evaluations
Individual data for 12-lead ECG, vital signs measurements will be listed by subject and 
summarized by region and overall by incidence of events/abnormalities or descriptive statistical 
summaries (n, mean, SD, median, Q1, Q3, minimum, and maximum), as appropriate. In 
comparison to pre-treatment (either Screening or pre-dose on Day 1) values, vital signs 
measurements and 12-lead ECG findings will additionally be summarized using pre-determined, 
clinically relevant thresholds. 
9.6.
Sample Size
The sample size justification is based on the Region 1 population. A sample size of 260 subjects 
in Region 1 will provide more than 80% power to detect an improvement of at least 6 percentage 
points in SVR12 rate from the performance goal of 85% by using a two-sided exact one-sample 
binomial test at the significance level of 0.05. 


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In addition, a confidence interval approach will be used to estimate the SVR12 rates for Region 2 
and for the overall population (ie, combined Region 1 and Region 2). With 100 subjects from 
Region 2, and 360 subjects from the overall population, the 2-sided 95% exact CIs for different 
observed SVR12 rates are presented in the table below.
Region
Observed SVR12 rate
2-sided 95% exact CI
Region 2 (n=100)
80% (80 out of 100)
71% - 87%
90% (90 out of 100)
82% - 95%
Overall (n=360)
80% (288 out of 360)
75% - 84%
90% (324 out of 360)
86% - 93%


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. For studies conducted under a United States IND, the investigator 
will ensure that the basic principles of “Good Clinical Practice,” as outlined in 21 CFR 312, 
subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 1998, and 
21 CFR, part 56, 1998, are adhered to.  These standards are consistent with the requirements of 
the European Community Directive 2001/20/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.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.”
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB or IEC. Approval from the IRB or IEC 
must be obtained before starting the study and should be documented in a letter to the 
investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation.
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 


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investigator must utilize an IRB or IEC-approved consent form for documenting written 
informed consent. Each informed consent will be appropriately signed and dated by the subject 
or the subject’s legally authorized representative and the person obtaining consent.
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, (where 
local regulations allow) and an identification code (i.e., not names) should be recorded on any 
form or biological sample submitted to the Sponsor, IRB or IEC, or laboratory. The investigator 
must keep a screening log showing codes, names, and addresses for all subjects screened and for 
all subjects enrolled in the trial.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the Investigator Brochure, this protocol, CRFs, the investigational new drug, and any 
other study information, remain the sole and exclusive property of Gilead Sciences during the 
conduct of the study and thereafter. This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from Gilead Sciences. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain.
10.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB 
or IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data are listed in the Source Data verification Plan, and should include 
sequential notes containing at least the following information for each subject:

subject identification (name, date of birth, gender);

documentation that subject meets eligibility criteria, i.e., history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

participation in trial (including trial number);

trial discussed and date of informed consent;

dates of all visits;


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
documentation that protocol specific procedures were performed;

results of efficacy parameters, as required by the protocol;

start and end date (including dose regimen) of trial medication (preferably drug dispensing 
and return should be documented as well);

record of all adverse events and other safety parameters (start and end date, and preferably 
including causality and intensity);

concomitant medication (including start and end date, dose if relevant; dose changes should 
be motivated);

date of trial completion and reason for early discontinuation, if applicable.
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (i.e., United States, Europe, or Japan) 
and until there are no pending or contemplated marketing applications in an ICH region; or, if no 
application is filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and regulatory authorities have been notified. Investigators may be 
required to retain documents longer if required by applicable regulatory requirements, by local 
regulations, or by an agreement with Gilead Sciences. The investigator must notify 
Gilead Sciences before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead Sciences must be notified in advance.
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences 
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples at the conclusion of this study may be retained in storage by the Sponsor for 
a period up to 10 years for purposes of this study.
10.1.6.
Electronic Case Report Forms (eCRF)
For each subject enrolled, an eCRF must be completed and signed by the principal investigator 
or sub-investigator (as appropriate) within a reasonable time period after data collection. This 
also applies to records for those subjects who fail to complete the study (even during a 
pre-randomization screening period if an eCRF was initiated). If a subject withdraws from the 
study, the reason must be noted on the eCRF. If a subject is withdrawn from the study because of 
a treatment-limiting adverse event, thorough efforts should be made to clearly document the 
outcome.


