Clinical trial NCT01958281
Conditions: HCV Infection
Sponsor: Gilead Sciences
Start date: 2013-10-07; Completion date: 2017-10-19
Enrollment: 38 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objectives of this study are to evaluate the safety and efficacy of sofosbuvir (SOF) plus ribavirin (RBV) for 24 weeks and ledipasvir/sofosbuvir (LDV/SOF) for 12 weeks, and to evaluate the steady state pharmacokinetics (PK) of SOF and its metabolites and LDV in participants with genotype (GT) 1, 3, or 4 hepatitis C virus (HCV) infection who have chronic renal insufficiency (impaired kidney function).

Detailed description:

Arms: arm 1: Participants with genotype 1 or 3 HCV infection will receive SOF 200 mg (2 × 100 mg tablets) plus RBV once daily for 24 weeks. arm 2: Participants with genotype 1 or 3 HCV infection will receive SOF 400 mg (4 × 100 mg tablets or 1 × 400 mg tablet) plus RBV once daily for 24 weeks. arm 3: Participants with genotype 1 or 4 HCV infection will receive LDV/SOF once daily for 12 weeks.
Interventions: intervention 1: SOF intervention 2: RBV intervention 3: LDV/SOF
Intervention descriptions: intervention 1: Tablet(s) administered orally once daily intervention 2: 200 mg tablet administered orally once daily intervention 3: 90/400 mg fixed-dose combination (FDC) tablet administered orally once daily

Protocol documents:
SAP_006.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2b, Open-Label Study of 200 mg or 400 mg 
Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 and 
Ledipasvir/Sofosbuvir (LDV/SOF) Fixed-Dose Combination 
(FDC) Tablet for 12 weeks in Genotype 1 or 4 HCV-Infected 
Subjects with Renal Insufficiency
Name of Test Drug:
Sofosbuvir, Ledipasvir/Sofosbuvir Fixed-Dose Combination
Study Number:
GS-US-334-0154 (Cohort 3)
Protocol Version (Date):
Original:   
11 July 2013
Amendment 1: 05 September 2013
Amendment 2: 20 February 2014
Amendment 3: 23 February 2015
Amendment 4: 23 April 2015
Analysis Type:
SVR12 and Final Analysis for Cohort 3
Analysis Plan Version:
Version 1
Analysis Plan Date:
26 July 2017
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD


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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN..............................................................................................................................1
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF TABLES.........................................................................................................................................................3
LIST OF ABBREVIATIONS........................................................................................................................................4
PHARMACOKINETIC ABBREVIATIONS................................................................................................................6
1.
INTRODUCTION ................................................................................................................................................7
1.1.
Study Objectives ......................................................................................................................................7
1.2.
Study Design............................................................................................................................................8
1.3.
Sample Size and Power............................................................................................................................8
2.
TYPE OF PLANNED ANALYSIS ......................................................................................................................9
2.1.
Interim Analyses ......................................................................................................................................9
2.1.1.
SVR12 Analysis .....................................................................................................................9
2.2.
Final Analysis ..........................................................................................................................................9
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................10
3.1.
Analysis Sets..........................................................................................................................................10
3.1.1.
All Enrolled Analysis Set.....................................................................................................10
3.1.2.
Full Analysis Set ..................................................................................................................10
3.1.3.
Safety Analysis Set...............................................................................................................10
3.1.4.
Pharmacokinetic Analysis Set..............................................................................................10
3.2.
Subject Grouping ...................................................................................................................................10
3.3.
Strata and Covariates..............................................................................................................................11
3.4.
Examination of Subject Subgroups........................................................................................................11
3.5.
Multiple Comparisons............................................................................................................................11
3.6.
Missing Data and Outliers......................................................................................................................11
3.6.1.
Missing Data ........................................................................................................................11
3.6.2.
Outliers.................................................................................................................................12
3.7.
Data Handling Conventions and Transformations .................................................................................12
3.8.
Analysis Visit Windows.........................................................................................................................14
3.8.1.
Definition of Study Day .......................................................................................................14
3.8.2.
Analysis Visit Windows.......................................................................................................14
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window................................................................................................................................16
4.
SUBJECT DISPOSITION ..................................................................................................................................17
4.1.
Subject Enrollment and Disposition.......................................................................................................17
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................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 and Baseline Characteristics ..........................................................................................20
5.2.
Medical History......................................................................................................................................21
6.
EFFICACY ANALYSES ...................................................................................................................................22
6.1.
Primary Efficacy Endpoint.....................................................................................................................22
6.2.
Secondary Efficacy Endpoints ...............................................................................................................22


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6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................22
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................23
7.
SAFETY ANALYSES........................................................................................................................................24
7.1.
Adverse Events and Deaths....................................................................................................................24
7.1.1.
Adverse Event Dictionary ....................................................................................................24
7.1.2.
Adverse Event Severity........................................................................................................24
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................24
7.1.4.
Serious Adverse Events........................................................................................................24
7.1.5.
Treatment-Emergent Adverse Events...................................................................................25
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................25
7.2.
Laboratory Evaluations ..........................................................................................................................26
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................27
7.2.2.
Graded Laboratory Values ...................................................................................................27
7.3.
Prior and Concomitant Medications.......................................................................................................28
7.4.
Body Weight, Height, BMI and Vital Signs...........................................................................................29
7.5.
Electrocardiogram (ECG) Results..........................................................................................................29
7.6.
Echocardiogram Results.........................................................................................................................30
7.7.
Other Safety Measures ...........................................................................................................................30
7.8.
Changes From Protocol-Specified Safety Analyses...............................................................................30
8.
PHARMACOKINETIC (PK) ANALYSES........................................................................................................31
9.
SOFTWARE.......................................................................................................................................................33
10.
SAP REVISION..................................................................................................................................................34
11.
APPENDICES ....................................................................................................................................................35
Appendix 1.
Schedule of Assesments for Cohort 3.....................................................................................36
Appendix 2.
Tables, Figures, and Listings..................................................................................................39
LIST OF TABLES
Table 3-1.
Analysis Windows for On-treatment HCV RNA, Vital Signs and Safety Laboratory 
Data ........................................................................................................................................15
Table 3-2.
Analysis Windows for On-treatment ECG Data.....................................................................15
Table 3-3.
Analysis Windows for Posttreatment HCV RNA, Vital Signs, Safety Laboratory 
and ECG Data.........................................................................................................................15


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CI
confidence interval
CK
creatine kinase
CRF
case report form
CSR
clinical study report
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
ET
early termination
FAS
Full Analysis Set
FU
follow-up
HCV
hepatitis C virus
HLGT
high-level group term
HLT
high-level term
IBW
ideal body weight
INR
international normalized ratio 
IL28B
IL28B gene
LDV
ledipasvir, GS-5885
LLOQ
lower limit of quantitation
LLT
lower level term
MedDRA
Medical Dictionary for Regulatory Activities
nadir
the lowest point
PK
pharmacokinetic
PT
preferred term
Q1, Q3
first quartile, third quartile
RNA
ribonucleic acid
SAE
serious adverse event
SAP
SD
statistical analysis plan
standard deviation
SOC
system organ class
SOF
sofosbuvir, GS-7977
SVR
sustained virologic response
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings


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TND
target not detected
ULN
upper limit of normal
VF
virologic failure
WHO
World Health Organization


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PHARMACOKINETIC ABBREVIATIONS
AUClast
area under the concentration versus time curve from time zero to the last quantifiable concentration
AUCtau
area under the concentration versus time curve over the dosing interval
Clast
last observed quantifiable concentration of the drug 
Cmax
maximum observed concentration of drug 
Ctau
observed drug concentration at the end of the dosing interval
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural log of 2 
by the terminal elimination rate constant (z)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination phase 
of the concentration of drug versus time curve


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INTRODUCTION 
Version 1 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Coh01i 3 from Study GS-US-334-0154. A separate SAP for Coh01is 1 and 2 was fmalized on 
05 Febmmy 2016, and the CSR for Coh01is 1 and 2 was approved on 26 May 2016. The cunent 
SAP is based on the study protocol Amendment 4 dated 23 April2015 and the electronic case 
rep01i fonn ( eCRF), and will only present the plan for statistical analyses of Coh01i 3 of this 
study. The SAP will be fmalized before SVR12 analysis database finalization. Any changes 
made after the fmalization of the SAP will be documented in the CSR. 
1.1. 
Study Objectives 
The prima1y objective of coh01i 3 in this study m·e as follows: 
• 
To evaluate the safety ofLDV/SOF for 12 weeks as assessed by review of the accumulated 
safety data 
• 
To evaluate the efficacy ofLDV/SOF for 12 weeks measured by the prop01iion of subjects 
with renal insufficiency who have achieved a sustained viral response 12 weeks after 
treatment discontinuation (SVR12) 
• 
To evaluate the steady state phmmacokinetics ofSOF and its metabolites and LDV upon 
dosing LDV /SOF in subjects with renal insufficiency 
The secondmy objectives of cohort 3 in this study are as follows: 
• 
To evaluate the prop01iion of subjects with renal insufficiency who attain SVR at 4 and 
24 weeks after discontinuation of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of plasma HCV RNA during and after treatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV during and after treatment 
discontinuation 
The explorat01y objective of coh01i 3 in this study is: 
PPO 
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1.2.
Study Design
This is a multicenter, open-label study cohort that will evaluate the safety, tolerability, and 
antiviral efficacy of LDV/ SOF in subjects with chronic renal insufficiency and genotype 1 or 
4 HCV infection, including subjects with compensated cirrhosis.
Approximately 35subjects with severe renal insufficiency will be enrolled as below.

Cohort 1: 10 subjects will receive SOF 200 mg + RBV 200 mg once daily for 24 weeks.

Cohort 2: Following review of safety, efficacy and pharmacokinetic (PK) data through post-
treatment Week 4 of Cohort 1, 10 additional subjects will receive SOF 400mg + RBV 200mg 
once daily for 24 weeks.

Cohort 3: Following review of safety and available PK data through Week 12 of Cohort 2, 15 
additional subjects will receive LDV/SOF once daily for 12 weeks.
The total time to complete all study visits in Cohort 3 is approximately 42 weeks including the 
following periods:

Up to 42-day (6-week) screening period

12-week treatment period

Up to 24-week posttreatment period
The schedule of assessments is provided as an appendix to the SAP (Appendix 1).
1.3.
Sample Size and Power
Due to the exploratory nature of this study, no formal power or sample size calculations were 
performed to determine treatment group size. The total sample size of 35 is largely based on 
feasibility.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analyses
2.1.1.
SVR12 Analysis
The analysis for the primary endpoint SVR12 will occur after all subjects complete the 
posttreatment Week 12 visit or prematurely discontinue from the study. All safety and efficacy
data through the posttreatment Week 12 visit will be cleaned, finalized and included in the 
analysis. 
2.2.
Final Analysis
After all subjects have completed the study or early terminated the study, outstanding data 
queries have been resolved or adjudicated as unresolvable, and the data have 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.
By-subject listings will be presented for all subjects in the All Enrolled Analysis Set and sorted 
by subject ID number, visit date, and time (if applicable). Data collected on log forms, such as 
AEs, will be presented in chronological order within the subject. Age, sex at birth, race, and 
ethnicity will be included in the listings, as space permits.
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 analysis set will be identified and included as a subtitle of each 
table, figure, and listing.
For each analysis set, the number and percentage of subjects eligible for inclusion, as well as the 
number and percentage of subjects who were excluded (if any), will be summarized.
3.1.1.
All Enrolled Analysis Set
All Enrolled Analysis Set includes all subjects who received a study subject identification 
number in the study after screening.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all subjects who were enrolled and took at least 1 dose of 
study drug. The study drug for Cohort 3 in this study is LDV/SOF. This is the primary analysis 
set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug. This is the 
primary analysis set for safety analyses.
3.1.4.
Pharmacokinetic Analysis Set
The Pharmacokinetic (PK) Analysis Set will include all enrolled subjects who took at least 
1 dose of study drug and have at least 1 nonmissing postdose concentration value reported by the 
PK laboratory. This is the primary analysis set for all PK analyses.
3.2.
Subject Grouping
In Cohort 3 of this study, there is only 1 treatment, which is LDV/SOF once daily for 12 weeks. 
Therefore, for all analysis sets, there will be only 1 group.