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10.1.7.
Drug Accountability
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational medicinal product. This includes acknowledgment of 
receipt of each shipment of study product (quantity and condition), subject dispensing records,
and returned or destroyed study product. Dispensing records will document quantities received 
from Gilead Sciences and quantities dispensed to subjects, including lot number, date dispensed, 
subject identifier number, subject initials, and the initials of the person dispensing the 
medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRBs or IECs, 
or to regulatory authority or health authority inspectors.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB or IEC 
in accordance with local requirements. Approval must be obtained before changes can be 
implemented.
10.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency(ies). 
Gilead Sciences will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may 
be prepared in certain cases.


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After conclusion of the study and without prior written approval from Gilead Sciences, 
investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

the results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead Sciences in an abstract, manuscript, or presentation form; or

the study has been completed at all study sites for at least 2 years.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 10.1.4).
The investigator will submit any proposed publication or presentation along with the respective 
scientific journal or presentation forum at least 30 days before submission of the publication or 
presentation. The investigator will comply with Gilead Sciences’ request to delete references to 
its confidential information (other than the study results) in any paper or presentation and agrees 
to withhold publication or presentation for an additional 60 days in order to obtain patent 
protection if deemed necessary.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the CRFs for consistency.
The monitor is responsible for routine review of the CRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences may conduct inspections or audits 
of the clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.
10.3.3.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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11.
REFERENCES
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Andrews E, Damle BD, Fang A, Foster G, Crownover P, LaBadie R, et al. 
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Sievert W, Altraif I, Razavi HA, Abdo A, Ahmed EA, Alomair A, et al. A 
systematic review of hepatitis C virus epidemiology in Asia, Australia and Egypt. 
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Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing 
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Final
Gilead Sciences, Inc.
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12.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table Study Visits
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


SOF/GS-5816 FDC 
Protocol GS-US-342-1518 
Final 
Gilead Sciences. lnc. 
Original 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3, M ulticenter, Open-Label Study to Investigate the Efficacy and Safety of 
Sofosbuvir/GS-5816 Fixed Dose Combination for 12 Weeks in Subjects with Chronic HCV 
GS-US-342-1518, Original Protocol, 16 January 2015 
This protocol has been approved by Gilead Sciences, [nc. The following signature documents 
this approval. 
Anu Osinusi, MD (Printed) 
Medical Monitor 
Date 
PPD 
Signature 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staffto conduct thjs 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. 
1 wi II provide all study personnel under my supervision copjes of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
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Appendix 2.
Study Procedures Table
Study Visits
Screening
Day 1
On-treatment Study Week (± 3 days)
Post treatment 
Study Week (± 5 days)i
1
2
4
6
8
10
12/ET
4
12
24
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
Height
X
Weight
X
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGc
X
X
X
X
AEs 
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention 
Counseling
X
X
X
Health Related Quality of 
Life Survey, SF-36
X
X
X
X
Review of Study 
Medication Complianceg
X
X
X
X
X
X
X
Study Drug Dispensinga
X
X
X