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3.3.
Strata and Covariates
This study does not use a stratified randomization schedule when enrolling subjects. 
No covariates will be included in efficacy and safety analyses.
3.4.
Examination of Subject Subgroups
There are no prespecified subject subgroupings for efficacy analyses.
3.5.
Multiple Comparisons
Adjustments for multiplicity will not be made, because no formal statistical testing will be 
performed in this study.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
For missing last dosing date of study drug, imputation rules are described in Section 4.2.1. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.5.2, and for
prior and concomitant medications in Section 7.3.
For analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have the 
missing data imputed. Missing on-treatment HCV RNA will have the missing data imputed up to 
the time of the last dose (for on-treatment displays). If the study day associated with the last 
dosing date is greater than or equal to the lower bound of a visit window, and the value at the 
visit is missing, the value will be imputed. If the study day associated with the last dosing date is 
less than the lower bound of a visit window then the on-treatment value at that visit will remain 
missing. 
If an HCV RNA data point is missing and is preceded and followed in time by values that are 
“< lower limit of quantification (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 for subjects who have no further HCV RNA measurements 
collected will be counted as a success for SVR24 due to the high correlation between these 2 
endpoints.


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For the analyses of continuous HCV RNA efficacy data, when and only when a missing HCV 
RNA value is imputed as < LLOQ TND or < LLOQ detected according to the imputation rule 
described above, the corresponding continuous value will be imputed to LLOQ – 1 IU/mL. No 
other imputation will be performed for continuous HCV RNA data.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
In general, age (in years) on the date of the first dose of study drug will be used for analyses and 
presentation in listings. If an enrolled subject was not dosed with any study drug, the enrollment 
date will be used instead of the first dosing date of study drug. For screen failures, the date the 
informed consent was signed will be used for age calculation. If only the birth year is collected 
on the CRF, “01 July” will be used for the unknown birth day and month for the purpose of age 
calculation. If only birth year and month are collected, “01” will be used for the unknown birth 
day.
Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ)
or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, 
etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to 
calculate summary statistics.

A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “> x” (where x is considered the LOQ). Values with decimal 
points will follow the same logic as above.

The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤ x” or “≥ x” (where x is considered the LOQ).
The COBAS®AmpliPrep/COBAS® TaqMan® HCV Quantitative Test v2.0 was used to determine 
HCV RNA results in this study. The LLOQ of the assay is 15 IU/mL.
When the calculated HCV RNA IU/mL is within the linear range of the assay, 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.


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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 “target not detected” will also 
be set to LLOQ – 1 IU/mL.
For selected analyses, HCV RNA data (IU/mL) will be transformed to the logarithmic (base 10) 
scale (log10 IU/mL).
Natural logarithm transformation will be used for plasma/blood concentrations and analysis of 
PK parameters. Plasma concentration values that are below the limit of quantitation (BLQ) will 
be presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated as 
0 at predose time points, and one-half the value of the limit of quantitation (LOQ) at postbaseline 
time points for determination of summary and order statistics.
The following conventions will be used for the presentation of summary and order statistics:

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ.”

If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”

If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”

If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
Exposure parameters selected for statistical analysis will be natural log-transformed. PK 
parameters that are BLQ will be imputed as one-half LOQ before log transformation or statistical 
model fitting.


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3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the first dosing date of study drug and derived as follows:

For postdose study days: Assessment Date – First Dosing Date + 1

For days prior to the first dose: Assessment Date – First Dosing Date
Therefore, Study Day 1 is the day of first dose of study drug administration.
The last dose date for an individual study drug will be the end date on study drug administration 
eCRF for the record where the “subject permanently discontinued” flag is ‘Yes’. 
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).
3.8.2.
Analysis Visit Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows. Analysis windows are defined for HCV 
RNA, vital signs, safety laboratory, and electrocardiogram (ECG).
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, safety laboratory and ECG data collected up to the last dose date 
+ 2 days are considered to be on-treatment data and HCV RNA, vital signs, safety laboratory and 
ECG data collected after the last dose date + 2 days are considered posttreatment data. 
The analysis windows for on-treatment HCV RNA, vital signs, and safety laboratory data are 
provided in Table 3-1. The analysis windows for on-treatment ECG data are provided in 
Table 3-2.


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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
Table 3-2.
Analysis Windows for On-treatment ECG Data
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
28
2
42
Week 8
56
43
70
Week 12
84
71
≥ 85
HCV RNA, vital signs, safety laboratory and ECG data collected after the last dose date + 2 days 
will be assigned to the posttreatment follow-up (FU) visits. Visit windows will be calculated 
from the last dose date (ie, FU Day = collection date minus the last dose date) as shown in 
Table 3-3. 
Table 3-3.
Analysis Windows for Posttreatment HCV RNA, Vital Signs, Safety 
Laboratory and ECG Data
Nominal FU a Visit
HCV RNA
Vital Signs, Safety Laboratory 
and ECG Data b
Nominal 
FU Day
Lower Limit
Upper Limit
Nominal 
FU Day
Lower Limit
Upper Limit
FU-4
28
21
69
28
3
30
FU-12
84
70
146
NA
FU-24
168
147
190
NA
a
FU-x visit = posttreatment Week-x follow-up visit. 
b
Vital signs and safety laboratory data will be summarized only for the FU-4 visit (up to 30 days after last dose).


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3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
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, continuous measurements exist in an analysis window, records 
will be chosen based on the following rules if a single value is needed:

In general, the baseline value will be the last nonmissing value on or prior to the first dosing 
date of study drug, unless specified differently. If multiple measurements occur on the same 
day, the last nonmissing value prior to the time of first dosing of study drug will be 
considered as the baseline value. If these multiple measurements occur at the same time or 
the time is not available, the average of these measurements (for continuous data) will be 
considered the baseline value.

For postbaseline values:

The record closest to the nominal day for that visit 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 measurements 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, the value with the lowest severity will be selected (eg, normal will be selected over 
abnormal for safety ECG findings).

For postbaseline visits, if there are multiple records with the same time or no time recorded 
on the same day, the value with the worst severity within the window will be selected (eg, 
abnormal will be selected over normal for safety ECG findings).


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided for each country and for each investigator 
within a country, and overall. The summary will present the number and percentage of subjects
enrolled. The denominator for the percentage calculation will be the total number of subjects in 
the Safety Analysis Set.
A summary of subject disposition will be provided. This summary will present the number of 
subjects screened, the number of subjects not enrolled, the number of subjects enrolled, and the 
number of subjects in each of the categories listed below:

Safety Analysis Set

FAS

PK Analysis Set

Completed study drug

Did not complete study drug with reasons for premature discontinuation of study drug

Completed study

Did not complete the study with reasons for premature discontinuation of study
For the status of study drug and study completion and reasons for premature discontinuation, the 
number and percentage of subjects in each category will be provided. The denominator for the 
percentage calculation will be the total number of subjects in the Safety Analysis Set. Among 
subjects who completed study drug and who discontinued study drug, the number and percentage 
of subjects will be summarized for the following:

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 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 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, a flowchart will be provided to depict the disposition.
The following by-subject listings will be provided by subject identification (ID) number in 
ascending order to support the above summary tables:

Subject disposition

Reasons for screen failure (will be provided by screening ID number in ascending order)

Lot number and kit ID
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence to study drug 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 dosing date minus first dosing 
date plus 1, regardless of any temporary interruptions in study drug administration, and will be 
expressed in weeks using up to 1 decimal place (eg, 4.5 weeks). If the last study drug dosing date 
is missing, the latest date among the study drug end date, clinical visit date, laboratory sample 
collection date, and vital signs assessment date that occurred during the on-treatment period will 
be used.
The total duration of exposure to study drug will be summarized using descriptive statistics and 
using the number (ie, cumulative counts) and percentage of subjects exposed through the 
following time periods: Baseline (Day 1), Week 1 (Day 7), Week 2 (Day 14), Week 4 (Day 28), 
Week 8 (Day 56), and Week 12 (Day 84).
Summaries will be provided for the Safety Analysis Set.
No formal statistical testing is planned.
4.2.2.
Adherence to Study Drug
The presumed total number of doses 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 Doses Dispensed
No. of Doses Returned

















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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.
The level of prescribed adherence to study drug will be determined by the total amount of study 
drug administered relative to the total amount of study drug specified by the protocol for a 
subject who completes treatment in the study.
The level of prescribed adherence will be expressed as a percentage using the following formula:
Total Amount of Study Drug Administered
Prescribed Adherence (%) =
 x 100
Total Amount of Study Drug Specified by Protocol






Note: If calculated adherence is greater than 100%, the result will be set to 100%.
In this study, the total amount of LDV/SOF prescribed for 12 weeks of treatment would require 
84 doses. 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.
Descriptive statistics for the level of prescribed adherence with the number and percentage of 
subjects belonging to adherence categories (eg, < 80%, ≥ 80 to < 90%, ≥ 90%) will be provided 
for the Safety Analysis Set. 
No formal statistical testing is planned.
A by-subject listing of study drug administration and drug accountability will be provided 
separately by subject ID number (in ascending order) and visit (in chronological order).
4.3.
Protocol Deviations 
A summary of majoy protocol deviations will be provided by the Clinical Operations group for 
subjects in the Safety Analysis Set.


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5.
BASELINE CHARACTERISTICS  
5.1.
Demographics and Baseline Characteristics
The following subject demographic and baseline characteristics will be summarized by treatment 
cohort and overall using descriptive statistics (n, mean, standard deviation, median, Q1, Q3, 
minimum and maximum) for continuous data and by the number and percent of subjects for 
categorical data. Variables to be summarized include the following:

age (on date of first dose of any study drug) as a continuous variable

sex at birth (male, female)

race 

ethnicity (hispanic or latino, not hispanic or latino)

body weight (in kg)

height (in cm)

body mass index (BMI; in kg/m2) as a continuous variable and as categories (< 30 kg/m2, 
≥30 kg/m2) 

HCV genotype

cirrhosis (presence, absence)

IL28B (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 
(< 6 log10 IU/mL, ≥ 6 log10 IU/mL)

baseline ALT as a continuous variable and as categories categories (≤1.5 ULN, 
> 1.5 ULN)

estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault equation

prior HCV treatment experience (treatment naive, treatment experienced)

prior HCV treatment response for treatment-experienced subjects

most recent HCV treatment regimen  for treatment-experienced subjects

fibrotest score as a continuous variable and fibrotest stage as a categorical variable


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Age is calculated as the integer of age in years at first dose of study regimen. 
eGFR will be calculated by the Cockcroft-Gault method using ideal body weight (IBW): 
eGFRCG (mL/min) = [(140 – age (yrs)) × IBW (kg) × (0.85 if female)] / (serum creatinine 
(mg/dL) × 72). IBW is estimated by the following equations:

Males: IBW (kg) = 50 kg + 2.3 kg for each inch over 5 feet

Females: IBW (kg) = 45.5 kg + 2.3 kg for each inch over 5 feet
The summary of demographic data and baseline characteristics will be provided for the Safety 
Analysis Set. 
A by-subject demographic and baseline characteristics listing will be provided by subject 
ID number in ascending order.
A data listing of cirrhosis determination will be provided. A data listing will also be provided for 
subjects’ prior HCV treatment and response.
5.2.
Medical History
General medical history data will be collected at screening and listed only. General medical 
history data will not be coded.


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint 
The primary efficacy endpoint is SVR 12 weeks after treatment discontinuation (SVR12) defined 
as HCV RNA < LLOQ (ie, < 15 IU/mL) 12 weeks after study drug cessation for the FAS. The 
COBAS® AmpliPrep/COBAS® TaqMan® HCV Test will be used to determine HCV RNA 
results in this study.
The 2-sided 95% exact confidence interval (CI) based on Clopper-Pearson method will be 
provided for the SVR12 rate. 
6.2.
Secondary Efficacy Endpoints 
6.2.1.
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints include the following:

The proportion of subjects who attain SVR at 4 and 24 weeks after treatment discontinuation, 
defined as HCV RNA < LLOQ (ie, < 15 IU/mL) 4 and 24 weeks after stopping treatment 
(SVR 4 and SVR 24)

The proportion of subjects with HCV RNA below LLOQ (ie, < 15 IU/mL) by study visit

HCV RNA (log10 IU/mL) and change from baseline in HCV RNA (log10 IU/mL) through end 
of treatment

The proportion 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 log10 IU/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 
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6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
For analyses of HCV RNA < LLOQ (ie, < 15 IU/mL) 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 categorical imputation rules described in Section 3.6.1. The 2-sided 95% exact confidence 
interval based on Clopper-Pearson method will be provided for the proportion. The overall 
category for “HCV RNA < LLOQ” will be split into the following 2 subcategories: “< LLOQ 
TND” for subjects with target not detected and “< LLOQ detected” for subjects with < LLOQ in 
tabular displays. 
Graphs for the proportion of subjects with HCV RNA < LLOQ over time during treatment will 
be displayed.
Summary statistics will be presented for absolute values and change from baseline in HCV RNA 
(log10 IU/mL) by visit through end of treatment (EOT). Imputation rules described in 
Section 3.6.1 will be used to assign HCV RNA values for missing values at a visit that are 
bracketed by “< LLOQ TND” and/or “< LLOQ detected”. Otherwise, a missing = excluded 
analysis will be performed. 
For the SVR12 endpoint analysis, a summary table of the number and percentage of subjects 
with SVR12, virologic failure (VF), and Other will be created. All subjects who achieve SVR12 
will be categorized as SVR12. Virologic failure will be descriptively summarized as 
“on-treatment virologic failure” and relapse (which will be broken down by study drug 
completed yes/no). Subjects who do not achieve SVR12 and do not meet criteria for VF will be 
categorized as Other. The denominator for relapse will be the number of subjects who had HCV 
RNA < LLOQ on their last observed on-treatment HCV RNA measurement; otherwise, the 
denominator will be the number of subjects in the FAS. 
A concordance table between SVR12 and SVR24 will be provided. Subjects with both observed 
SVR12 and observed SVR24 data will be included for this analysis.
In addition, the proportion of subjects with ALT normalization (defined as ALT > ULN at 
baseline and ALT ≤ ULN at each visit) will be presented by study visit. Tables for ALT 
normalization by visit will use methodology similar to the analyses of HCV RNA < LLOQ, but 
will use a missing = excluded analysis. Only those subjects with ALT > ULN at baseline 
(defined as the last ALT value collected prior to first dose of study drug) will be included in the 
analysis of ALT normalization. 


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7.
SAFETY ANALYSES
Safety data will be summarized for subjects included in the safety analysis set. Summaries of 
safety data (treatment-emergent [TE] adverse events [AEs], TE maximum toxicity grades, 
changes from baseline in laboratory tests and vital signs parameters) will include all data 
collected on or after the first dose date of study drug through the last dose date of study drug plus 
30 days for subjects who have stopped the study drug.
All safety data (except for laboratory tests with results that were cancelled by the lab) will be 
included in data listings based on the Safety Analysis Set.
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory 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.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity criteria 
specified in the protocol. The severity grade of events for which the investigator did not record 
severity will be categorized as “missing” for tabular summaries and data listings. The missing 
category will be listed last in summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious AEs (SAEs) will be identified and captured as SAEs if the AEs met the definitions of 
SAEs that were specified in the study protocol. SAEs captured and stored in the clinical database 
will be reconciled with the SAE database from the Gilead Drug Safety and Public Health 
Department before data finalization.


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7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent AEs (TEAEs) are defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days
after permanent discontinuation of study drug

Any AEs leading to premature discontinuation of study drug.
7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dosing date of 
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days 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 dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
Summaries (number and percentage of subjects) of adverse events (by SOC and PT) will be 
provided using the safety analysis set as follows:

All TE AEs

Combined Grade 3 or 4 TE AEs

Combined Grade 2, 3 or 4 TE AEs

TE nonserious AEs occurring in at least 5% of subjects (this will be produced for 
ClinicalTrials.gov website)

TE treatment-related AEs


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
Combined Grade 3 or 4 TE treatment-related AEs

Combined Grade 2, 3 or 4 TE treatment-related AEs

TE SAEs

TE treatment-related SAEs 

AEs leading to permanent discontinuation from the study drug

AEs leading to interruption of the study drug
A brief, high-level summary of AEs described above will be provided by the number and 
percentage of subjects who experienced the above AEs. All deaths observed in the study will 
also be included in this summary.
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC and then by PT in descending order of 
total frequency within each SOC. For 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, all TEAEs and TE treatment-related AEs will be 
summarized by PT only, in descending order of total frequency.
Data listings, with a variable indicating whether the event is treatment-emergent, will be 
provided for the following:

All AEs

All AEs of Grade 3 or higher

SAEs

Deaths

AEs leading to premature discontinuation of study drug 
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days
for subjects who have permanently discontinued study drug. The analysis will be based on values 
reported in conventional units. When values are below the LOQ, they will be listed as such, and 
the closest imputed value will be used for the purpose of calculating summary statistics as 


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specified in Section 3.7. Hemolized test results will not be included in the analysis, but they will 
be listed in by-subject laboratory listings.
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and coagulation and other laboratory tests. 
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 formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum and maximum) will be provided 
for ALT, AST, total bilirubin, alkaline phosphatase, white blood cell (WBC) counts, neutrophils, 
lymphocytes, hemoglobin, platelets, reticulocytes, creatinine, INR, and creatinine clearance 
(calculated by the Cockcroft-Gault equation, using IBW) as follows:

Baseline values 

Values at each postbaseline analysis window

Change from baseline at each postbaseline analysis window
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
values will be displayed to the reported number of digits; SD values will be displayed to the 
reported number of digits plus 1.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3.
The number of subjects with hemoglobin < 10 g/dL and < 8.5 g/dL at any postbaseline visits (up 
to 30 days after the last dose of any study drug) will be summarized.
7.2.2.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
used for assignment of toxicity grades to laboratory results for purposes of analysis as Grade 0, 
Grade 1 (mild) , Grade 2 (moderate), Grade 3 (severe) or Grade 4 (potentially life threatening). 
Grade 0 includes all values that do not meet the criteria for an abnormality of at least Grade 1. 
For laboratory tests with criteria for both increased and decreased levels, analyses for each 
direction (ie, increased, decreased) will be presented separately. 


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7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days. If the relevant baseline laboratory value is missing, any 
abnormality of at least Grade 1 observed within the time frame specified above will be 
considered treatment emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test; subjects will be categorized according to the most 
severe postbaseline abnormality grade for a given lab test:

TE Graded laboratory abnormalities

TE Grade 3 or 4 laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 after last dosing date.
A by-subject listing of treatment-emergent Grade 3 or 4 laboratory abnormalities will be 
provided by subject ID number and visit in chronological order. This listing will include all test 
results that were collected throughout the study for the lab test of interest, with all applicable 
severity grades displayed.
All valid laboratory values will be listed. Values falling outside of the relevant reference range 
and/or meeting Gilead Grading Scale will be flagged, as appropriate, in the data listings.
7.3.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary. The medications will be categorized 
as prior or concomitant using the following definitions:

Prior medications: any medications taken and stopped prior to or on the date of first study 
drug administration

Concomitant medications: any medications taken after the date of first study drug 
administration and up to the last dosing date of study drug


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Use of concomitant medications will be summarized by Anatomical Therapeutic Chemical
(ATC) drug class Level 2 and preferred name using the number and percentage of subjects. A 
subject reporting the same medication more than once will be counted only once when 
calculating the number and percentage of subjects who received that medication. The summary 
will be ordered alphabetically by ATC medical class and then by preferred term in descending 
overall frequency within each ATC medical class. For drugs with the same frequency, sorting 
will be done alphabetically.
For purposes of programming, any medication with a stop date that is on/prior to first dosing 
date or start date that is after the last dose of any study drug will be excluded from this summary. 
Otherwise, dates that are completely missing will be included in the summary. If a partial stop 
date is entered, then the month and year (if day is missing) or year (if day and month are 
missing) that is prior to the study drug start date will be excluded from the summary. If a partial 
start date is entered, then the month and year (if day is missing) or year (if day and month are 
missing) that is after the study drug stop date will be excluded from the summary. Medications 
with completely missing start and stop dates will be included in the concomitant medication 
summary, unless otherwise specified. Summaries will be based on the Safety Analysis Set. No 
formal statistical testing is planned.
A summary of concomitant medications will be provided.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.4.
Body Weight, Height, BMI and Vital Signs
Absolute value and change from baseline in vital signs (systolic blood pressure [SBP], diastolic 
blood pressure [DBP] and pulse) at each visit will be summarized for the Safety Analysis Set 
using descriptive statistics by treatment cohort for each postbaseline analysis window. In the case 
of multiple values in an analysis window, data will be selected for analysis as described in 
Section 3.8.3. No inferential statistics will be generated.
A listing of height (at screening), body weight, and BMI, and a listing of SBP, DBP, pulse, 
respiration and temperature will be provided.
7.5.
Electrocardiogram (ECG) Results
Absolute value and change from baseline in PR interval, QRS interval, QT interval and QTcF at 
each visit will be summarized for the Safety Analysis Set using descriptive statistics by treatment 
cohort for each postbaseline analysis window. A listing of PR interval, QRS interval, QT 
interval, and QTcF will be provided.
A listing of overall assessment of ECG results including description regarding clinically 
significant abnormalities will be provided.