SOF/GS-5816 FDC 
Protocol GS-US-342-1518 
Gilead Sciences, Inc. 
Laboratory Assessments 
Hematology, Chemistry 
Coagulation Tests 
HCVRNA 
Viral RNA Sequencing I 
Phenotyping Sample! 
Pregnancy Testingd 
Urinalysis, 
Urine Drug Screen 
HCV Genotyping, IL28B 
HCV, HIV, HBV Serology 
HbA 1 c, Fibrotest® 
FPD 
Pharmacogenomic Samplee 
Imaging for Hepatocellular 
Carcinoma (Heel 
Screening 
Dayl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Day 1 assessments must be performed prior to dosing. 
1 
X 
X 
X 
On-treatment Study Week(± 3 days) 
I 
2 
I 
4 I 
6 I 
8 I 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
b 
Vital signs include resting blood pressure, pulse, respiratory rate, and temperature. 
10 
I 12/ET 
X 
X 
X 
X 
X 
X 
X 
X 
Final 
Original 
Post treatment 
Study Week(± 5 days)i 
4 I 12 I 24 
X 
X 
X 
X 
X 
X 
X 
X 
c 
Subjects will be required to rest in a supine position for 2: 5 minutes prior to making a recording. The investigator (or qualified designee) should review the ECG traces 
recorded in real time for gross abnormalities. 
d 
Females of childbearing potential only. Serum P-hCG pregnancy test performed at screening and confirmation of positive urine pregnancy test. All females of childbearing 
potential will have urine pregnancy testing every 4 weeks during the dosing period. If urine is positive, confirm immediately with serum P-hCG. 
e 
Only for subjects who have provided consent for this sample and testing. This sample can be obtained at a subsequent visit if not obtained at Day 1. 
CONFIDENTIAL 
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I 


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Gilead Sciences, Inc. 
Final 
Original 
f 
If presence of cirrhosis is determined, then appropriate diagnostic imaging (e.g., cr or ultrasound) should be performed to exclude the presence ofhepatocellular carcinoma 
(HCC) 
g 
Subjects must be instructed to bring back all medication in the original container at every post-Day 1 study visit through the end of treatment. Study medication will be 
reconciled at every post-Day 1 visit by the investigator in order to monitor the subject's adherence with the medication regimen. 
h 
PPD 
All subjects will complete Post treatment Week 4. Subjects with HCV RNA < LLOQ at the post treatment Week 4 and/or Week 12 visits will complete the subsequent post 
treatment visits, unless viral relapse is determined. 
Plasma samples will be collected for possible viral resistance and other Virology studies 
CONFIDENTIAL 
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Gilead Sciences, Inc.
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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18June2012
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR 
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR 
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV positive or negative)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Infant, 2 – 7 Days
1250 to 1500/mm3
1.25 to 1.50 GI/L
1000 to 1250/mm3
1.00 to < 1.25 GI/L
750 to 1000/mm3
0.75 to < 1.00 GI/L
750/mm3
< 0.75 GI/L
Infant, 1 Day
4000 to 5000/mm3
4.00 to 5.00 GI/L
3000 to 4000/mm3
3.00 to < 4.00 GI/L
1500 to 3000/mm3
1.50 to < 3.00 GI/L
1500/mm3
< 1.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L


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


SOF/GS-5816 FDC
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Final
Gilead Sciences, Inc.
Original
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
146  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 78
16 January 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4  mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*) 
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 79
16 January 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63  to LLN mmol/L
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.14 mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 80
16 January 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol/L to LLN
57 to 87 μmol/L
27 to 57 μmol/L
27 μmol/L
Creatinine 
1.50 to 2.00 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol/L
177 to 265 μmol/L
265 to 530 μmol/L
530 μmol/L
Bicarbonate
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L
LDL
(Fasting)
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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16 January 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 82
16 January 2015
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA 
Notes: 
Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to Dipstick 
Hematuria.
With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for the 
AE.