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7.6.
Echocardiogram Results
Absolute value and change from baseline in ejection fraction, fractional shortening, left 
ventricular end diastolic volume (LVEDV) and left ventricular internal dimension in diastole 
(LVIDd) at each visit will be summarized for the safety analysis set using descriptive statistics 
by treatment cohort for each postbaseline visit. A shift table of diastolic function score 
assessment at baseline versus each on-treatment visit will be presented.
A listing of ejection fraction, fractional shortening, LVEDV, LVIDd and diastolic function score 
will be provided.
7.7.
Other Safety Measures
A data listing will be provided for subjects who received dialysis during the study.
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.


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8.
PHARMACOKINETIC (PK) ANALYSES
Steady-state PK over the dosing interval will be determined from intensive PK assessments at the 
Week 2 or Week 4 on-treatment visit.
Concentration of SOF (and its metabolites GS-566500 and GS-331007) and LDV in plasma will 
be determined using validated bioanalytical assays. The PK parameters for these analytes will be 
computed for all subjects with evaluable PK profiles.  For each subject, the following PK 
parameters will be calculated, as appropriate:
Parameter
Description
AUCtau
area under the concentration versus time curve over the dosing interval
Clast
last observed quantifiable concentration of the drug in plasma
Cmax
maximum observed concentration of drug in plasma
Ctau
observed drug concentration at the end of the dosing interval
t1/2
estimate of the terminal elimination half-life of the drug in plasma, calculated by dividing the 
natural log of 2 by the terminal elimination rate constant (z)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination phase 
of the plasma concentration of drug versus time curve
PK parameters will be estimated by application of a nonlinear model using standard 
noncompartmental methods (WinNonlinsoftware). The linear up/log down trapezoidal rule will 
be used in conjunction with the appropriate noncompartmental model (usually input Model 200 
for oral dosing), with input values for dose, time of dose, plasma concentration, and 
corresponding real time values, based on drug dosing times whenever possible. In oder to 
calculate AUCtau (dosing interval = 24 h), the pre-dose concentration will also be used as the 
24h concentration since these samples are obtained at steady state conditions.  However, missing 
concentrations from scheduled PK time-points will not be imputed. 
All predose sample times of less than time zero will be converted to zero. Samples below the 
limit of quantitation of the bioanalytical assays that occur prior to the achievement of the first 
quantifiable concentration will be assigned a concentration value of zero to prevent 
overestimation of the initial AUC. Samples that are BLQ at all other time points will be treated 
as missing data. The nominal time point for a key event or dosing interval (tau) may be used to 
permit direct calculation of AUC over specific time intervals. The appropriateness of this 
approach will be assessed by the pharmacokineticist on a profile-by-profile basis. 


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Accurate estimation of several PK parameters, such as λz and t1/2, are dependent on the measured 
terminal elimination phase of the drug. The appropriateness of calculating these parameters will 
be assessed by the pharmacokineticist on a profile-by-profile basis.
Ten descriptive statistics (sample size, mean, SD, coefficient of variation [%CV], median, Q1, 
Q3, minimum, maximum, and geometric mean and its 95% CI) will be presented for PK 
concentration data and PK parameter data. For concentration values BLQ, the number of subjects 
with values of BLQ will be presented.
Plasma concentrations of SOF (and its metabolites GS-566500 and GS-331007) and LDV over 
time from the intensive PK assessments will be plotted in linear and semi-logarithmic scales as 
mean ± SD and as Q1, median, and Q3 by visit.


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9.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.
PhoenixWinNonlin, Version 6.4, Pharsight Corporation, Mountain View, CA, USA.


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10.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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11.
APPENDICES
Appendix 1.
Schedule of Assesments for Cohort 3
Appendix 2.
Tables, Figures, and Listings


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Appendix 1.
Schedule of Assesments for Cohort 3
Study Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
4
Week
12
Week
24
Written Informed Consent
X
Medical History 
X
HCV RNA Genotype
X
IL28B Genotyping
X
HbA1c
X
HCV, HBV, HIV Serology
X
TSH
X
Physical Exam, including 
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
Echocardiogram 
X
X
Height
X
Weight
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
(PT, PTT, and INR)
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA Viral Load
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA Sequencing 
X
X
X
X
X
X
X
X
X
X
X
X


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Study Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
4
Week
12
Week
24
Serum Pregnancy Teste
X
X
X
X
X
X
X
X
X
Creatinine Clearance
X
Optional Pharmacogenetic 
Samplek
X
Intensive PK
Xf
Xf
Trough PK Sampleg
X
X
X
X
X
X
Archive Plasma Sample
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Administration
X
Weeks 1-12
Review Dosing Diary/
Perform Accountabilityh
X
X
X
X
X
X
X
AEs/Concomitant Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Screening evaluations must be completed within 42 days prior to Day 1.
b
Day 1 tests and procedures must be completed prior to administration of the first dose of study drugs 
c
Within 72 hours of permanently discontinuing study drug.
d
Full PE at Day 1 and ET visits only; symptom-directed PE at all other timepoints. Vital signs include blood pressure, pulse, respiration rate, and temperature
e
Females of childbearing potential only. To confirm eligibility at Day 1, a urine pregnancy test may be collected for subjects able to pass urine. For subjects unable to pass 
urine, a serum pregnancy test at Day 1 must be performed at a local lab prior to dosing to confirm eligibility along with sample collected and send to central lab. During post-
treatment of the study, serum or urine pregnancy testing will occur every month during non-clinic post treatment visits. The subject will be contacted by telephone to confirm 
that pregnancy testing has been performed post-treatment during non-clinic visits.
f
Intensive plasma PK evaluations will be assessed at the following timepoints: 0 (predose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose once either on 
Week 2 OR 4, per investigator discretion.
g
Trough plasma PK samples will be drawn prior to dosing. 
h
Dosing Diaries will be completed for all non-observed doses and will be reviewed at every visit. Unused study drug will be returned to perform study drug accountability in 
the original container at each visit following Day 1 for study drug compliance assessment.


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i
A window of ± 2 days is allowed for the treatment visits on weeks 1, 2, and 12.  A window of ± 4 days is allowed for the treatment visits weeks, and 4-10. Subjects who 
cannot complete their study visit per the visit schedule should ensure they do not run out of study drug prior to their next study visit.  Compliance is critical to ensure adequate 
drug exposure.
j
A window of ± 7 days is allowed for the post treatment visits. 
k
The sample should be collected on Day 1 prior to dosing, but may be collected at any time during the study or at a separate post-study visit, if necessary.


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Appendix 2.
Tables, Figures, and Listings
Table Number
Title
Analysis Set
15.8.1.1
Subjects Enrolled and Treated by Country and Investigator
Safety Analysis Set 
15.8.1.2
Subject Disposition
Screened Subjects
15.8.1.3
Reasons for Screen Failure
Screened Subjects
15.8.3
Demographics and Baseline Characteristics
Safety Analysis Set
15.8.4
Adherence to Study Drug
Safety Analysis Set
15.9.1
SVR12
Full Analysis Set
15.9.2.1
Virologic Outcomes
Full Analysis Set
15.9.2.2
SVR by Visit During Posttreatment Follow Up
Full Analysis Set
15.9.2.3
Concordance between SVR12 and SVR24
Full Analysis Set
15.9.2.4
Proportion of Subjects with HCV RNA Less than LLOQ (15 IU/mL) 
While on Treatment by Visit
Full Analysis Set
15.9.2.5
HCV RNA (log10 IU/mL) and Change from Baseline by Visit Through 
End of Treatment
Full Analysis Set
15.9.2.6
Proportion of Subjects with ALT Normalization by Visit
Full Analysis Set with 
ALT>ULN at 
Baseline
15.10.1.1.1
Individual Data and Summary Statistics of Plasma Intensive 
Concentration (ng/mL) at Protocol-Specified Sampling Times by Visit 
SOF PK Analysis Set
15.10.1.1.2
Individual Data and Summary Statistics of Plasma Intensive 
Concentration (ng/mL) at Protocol-Specified Sampling Times by Visit
GS-566500 PK 
Analysis Set
15.10.1.1.3
Individual Data and Summary Statistics of Plasma Intensive 
Concentration (ng/mL) at Protocol-Specified Sampling Times by Visit
GS-331007 PK 
Analysis Set
15.10.1.1.4
Individual Data and Summary Statistics of Plasma Intensive 
Concentration (ng/mL) at Protocol-Specified Sampling Times by Visit
LDV PK Analysis Set
15.10.1.2.1
Individual Estimate and Summary Statistics for Pharmacokinetic 
Parameters by Visit
SOF PK Analysis Set
15.10.1.2.2
Individual Estimate and Summary Statistics for Pharmacokinetic 
Parameters by Visit
GS-566500 PK 
Analysis Set
15.10.1.2.3
Individual Estimate and Summary Statistics for Pharmacokinetic 
Parameters by Visit
GS-331007 PK 
Analysis Set
15.10.1.2.4
Individual Estimate and Summary Statistics for Pharmacokinetic 
Parameters by Visit
LDV PK Analysis Set
15.11.1
Duration of Exposure to Study Regimen
Safety Analysis Set
15.11.2.1.1
Adverse Events: Brief Summary
Safety Analysis Set
15.11.2.1.2
All Treatment-Emergent Adverse Events
Safety Analysis Set
15.11.2.1.3
All Treatment-Emergent Adverse Events by Preferred Term
Safety Analysis Set


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Table Number
Title
Analysis Set
15.11.2.1.4
Treatment-Emergent Non-Serious AEs Occurring in At Least 5% of 
Subjects 
Safety Analysis Set
15.11.2.2.1
Grade 3 or 4 Treatment-Emergent Adverse Events
Safety Analysis Set
15.11.2.2.2
Grade 2, 3, or 4 Treatment-Emergent Adverse Events
Safety Analysis Set
15.11.2.3.1
Treatment-Emergent Treatment-Related Adverse Events
Safety Analysis Set
15.11.2.3.2
Treatment-Emergent Treatment-Related Adverse Events by Preferred 
Term
Safety Analysis Set
15.11.2.3.3
Grade 3 or 4 Treatment-Emergent Treatment-Related Adverse Events
Safety Analysis Set
15.11.2.3.4
Grade 2, 3, or 4 Treatment-Emergent Treatment-Related Adverse Events
Safety Analysis Set
15.11.4.1
Treatment-Emergent Serious Adverse Events
Safety Analysis Set
15.11.4.3
Treatment-Emergent Treatment-Related Serious Adverse Events
Safety Analysis Set
15.11.5.1
Adverse Events Leading to Premature Discontinuation of Study Drug
Safety Analysis Set
15.11.5.2
Adverse Events Leading or Interruption of Study Drug
Safety Analysis Set
15.11.6.1.1
Hemoglobin (g/dL) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.1.2
Subjects with Postbaseline Hemoglobin < 10 g/dL and < 8.5 g/dL
Safety Analysis Set
15.11.6.1.3
Reticulocytes (x10^3 /uL) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.1.4
WBC (x10^3 /uL) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.1.5
Neutrophils (x10^3 /uL) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.1.6
Lymphocytes (x10^3 /uL) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.1.7
Platelets (x10^3 /uL) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.2.1
ALT (U/L) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.2.2
AST (U/L) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.2.3
Total Bilirubin (mg/dL) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.2.4
Alkaline Phosphatase (U/L) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.2.5
Creatinine (mg/dL) and Change from Baseline by Visit
Safety Analysis Set
15.11.6.2.6
Estimated Glomerular Filtration Rate by Cockcroft-Gault (mL/min) and 
Change from Baseline by Visit
Safety Analysis Set
15.11.6.3
INR and Change from Baseline by Visit
Safety Analysis Set
15.11.6.4.1
Treatment-Emergent Graded Laboratory Abnormalities
Safety Analysis Set
15.11.6.4.2
Treatment-Emergent Grade 3 or 4 Laboratory Abnormalities
Safety Analysis Set
15.11.7.1.1
Systolic Blood Pressure (mmHg) and Change from Baseline by Visit
Safety Analysis Set
15.11.7.1.2
Diastolic Blood Pressure (mmHg) and Change from Baseline by Visit
Safety Analysis Set
15.11.7.1.3
Pulse (bpm) and Change from Baseline by Visit
Safety Analysis Set
15.11.7.3
Concomitant Medications
Safety Analysis Set