SOF/GS-5816 FDC
Protocol GS-US-342-1518
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


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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16 January 2015
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
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
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) 


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
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
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


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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16 January 2015
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)


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
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16 January 2015
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Thinning detectable by 
study participant or  
caregiver (for disabled 
adults)
Thinning or patchy hair loss 
detectable by health care 
provider
Complete hair loss
NA
Cutaneous Reaction – Rash
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or morbilliform 
rash with vesicles or limited 
number of bullae OR 
Superficial ulcerations of 
mucous membrane limited to 
one site
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson syndrome 
OR Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or generalized
NA
NA
Pruritis (itching – no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or 
minimal interference with 
usual social & functional 
activities
Itching causing greater than 
minimal interference with 
usual social & functional 
activities
Itching causing inability to 
perform usual social & 
functional activities 
NA


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
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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


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids)
Life-threatening consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(eg, hypotensive shock)


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Protocol GS-US-342-1518
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Original
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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 


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 91
16 January 2015
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate 
for the setting 
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting 
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or
other neurologic function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic self-
care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual 
social & functional activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 92
16 January 2015
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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)
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


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 93
16 January 2015
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


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 94
16 January 2015
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]


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 95
16 January 2015
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


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 96
16 January 2015
ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, back 
of neck, breasts, 
abdomen)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current meds to regain glucose 
control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences 
(eg, ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, myxedema coma)
Lipoatrophy (eg, fat loss 
from the face, extremities, 
buttocks)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 97
16 January 2015
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


SOF/GS-5816 FDC
Protocol GS-US-342-1518
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 98
16 January 2015
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1.
Background
Non-clinical toxicity studies of SOF demonstrated no adverse effects on fertility or embryo-fetal 
development. Clinical data available at this time suggest that this drug does not have a drug-drug 
interaction (DDI) with hormones used for contraception.
Non-clinical toxicity studies of GS-5816 demonstrated no effects on fertility or embryo-fetal 
development. Preliminary clinical pharmacological data available at this time suggest that 
GS-5816 does not have a drug-drug interaction (DDI) with hormones used for contraception. 
Therefore SOF/GS-5816 can be administered with hormonal contraceptives. 
However, the risks of treatment with SOF/GS-5816 during pregnancy in human have not been 
evaluated. Please refer to the latest version of the investigator’s brochure for additional 
information. 
2. Definition of Female of Childbearing Potential and Contraceptive Requirements for 
Female Subjects (and their male partners)
Women ≥ 54 years of age with cessation for ≥ 12 months of previously occurring menses, or 
women of any age who have had a hysterectomy, or have had both ovaries removed, or have had 
medically documented ovarian failure will be considered to be of non-childbearing potential. 
Women < 54 years of age (including those with amenorrhea of any duration) who have not had a 
hysterectomy, and have not had both ovaries removed, and have not had medically documented 
ovarian failure will be considered to be of childbearing potential. 
Women of childbearing potential must have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test on the Day 1 visit prior to enrollment. They must also agree to one 
of the following from 3 weeks prior to Day 1 until 30 days after the last dose of SOF/GS-5816.

Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) is not permitted.
Or

Consistent and correct use of 1 of the following methods of birth control listed below, in 
addition to a male partner who correctly uses a condom from the date of Screening until 
30 days after the last dose of SOF/GS-5816: 
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent (where 
available)


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Gilead Sciences, Inc.
Original
CONFIDENTIAL
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16 January 2015
tubal sterilization
vasectomy in male partner
hormone-containing contraceptive:
■
implants of levonorgestrel
■
injectable progesterone
■
oral contraceptives (either combined or progesterone only)
■
contraceptive vaginal ring 
■
transdermal contraceptive patch
3. Contraceptive Requirements for Male Subjects (and their female partners)
All male study participants must agree to consistently and correctly use a condom from Baseline 
until 90 days after the last dose of SOF/GS-5816. 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 90 days after the last dose of SOF/GS-5816.
Male subjects must agree to refrain from sperm donation for at least 90 days after the last dose of 
SOF/GS-5816.
4. Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days (or 90 days for partners of male subjects) of 
the last dose of SOF/GS-5816. Subjects who become pregnant or who suspect that they are 
pregnant must report the information to the investigator and discontinue study drug immediately. 
Subjects whose partner has become pregnant or suspects she is pregnant must report the 
information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 8.5.2.1.