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Table Number
Title
Analysis Set
15.11.9.1
Summary of On-Treatment ECG Abnormality
Safety Analysis Set
15.11.9.2.1
PR Interval (ms) and Change from Baseline by Visit
Safety Analysis Set
15.11.9.2.2
QRS Interval (ms) and Change from Baseline by Visit
Safety Analysis Set
15.11.9.2.3
QT Interval (ms) and Change from Baseline by Visit
Safety Analysis Set
15.11.9.2.4
QTcF (ms) and Change from Baseline by Visit
Safety Analysis Set
15.11.10.1.1
Echocardiogram: Ejection Fraction (%) and Change from Baseline by 
Visit
Safety Analysis Set
15.11.10.1.2
Echocardiogram: Fractional Shortening (%) and Change from Baseline 
by Visit
Safety Analysis Set
15.11.10.2.1
Echocardiogram: LVEDV (mL) and Change from Baseline by Visit
Safety Analysis Set
15.11.10.2.2
Echocardiogram: LVIDd (cm) and Change from Baseline by Visit
Safety Analysis Set
15.11.10.3
Echocardiogram: Shift Table of Baseline versus On-Treatment Diastolic 
Function Score Assessment by Visit
Safety Analysis Set
Figure Number
Title
Analysis Set
15.8.1
Subject Disposition
Screened Subjects
15.9.2.3
Proportion of Subjects with SVR (HCV RNA < LLOQ) by Posttreatment 
Visit
Full Analysis Set
15.9.2.4
Proportion of Subjects with HCV RNA < LLOQ While on Treatment by 
Visit
Full Analysis Set
15.10.1.1.1
Mean (SD) Plasma Concentration - Time (0 hour - 12 hours) Profiles by 
Visit
SOF PK Analysis 
Set
15.10.1.1.2
Mean (SD) Plasma Concentration - Time (0 hour - 12 hours) Profiles by 
Visit
GS-566500 PK 
Analysis Set
15.10.1.1.3
Mean (SD) Plasma Concentration - Time (0 hour - 12 hours) Profiles by 
Visit
GS-331007 PK 
Analysis Set
15.10.1.1.4
Mean (SD) Plasma Concentration - Time (0 hour - 12 hours) Profiles by 
Visit
LDV PK Analysis 
Set
15.10.1.1.5
Median (Q1, Q3) Plasma Concentration - Time (0 hour - 12 hours) 
Profiles by Visit
SOF PK Analysis 
Set
15.10.1.1.6
Median (Q1, Q3) Plasma Concentration - Time (0 hour - 12 hours) 
Profiles by Visit
GS-566500 PK 
Analysis Set
15.10.1.1.7
Median (Q1, Q3) Plasma Concentration - Time (0 hour - 12 hours) 
Profiles by Visit
GS-331007 PK 
Analysis Set
15.10.1.1.8
Median (Q1, Q3) Plasma Concentration - Time (0 hour - 12 hours) 
Profiles by Visit
LDV PK Analysis 
Set


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Listing 
Number
Title
Analysis Set
16.1.6
Lot Number and Kit ID
Safety Analysis Set 
16.2.1.3
Subject Disposition
Safety Analysis Set
16.2.1.4
Reasons for Screen Failure
Subjects Screened But 
Not Enrolled
16.2.2.1
Eligibility Criteria Deviations
Safety Analysis Set
16.2.4.1
Subject Demographics and Baseline Characteristics
Safety Analysis Set
16.2.4.2
Cirrhosis Determination
Safety Analysis Set
16.2.4.3.1
Medical History
Safety Analysis Set
16.2.4.3.2
Prior HCV Treatment and Response
Safety Analysis Set
16.2.4.4
Prior and Concomitant Medications
Safety Analysis Set
16.2.5.1
Study Drug Administration
Safety Analysis Set
16.2.5.2
Study Drug Accountability and Adherence
Safety Analysis Set
16.2.5.3
Plasma PK Sampling Details and PK Concentrations
PK Analysis Set
16.2.6.1
HCV RNA (log10 IU/mL) and Change from Baseline 
Safety Analysis Set
16.2.6.2
Subjects with Virologic Failure
Safety Analysis Set
16.2.6.3
Subjects with ‘Other’ Virologic Outcome
Safety Analysis Set
16.2.6.4
Subjects with Relapse After Posttreatment Week 12
Safety Analysis Set
16.2.7.1
All Adverse Events
Safety Analysis Set
16.2.7.2.1
Deaths
Safety Analysis Set
16.2.7.3
Serious Adverse Events
Safety Analysis Set
16.2.7.4
Grade 3 or 4 Adverse Events
Safety Analysis Set
16.2.7.5
Adverse Events Leading to Premature Discontinuation from Any Study 
Drug
Safety Analysis Set
16.2.8.1.1
Subjects with Postbaseline Hemoglobin < 10 g/dL and <8.5 g/dL
Safety Analysis Set
16.2.8.1.2
Central Laboratory (Covance) Reference Ranges
Safety Analysis Set
16.2.8.1.3
Subjects with Treatment-Emergent Grade 3 or 4 Laboratory 
Abnormalities
Safety Analysis Set
16.2.8.1.4
Screen Labs: HBsAg, Anti-HIV Ab, Anti-HCV Ab, HbA1c,
and Serum Beta hCG
Safety Analysis Set
16.2.8.1.5.1
Hematology: Hematocrit, Hemoglobin, Reticulocyte Count,
MCV, RBC, WBC, and Platelets
Safety Analysis Set
16.2.8.1.5.2
Hematology: WBC, Neutrophils, and Lymphocytes
Safety Analysis Set
16.2.8.1.5.3
Hematology: Eosinophils, Basophils, and Monocytes
Safety Analysis Set


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Listing 
Number
Title
Analysis Set
16.2.8.1.6.1
Chemistry: Sodium, Potassium, Serum Creatinine,
Estimated GFR (Cockcroft-Gault), and Glucose
Safety Analysis Set
16.2.8.1.6.2
Chemistry: AST, ALT, Total Bilirubin, Direct Bilirubin,
Alkaline Phosphatase, GGT, and Albumin
Safety Analysis Set
16.2.8.1.7
Coagulation and Other Laboratory Tests: INR, APTT, and TSH
Safety Analysis Set
16.2.8.2.1
Vital Signs
Safety Analysis Set
16.2.8.2.2
Height, Weight, and BMI
Safety Analysis Set
16.2.8.2.3.1
Overall Assessment of  Electrocardiogram Results
Safety Analysis Set
16.2.8.2.3.2
Electrocardiogram measurements
Safety Analysis Set
16.2.8.3.1
Echocardiogram Results
Safety Analysis Set
16.2.8.3.2
Echocardiogram: Ejection Fraction and LVEDV
Safety Analysis Set
16.2.8.4
Dialysis
Safety Analysis Set
16.2.8.5
Pregnancy
Safety Analysis Set
16.2.8.6
Comments
Safety Analysis Set

Prot_003.pdf: 
Study Title: 
Sponsor: 
IND No.: 
EudraCT No: 
Indication: 
Protocol ID: 
Gilead Sciences 
Study Director 
Gilead Sciences 
Medical Monitor 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2b, Open-Label Study of200 mg or 400 mg 
Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 and 
Ledipasvir/Sofosbuvir (LDV/SOF) Fixed-Dose Combination 
(FDC) Tablet for 12 weeks in Genotype 1 or 4 HCV-Infected 
Subjects with Renal Insufficiency 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
106739 
2013-002897-30 
Hepatitis C Vims Infection 
GS-US-3 34-0154 
Name: 
Telephone: 
Fax: 
E-mail: 
Name: 
Telephone: 
Fax: 
E-mail: 
Original: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
PPD 
t-'t-'U 
PPD 
PPD 
Theo Sarif, MD 
PPD 
PPD 
t-'t-'U 
11 July 2013 
05 September 2013 
20 Febmmy 2014 
23 Febmmy 2015 
CONFIDENTIALITY STATEMENT 
I 
I 
The inf01mation contained in this document, pmiiculm·ly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 


Sovaldi® (Sofosbuvir)
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 2
23 February 2015
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................11
1.
INTRODUCTION ..............................................................................................................................................14
1.1.
Background ............................................................................................................................................14
1.2.
Sofosbuvir (formerly GS-7977) .............................................................................................................14
1.3.
Ribavirin (RBV).....................................................................................................................................14
1.4.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................15
1.5.
Preliminary Results of Study GS-US-334-0154, Cohort 1.....................................................................15
1.5.1.
Pharmacokinetics .................................................................................................................15
1.5.2.
Safety....................................................................................................................................16
1.5.3.
Efficacy ................................................................................................................................16
1.6.
Rationale for the Current Study .............................................................................................................16
1.6.1.
Cohorts 1 and 2 ....................................................................................................................17
1.6.2.
Cohort 3................................................................................................................................17
1.7.
Rationale for SOF Dose Selection .........................................................................................................19
1.8.
Rationale for RBV Dose Selection.........................................................................................................19
1.9.
Rationale for Ledipasvir/Sofosbuvir Fixed Dose Combination (FDC) Dose Selection.........................20
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
4.
SUBJECT POPULATION..................................................................................................................................25
4.1.
Number of Subjects and Subject Selection ............................................................................................25
4.2.
Inclusion Criteria....................................................................................................................................25
4.3.
Exclusion Criteria...................................................................................................................................27
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................29
5.1.
Sofosbuvir (SOF) ...................................................................................................................................29
5.1.1.
Formulation..........................................................................................................................29
5.1.2.
Packaging and Labeling .......................................................................................................29
5.1.3.
Storage and Handling...........................................................................................................29
5.1.4.
Sofosbuvir (SOF) Dosage and Administration.....................................................................30
5.2.
Ribavirin (RBV).....................................................................................................................................30
5.2.1.
Formulation..........................................................................................................................30
5.2.2.
Packaging and Labeling .......................................................................................................30
5.2.3.
Storage and Handling...........................................................................................................30
5.2.4.
RBV Dosage and Administration.........................................................................................30
5.3.
Co-administration of Sofosbuvir (SOF) and Ribavirin (RBV) ..............................................................31
5.4.
Ledipasvir/ Sofosbuvir (LDV/SOF).......................................................................................................31
5.4.1.
Formulation..........................................................................................................................31
5.4.2.
Packaging and Labeling .......................................................................................................31
5.4.3.
Storage and Handling...........................................................................................................31
5.4.4.
LDV/SOF Dosage and Administration ................................................................................32


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5.5.
Study Drug Compliance.........................................................................................................................32
5.6.
Dispensing and Accountability of Study Drugs .....................................................................................32
5.7.
Study Drug Return or Disposal ..............................................................................................................32
5.8.
Concomitant Medications ......................................................................................................................33
5.8.1.
Cohorts 1 and 2 ....................................................................................................................33
5.8.2.
Cohort 3................................................................................................................................33
5.8.3.
All Cohorts...........................................................................................................................34
6.
STUDY PROCEDURES ....................................................................................................................................38
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................38
6.2.
Pretreatment Assessments......................................................................................................................44
6.2.1.
Screening Visit .....................................................................................................................44
6.2.2.
Medical History....................................................................................................................44
6.3.
Day 1 Assessments.................................................................................................................................45
6.3.1.
Dosing Diary ........................................................................................................................45
6.4.
Treatment Assessments..........................................................................................................................45
6.4.1.
Cohorts 1 and 2 ....................................................................................................................45
6.4.2.
Cohort 3................................................................................................................................45
6.5.
Safety Assessments ................................................................................................................................45
6.5.1.
Safety ECGs.........................................................................................................................45
6.5.2.
Safety Echocardiograms.......................................................................................................46
6.5.3.
Physical Examination...........................................................................................................46
6.5.4.
Vital Signs............................................................................................................................46
6.5.5.
BMI ......................................................................................................................................47
6.5.6.
Creatinine Clearance ............................................................................................................47
6.5.7.
Clinical Laboratory Tests/Assessments................................................................................47
6.5.8.
Adverse Events/Concomitant Medications/Protocol Restrictions........................................48
6.6.
Pharmacokinetic (PK) Assessments.......................................................................................................48
6.7.
Early Termination (ET)/Unscheduled Visit ...........................................................................................49
6.8.
Post-Treatment Assessments..................................................................................................................50
6.9.
Optional Samples for Pharmacogenetic Testing ....................................................................................50
6.10.
Archived Plasma Sample .......................................................................................................................51
6.11.
Blood Storage.........................................................................................................................................51
7.
ADVERSE EVENTS MANAGEMENT ............................................................................................................52
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................52
7.1.1.
Adverse Events.....................................................................................................................52
7.1.2.
Serious Adverse Events........................................................................................................52
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................53
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................53
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................53
7.2.2.
Assessment of Severity ........................................................................................................54
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................54
7.4.
Gilead Reporting Requirements.............................................................................................................56
7.5.
Toxicity Management ............................................................................................................................56
7.5.1.
Stopping Rules for Toxicity .................................................................................................56
7.5.2.
Sofosbuvir (SOF) or LDV/SOF............................................................................................56
7.5.3.
Ribavirin (RBV)...................................................................................................................57
7.6.
Special Situations Reports......................................................................................................................57
7.6.1.
Definitions of Special Situations..........................................................................................57
7.6.2.
Instructions for Reporting Special Situations.......................................................................57


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8.
STATISTICAL CONSIDERATIONS................................................................................................................59
8.1.
Analysis Objectives and Endpoints........................................................................................................59
8.1.1.
Analysis Objectives..............................................................................................................59
8.1.2.
Primary Endpoint .................................................................................................................59
8.1.3.
Secondary Endpoint .............................................................................................................60
8.1.4.
Other Endpoints of Interest ..................................................................................................60
8.2.
Analysis Conventions.............................................................................................................................60
8.2.1.
Analysis Sets ........................................................................................................................60
8.2.2.
Data Handling Conventions .................................................................................................61
8.2.3.
Interim Analysis ...................................................................................................................62
8.3.
Demographic Data and Baseline Characteristics ...................................................................................62
8.4.
Efficacy Analysis ...................................................................................................................................62
8.4.1.
Primary Analysis..................................................................................................................62
8.4.2.
Secondary Analysis..............................................................................................................62
8.5.
Safety Analysis.......................................................................................................................................63
8.5.1.
Extent of Exposure...............................................................................................................63
8.5.2.
Adverse Events.....................................................................................................................63
8.5.3.
Laboratory Evaluations ........................................................................................................64
8.6.
Pharmacokinetic Analysis......................................................................................................................64
8.7.
Stopping Rules for Individual Groups....................................................................................................64
8.8.
Sample Size............................................................................................................................................65
8.9.
Data Monitoring Committee ..................................................................................................................65
9.
RESPONSIBILITIES..........................................................................................................................................66
9.1.
Investigator Responsibilities ..................................................................................................................66
9.1.1.
Good Clinical Practice..........................................................................................................66
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval...............................................................................................................................66
9.1.3.
Informed Consent.................................................................................................................66
9.1.4.
Confidentiality......................................................................................................................67
9.1.5.
Study Files and Retention of Records ..................................................................................67
9.1.6.
Case Report Forms...............................................................................................................68
9.1.7.
Drug Accountability.............................................................................................................69
9.1.8.
Inspections............................................................................................................................69
9.1.9.
Protocol Compliance............................................................................................................69
9.2.
Sponsor Responsibilities ........................................................................................................................70
9.2.1.
Protocol Modifications.........................................................................................................70
9.2.2.
Study Report and Publications .............................................................................................70
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................70
9.3.1.
Access to Information for Monitoring..................................................................................70
9.3.2.
Access to Information for Auditing or Inspections ..............................................................71
9.3.3.
Study Discontinuation..........................................................................................................71
10.
REFERENCES ...................................................................................................................................................72
11.
APPENDICES ....................................................................................................................................................74
VERSION: 18 JUNE 2012..........................................................................................................................................79
Appendix 1.
Investigator Signature Page....................................................................................................75
Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................76
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............79


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LIST OF IN-TEXT TABLES
Table 1-1.
Preliminary Comparison of the Effect of Severe Renal Impairment on GS-331007 
and SOF Exposure in HCV-infected and Non-HCV-Infected Subjects .................................16
Table 1-2.
SVR4 Rates in Genotype 4 Subjects from Study GS-US-337-1119 ......................................18
Table 1-3.
Observed and Predicted GS-331007 and SOF Exposure in Subjects with Renal 
Impairment .............................................................................................................................21
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................34
Table 6-1.
Schedule of Assessments for Cohorts 1 and 2........................................................................39
Table 6-2.
Schedule of Assessments for Cohort 3 ...................................................................................42


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title:
A Phase 2b, Open-Label Study of 200 mg or 400 mg
Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 and 
Ledipasvir/Sofosbuvir (LDV/SOF) Fixed-Dose Combination (FDC) 
Tablet for 12 weeks in Genotype 1 or 4 HCV-Infected Subjects with 
Renal Insufficiency
IND Number:
Eudra CT Number:
106739
2013-002897-30
Study Centers Planned:
Multiple sites in New Zealand, Europe, North America and 
South America
Number of Subjects 
Planned:
Approximately 30 subjects
Target Population:
Adults with chronic renal insufficiency and HCV infection
Treatment Duration:
12 weeks or 24 weeks
Objectives:
The primary objectives of this study are:

To evaluate the safety of sofosbuvir (SOF) 200 mg or 400 mg
+ ribavirin (RBV) for 24 weeks and LDV/SOF for 12 weeks as 
assessed by review of the accumulated safety data in each 
treatment arm

To evaluate the efficacy of sofosbuvir (SOF) 200 mg or 400 mg
+ ribavirin (RBV) for 24 weeks and LDV/SOF for 12 weeks
measured by the proportion of subjects with renal insufficiency 
who have achieved a sustained viral response 12 weeks after 
treatment discontinuation (SVR12) in each treatment arm

To evaluate the steady state pharmacokinetics of SOF and its 
metabolites and LDV upon dosing SOF 200 mg or 400 mg or
LDV/SOF in subjects with renal insufficiency 


Sovaldi® (Sofosbuvir) 
Protocol GS-US-334-0154 
Gilead Sciences, Inc. 
Study Design: 
Diagnosis and Main 
Eligibility Criteria: 
Study Procedures/ 
Frequency: 
CONFIDENTIAL 
The secondruy objectives of this study ru·e: 
Final 
Amendment3 
• 
To evaluate the prop01tion of subjects with renal insufficiency 
who attain SVR at 4 and 24 weeks after discontinuation of 
u·eatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of plasma HCV RNA during and after 
u·eatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV 
during and after u·eahnent discontinuation 
The explorat01y objective of this study is: 
This study will emoll approximately 30 subjects with severe renal 
insufficiency. 
• 
Cohort 1: 10 subjects will receive SOF 200 mg QD + 
RBV 200 mg QD for 24 weeks. 
• 
Cohort 2: Following review of safety, efficacy and PK data 
through post-u·eatment Week 4 ofCoh01t 1, 
10 additional subjects will receive SOF 400 mg QD + 
RBV 200 mg QD for 24 weeks. 
• 
Cohort 3: Following review of safety and available PK data 
through Week 12 of Coh01t 2, 10 additional subjects will receive 
LDV/SOF QD for 12 weeks. 
Adults (~ 18 years) with chronic genotype 1 or genotype 3 
(for Coh01ts 1 and 2) or genotype 1 or 4 (for Coh01t 3) HCV 
infection. Reference Sections 4.2 and 4.3 for detailed Inclusion and 
Exclusion criteria. 
Screening assessments will be completed within 42 days of the 
Day 1 visit. 
Study visits will occur at Screening, Day 1, and at the end of 
Weeks 1, 2, 4, 6, 8, 10, 12 (all cohorts), and Weeks 16, 20 and 24 
(Cohorts 1 and 2 only) and at Post-Treatment Weeks 4, 12, and 24 
(all coh01ts). Screening assessments will include physical 
examination, height, weight, vital signs, 12-lead ECG, 
echocru·diogram, concomitant medications, safety laborat01y tests, 
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HCV RNA, serology (HIV, HCV, HBV), hemoglobin A1c (HbA1c), 
serum β-hCG (females of child bearing potential only), IL28B 
genotyping.
On-treatment assessments will include adverse events (AEs), 
concomitant medications, study medication pill count, physical 
examination, vital signs, 12-lead ECGs, echocardiogram, safety 
laboratory tests, HCV RNA, pharmacokinetic samples, and serum 
pregnancy tests (females of child bearing potential only). 
Post-treatment assessments will include AEs, concomitant 
medications, vital signs, safety laboratory tests, HCV RNA, and 
serum pregnancy tests (females of child bearing potential only).
Samples for viral RNA sequencing will be collected at Day 1 and 
every visit thereafter. Samples will be collected during treatment 
visits for PK analysis of study drug(s).
PK assessments
Intensive PK Assessments
Cohorts 1 and 2:
Serial blood samples will be collected on week 2 and 12 at the 
following timepoints:

0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours 
post-dose.
Cohort 3:
Serial blood samples will be collected once either on week 2 or 4 
(per investigator discretion) at the following timepoints:

0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours 
post-dose.
Plasma concentrations of SOF and its metabolites and LDV will be 
determined and PK parameters will be estimated as appropriate. 
Plasma concentrations of RBV may be determined, if necessary.
Trough PK Assessments:
Trough PK plasma samples for analyses of SOF, its metabolites,
RBV (as applicable) and LDV concentrations will be collected at all 
other on treatment visits beginning at the Week 1 visit.
PK Parameters for SOF, its metabolites, LDV and RBV will be 
estimated as appropriate. 


Sovaldi® (Sofosbuvir) 
Protocol GS-US-334-0154 
Gilead Sciences, Inc. 
Test Product, Dose, and 
Mode of Administration: 
Reference Therapy: 
Criteria for Evaluation: 
Safety: 
Efficacy: 
CONFIDENTIAL 
Optional Genetic Sample Collection 
PPD 
Archived Plasma Sample 
Final 
Amendment3 
Archive plasma samples are being collected for possible additional 
analyses, including but not limited to, study dmg or metabolite 
measmements, viral load, safety/efficacy assessments, HCV gene 
sequencing, HCV resistance testing and other possible predictors of 
response as detennined by Gilead. 
Sofosbuvir is manufactmed as 100 mg and 400 mg tablets for oral 
adminisu·ation. Subjects emolled to take the 200 mg dose will take 
2 x 100 mg tablets for a total dose of 200 mg orally QD in the 
moming with RBV and with food. Subjects emolled to take the 
400 mg dose will take 1 x 400 mg tablet for a total dose of 400 mg 
orally QD in the moming with RBV and with food. 
RBV will be supplied as a 200 mg tablet for oral adminisu·ation by 
Gilead Sciences. Subjects will take 1 x 200 mg tablet in the moming 
with SOF and with food. 
LDV/SOF is manufactmed as a fixed-dose combination tablet, 
consisting of90 mg LDV and 400 mg SOF, for oral adminisu·ation. 
All subjects will take 1 tablet daily with or without food. 
None 
AEs, SAEs, and safety labs will be collected throughout the study. 
Safety will be evaluated by assessment of clinicallaborat01y tests, 
ECG, echocardiogram, periodic physical examinations including 
vital signs at various time points dming the study, and by the 
documentation of adverse events. 
Efficacy will be evaluated usini scheduled assessments of HCV 
RNA perf01m ed using COBAS AmpliPrep/COBAS® TaqMan® 
HCV Test. 
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PK:
Plasma PK parameters will be calculated for sofosbuvir and its 
metabolites GS-566500 and GS-331007, LDV and RBV, as 
applicable. Examples are AUClast, AUCtau, Cmax, Clast, Ctau, and t1/2.
Statistical Methods:
Safety data will be listed by subject and summarized by treatment 
cohort using frequency of event/abnormality or descriptive statistics 
(e.g., sample size, arithmetic mean, geometric mean, % coefficient 
of variation [CV], standard deviation [SD], minimum, Q1, median, 
Q3, and maximum).
The steady state PK plasma concentrations and parameters will be 
listed by subject and summarized by treatment cohort using 
descriptive statistics for each analyte (SOF, GS-566500, GS-331007, 
RBV and LDV, as appropriate). 
In the efficacy analysis, no statistical hypothesis testing will be 
performed and no formal inferences will be made on the primary 
efficacy endpoint SVR12. A point-estimate with two-sided 95% 
exact confidence interval (CI) using the binomial distribution 
(Clopper-Pearson method) will be constructed for the SVR12 rate by 
treatment cohort. Similar analysis will be also performed for 
secondary endpoints SVR4 and SVR24.
To evaluate the kinetics of circulating HCV RNA during and after 
treatment discontinuation, viral load data will be listed by subject 
and summarized by treatment cohort and visit using descriptive 
statistics.
Due to the exploratory nature of this study, no formal power or 
sample size calculations were performed to determine treatment 
group size. The total sample size of 30 is largely based on 
feasibility.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
β-hCG
β-human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase  (also SGOT)
AUC
area under the curve
AUCtau
area under the plasma concentration versus time curve over the dosing interval 
(tau)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BW
body weight
CLcr
Creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Ctau
observed drug concentration at the end of the dosing interval (tau)
CRF
case report form(s)
CRO
Contract (or clinical) research organization 
DAA
direct-acting antiviral
dL
Deciliter
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
ESAs
Erythropoiesis stimulating agents
ESRD
End Stage Renal Disease
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
Hb
Hemoglobin
HbA1c
Hemoglobin A1c


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDPE
high-density polyethylene
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
High-Level Term
IBW
Ideal Body Weight
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL28B
IL28B gene
IND
Investigational New Drug (Application)
IRB
institutional review board
IUD
intrauterine device
IV
Intravenous
kg
Kilogram
L
Liter
LDH
Lactase dehydrogenase
LDV
Ledipasvir
LLN
lower limit of the normal range
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MH
Mantel-Haenszel
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PBMC
peripheral blood mononuclear cell(s)
PEG
Pegylated interferon
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
po
Per os (by mouth)
QD
once daily (use only in tables)
QTcF
QT interval corrected using Fridericia’s formula
RBC
Red blood cell count 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
RBV
Ribavirin
RNA
ribonucleic acid
RVR
rapid virologic response 
SADR
Serious adverse drug reaction
SAE
serious adverse event
SD
Standard deviation
SOC
Standard of Care
SOF
Sofosbuvir
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TND
Target not detected
TSH
Thyroid stimulating hormone
t½
An estimate of the terinal elimination half-life of the drug in 
serum/plasma/PBMC, calculated by dividing the natural log of 2 by the terminal 
elimination rate contstant (λz)
ULN
upper limit of the normal range
US
United States
WBC
white blood cell count


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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) is responsible for a large proportion of chronic liver disease worldwide 
and accounts for 70% of cases of chronic hepatitis in industrialized countries. The global 
prevalence of chronic hepatitis C is estimated to average 3% {19705}. The most common 
genotype worldwide is genotype 1 followed by genotypes 2 and 3 {19705}. Although there is 
evidence that the incidence of viral infection may be decreasing, the prevalence of liver disease 
caused by HCV is on the rise, primarily due to the lag between the onset of infection and the 
clinical manifestation of liver disease {19705}. The prevalence of chronic HCV is significantly 
higher among patients with chronic renal failure, and HCV itself is associated with impaired 
renal function. Treatment of these individuals is therefore recommended but is often complicated 
by the substantial increase in hematologic toxicities associated with the use of ribavirin in the 
setting of low creatinine clearance {23275}.
1.2.
Sofosbuvir (formerly GS-7977)
Sovaldi® (sofosbuvir) is a potent nucleotide analogue that inhibits HCV RNA replication in vitro 
and has demonstrated high rates of sustained viral response (SVR) when administered with RBV, 
with or without pegylated interferon, to subjects with chronic genotype 1-6 HCV infection 
{32081}, {23275}, {24713}, {24715}, {27832}. Sovaldi® has been approved in the United States 
(GT1-4) and in the European Union (GT1-6) for the treatment of chronic HCV infection 
including treatment naïve and experienced patients and HIV/HCV co-infected patients.
For further information on the clinical pharmacology, virology, safety and efficacy of sofosbuvir 
(SOF), please refer to the current version of the Investigator’s Brochure and US and EU 
prescribing information.
1.3.
Ribavirin (RBV)
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of RNA 
and DNA viruses {15572}, {15668}. Ribavirin monotherapy has little or no effect on the 
replication of HCV but can result in short term normalization of serum ALT activity. When 
combined with interferon or PEG therapy, RBV decreases substantially the relapse rate seen after 
cessation of interferon therapy {12557}, {12558}.
Ribavirin is a known teratogen (FDA category X). Furthermore, RBV is known to accumulate 
intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, extreme care 
must be taken to avoid pregnancy during RBV therapy and for up to 6 months following 
completion of treatment. A comprehensive review of RBV is contained in the package 
insert/SmPC.


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1.4.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
Harvoni® (ledipasvir/sofosbuvir fixed-dose combination (LDV/SOF) combines 
two HCV specific-direct acting antivirus (DAA) agents into a single tablet for the treatment of 
chronic HCV infection. Sofosbuvir is a nucleotide analog that is a potent and selective inhibitor 
of NS5B-directed HCV replication, irrespective of HCV genotype. Ledipasvir is a novel HCV 
NS5A inhibitor that has demonstrated potent anti-HCV activity against genotypes 1 and 4 HCV 
infection. Harvoni® has been approved in the United States and Europe for the treatment of 
chronic HCV infection including treatment naïve and experienced patients with genotype 1. 
For further information on the clinical pharmacology, virology, safety and efficacy of LDV/SOF, 
please refer to the current version of the Investigator’s Brochure and US prescribing information.
1.5.
Preliminary Results of Study GS-US-334-0154, Cohort 1
Preliminary results are available and presented below for Cohort 1: 10 subjects with estimated 
glomerular filtration rate (eGFR by Cockcroft-Gault) less than 30 mL/min within six months of 
screening, not on dialysis, treated with SOF 200 mg + RBV 200 mg daily for 24 Weeks. A 
review of the integrated safety, PK and efficacy from this first cohort demonstrate that 
SOF 200 mg + RBV 200 mg daily for 24 weeks is safe and relatively well tolerated.
1.5.1.
Pharmacokinetics
Preliminary pharmacokinetic data are available for subjects in Cohort 1 who received 
200 mg SOF + 200 mg RBV for 24 weeks. Exposure (from intensive PK sampling) of SOF and 
its predominant circulating renally eliminated metabolite (GS-331007) were similar at 
Week 2 and Week 12; as such further PK analyses are conducted with the Week 12 data 
(Table 1-1). 
As expected, in the Cohort 1 HCV-infected subjects, severe renal impairment increases 
GS-331007 and SOF exposures. In general, when normalized to subjects with normal renal 
function, the results are comparable to that observed in the non HCV-infected renal impairment 
study (P7977-0915, %GMR in Table 1-1). The only exception was the increase in GS-331007 
Cmax seen in severe renal impaired HCV-infected subjects as opposed to the non-infected subjects 
(%GMR HCV-infected vs. non-infected: 589% vs. 134%). This difference in GS-331007 Cmax is 
likely a result of expected accumulation of GS-331007 upon steady state dosing in the 
Study GS-US-334-0154 as compared to single dose administration in the P7977-0915 study.


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Table 1-1.
Preliminary Comparison of the Effect of Severe Renal Impairment 
on GS-331007 and SOF Exposure in HCV-infected and 
Non-HCV-Infected Subjects
Mean (%CV) PK Parameter
GS-331007
SOF
AUCinf or tau 
(ng•hr/ml)
Cmax
(ng/ml)
AUCinf or tau 
(ng•hr/ml)
Cmax
(ng/ml)
HCV-Infected Subjects
GS-US-334-0154 SOF 200 mg cohort
Week 12 (n = 10)
31,100 (53.9)
1730 (44.9)
1280 (50.3)a
904 (66.2)
Phase 2/3 Population Dose normalized to SOF 200 mg
(SOF n = 838, GS-331007 n = 1695)
3561 (30.7)
291 (36.3)
513 (36.5)
256 (32.5)
%GMR (90% CI)
817
(694, 963)
589
(481, 721)
233
(193, 282)
321
(261, 395)
Non HCV-Infected Subjects (P7977-0915)
%GMR (90% CI)
(Severe Impairment/Normal Function)
551
(313, 968)
134
(98.6, 183)
271
(183, 402)
177
(96.6, 324)
Note: PK parameters are presented as mean (%CV) to three significant digits.
a
n = 9
Source: Ad Hoc Table 6822.2, P7977-0915 Table 11.13
1.5.2.
Safety
Sofosbuvir was generally well-tolerated and safe when administered with RBV in Cohort 1. 
Most adverse events (AEs) were mild to moderate in severity. There were two serious AEs 
(SAEs) of unstable angina and hyperglycaemic hyperosmolar nonketotic syndrome which were 
assessed by the investigators as not related to the study drugs. Neither event led to change in 
study drug administration. The most frequently reported AEs were anemia, headache, pruritus, 
and rash. Renal function and cardiac function were stable during treatment as assessed by eGFR,
safety ECG and echocardiograms, respectively.
1.5.3.
Efficacy
All subjects experienced rapid on-treatment virologic decline similar to those with normal renal 
function and full-dose SOF+RBV. There were no subjects with virologic breakthrough. 
One subject withdrew consent and stopped treatment at Week 12; he did not return for 
post-treatment visits. One subject prematurely discontinued treatment at Week 21. Overall, 
4 of the 10 (40%) subjects achieved SVR4.
1.6.
Rationale for the Current Study
This study will evaluate the safety, efficacy and pharmacokinetics of treatment with SOF+RBV 
for 24 weeks (for genotype 1 or 3) and of treatment with LDV/SOF for 12 weeks (for genotype 1 
or 4) in subjects with chronic HCV infection and severe renal impairment.


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Interferon monotherapy, however, is associated with poor tolerability, a 48 week treatment 
duration, and efficacy of approximately 40%. Furthermore, once patients have failed this course 
of treatment, they have no further treatment options and are at risk for progression of liver 
disease, cirrhosis, and hepatocellular carcinoma.
1.6.1.
Cohorts 1 and 2
To date, SOF+RBV has demonstrated safety and efficacy in a broad range of subjects with 
chronic HCV infection in Phase 2 and Phase 3 clinical trials. However, subjects with 
Cr clearance <60 mL/min have been excluded from these studies due to the recommendation 
that RBV not be administered to patients with Cr clearance <50 mL/min. In addition,
study P7977-0915 has shown the major circulating metabolite of SOF, GS-331007, is renally 
cleared and a single dose study conducted in subjects with severe renal impairment or end-stage 
renal disease on hemodialysis demonstrated exposures approximately 1.6-fold and 14 to 22-fold 
higher, respectively, than those observed in matched controls with normal renal function. Whilst 
dose reduction of SOF would reduce these exposures, viral efficacy is dependent on SOF 
exposures such that lower SOF doses or intermittent administration could be associated with 
reduced efficacy. Thus, this exploratory study of safety and efficacy of standard (400 mg) and 
reduced (200 mg) doses of SOF in combination with low-dose RBV in a small number of 
subjects will provide important data regarding dosing recommendations for use of SOF in this 
patient population with a high unmet medical need.
Phase 3 studies of SOF+RBV for 12 or 16 weeks in treatment-naïve and treatment-experienced 
genotype 3 HCV-infected subjects demonstrated SVR12 rates of 56% and 62%, respectively. 
Increasing treatment duration to 24 weeks may further improve response rates. In Phase 2 studies 
of SOF+RBV for 12 or 24 weeks in treatment-naïve genotype 1 HCV-infected subjects, SVR 
rates have varied from 47% to 84% depending on the study and patient population. In both 
genotypes 1 and 3, lower doses of RBV have been associated with reduced efficacy of the 
regimen. Given the safety need for a reduced RBV dose in the current study (Section 1.8), 
treatment with SOF+RBV will be administered for 24 weeks to maximize efficacy. Subjects with 
genotypes 1 or 3 HCV infection have been selected for this study since they represent the largest 
group of HCV-infected individuals in the regions where this study will be conducted and because 
the 24 week treatment regimen is appropriate. In contrast, genotype 2 HCV-infected subjects 
have been shown to have high response rates following 12 weeks of SOF+RBV therapy. If 
SOF+RBV is well tolerated for 24 weeks in patients with severe renal insufficiency, safety for 
12 weeks in this smaller HCV population may be inferred.
1.6.2.
Cohort 3
To date in subjects with a CrCl > 60 mL/min, LDV/SOF without RBV has an excellent safety 
profile, with efficacy > 93% in all patient populations {31179}. Cohort 3, in which LDV/SOF for 
12 weeks will be the treatment regimen, will generate clinical data in a patient population with a 
regimen which is the Standard of Care (SOC) for genotype 1. 


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Phase 3 trials with LDV/SOF demonstrated the addition of RBV to LDV/SOF for the treatment 
of HCV in genotype 1 subjects did not increase efficacy. As such, Cohort 3 will not include RBV 
which is of particular benefit for this patient population in which chronic anemia is common; the 
preliminary data from Cohort 1 with SOF 200mg + RBV indicate that anemia was the most 
frequent AE and led to increased epoetin use.
In Cohort 3, the safety, efficacy and pharmacokinetics of LDV/SOF 90/400 mg will be evaluated 
in subjects with severe renal impairment. Data from GS-US-344-0108 demonstrated that severe 
renal impairment had no effect on LDV exposure. As described above for Cohorts 1 and 2, 
impaired renal function significantly increases GS-331007 exposure. As such, progression of 
GS-331007 exposure across cohorts was a major consideration in determining the appropriate 
design for this study (see Section 1.9). 
Because over 70% of HCV-infected individuals in the US and Europe have genotype 1, they 
represent the greatest unmet medical need, and therefore will be the priority for generating data 
in renal impairment across cohorts of this study. For Cohort 3, both preclinical and clinical data 
support the inclusion of genotype 4 HCV-infected subjects. Activity of LDV was evaluated in a 
subgenomic genotype 4d HCV replicon. In the replicon system, the EC50 value of LDV against 
genotype 4d HCV was 0.60 nM and 0.39 nM for genotype 4a HCV (compared with EC50 values 
of LDV against genotype 1a and genotype 1b of 0.031 nM and 0.004 nM, respectively).
In the Phase 3 Study GS-US-337-0102 (ION-1), 2 subjects with genotype 4d HCV infection 
were inadvertently randomized in violation of the protocol inclusion/exclusion criteria. Both 
subjects achieved SVR12. Subject 
 was treated for 12 weeks with LDV/SOF and 
Subject
 was treated for 24 weeks with LDV/SOF+RBV.
In Study GS-US-337-1119, a European study investigating the efficacy and safety of LDV/SOF 
in treatment-naive and treatment-experienced subjects with chronic genotype 4 or genotype 
5 HCV infection, a total of 44 subjects with genotype 4 HCV infection, of whom 10 (23%) have 
cirrhosis and 22 (50%) are treatment experienced, have been enrolled to receive LDV/SOF for 
12 weeks. SVR4 data are available from Study GS-US-337-1119 in 25 subjects with genotype 4 
and18 subjects with genotype 5 HCV infection. 
Table 1-2.
SVR4 Rates in Genotype 4 Subjects from Study GS-US-337-1119
Genotype 4
Overall
96% (24/25)
Treatment Naive
100% (12/12)
Treatment Experienced
92% (12/13)
Cirrhosis
100% (7/7)
No Cirrhosis
94% (17/18)
PPD
PPD


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In addition, preliminary data are available from Group E of the NIAID/NIH collaborative 
Study CO-US-337-0117. In this group, 21 subjects with genotype 4 HCV infection, of whom 
13 are treatment naive and 8 are treatment experienced, are receiving 12 weeks of LDV/SOF 
treatment. In total, 6 subjects have cirrhosis. Post-treatment week 12 data is available for 
20 subjects, 19 of 20 subjects have achieved SVR12.
Study GS-US-337-0115 (ION-4) is investigating the efficacy and safety of LDV/SOF in 
genotype 1 and genotype 4 HCV-infected subjects coinfected with HIV. A total of 8 subjects 
with genotype 4 HCV infection have been enrolled. All 8 subjects have achieved SVR4. 
1.7.
Rationale for SOF Dose Selection
Sofosbuvir 400 mg, once daily, when dosed in combination with RBV with or without PEG has 
demonstrated broad genotypic efficacy and a favorable safety profile in over 3300 HCV-infected 
subjects across multiple patient populations in Phase 2 and 3 trials. This dose (400 mg) is the 
proposed to be marketed dose of sofosbuvir for the treatment of HCV-infection.
In study P7977-0915, a single dose PK study in subjects with varying degrees of renal 
impairment, exposure (AUCinf) of sofosbuvir and the renally eliminated metabolite, GS-331007, 
were 2.7- and 5.5-fold higher respectively in subjects with severe renal impairment compared to 
matched controls with normal renal function.  A significant dose reduction (eg, 2- to 4-fold) of 
sofosbuvir would be necessary to provide comparable GS-331007 exposures in subjects with 
severe renal impairment and those with normal renal function. Data from dose-finding and 
Phase 2 studies demonstrated that sofosbuvir, dosed once daily, was necessary to provide the 
active anabolite at the site of action (circulating GS-331007 cannot be phosphorylated to the 
active anabolite); therefore, dose interval modifications may not be appropriate. The efficacy of a 
substantially reduced dose of sofosbuvir in subjects with severe renal impairment has not been 
established.  
Cohorts 1 and 2 of this study will evaluate the safety, efficacy and pharmacokinetics of 2 doses 
of sofosbuvir (200 and 400 mg) in subjects with severe renal impairment. The reduced dose of 
200 mg sofosbuvir provided comparable systemic exposures of sofosbuvir, and approximately 
4-fold higher GS-331007 exposure compared to HCV-infected in subjects with normal renal 
function at the 400 mg dose. As such, GS-331007 and SOF exposures in Cohort 2 (400 mg SOF) 
are expected to increase 2-fold over that observed in Cohort 1. Review of safety, efficacy and 
pharmacokinetic data from Cohort 2 through 12 weeks of treatment will inform the initiation of 
Cohort 3 (90/400 mg LDV/SOF in subjects with severe renal impairment).
1.8.
Rationale for RBV Dose Selection
Ribavirin increases treatment response rates when administered with interferon or PEG. In 
addition, reducing the RBV dose from 1000-1200 mg/day to 600 or 800 mg/day when given in 
combination with SOF reduced SVR rates, as did SOF monotherapy. It is therefore desirable to 
keep RBV as part of the SOF treatment regimen. Since RBV is cleared renally and its main 
toxicity is hemolytic anemia which is poorly tolerated in patients with advanced renal 
insufficiency who are usually anemic at baseline and have little bone marrow reserve, the 


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starting dose of RBV must be substantially lower than 1000-1200 mg/day. For this study, a dose 
of 200 mg/day has been selected based on investigator input in light of the high frequency of 
hemotoxicity of RBV and the general desire to optimize the efficacy of the treatment regimen
{24149}.
To date there has been no safety signal identified that is attributable to SOF when administered 
as part of a combination regimen. Furthermore, SOF does not exacerbate the toxicities associated 
with RBV, most notably hemolytic anemia. Clinical data with SOF in severe renal insufficiency 
and in subjects requiring hemodialysis is limited to a single dose study in non-HCV infected 
subjects. No specific safety signals were identified. The current study is designed to assess the 
safety and efficacy of therapeutic treatment with SOF+RBV in a small number of subjects with 
severe renal insufficiency. 
The potential benefit of successful treatment of HCV in these subjects is substantial. Few 
patients with severe renal insufficiency can tolerate combination therapy with PEG+RBV due to 
profound anemia. SVR rates to interferon monotherapy administered for 48 weeks are less than 
50%. Interferon-free treatment for 24 weeks could provide substantial improvements in safety, 
tolerability and efficacy for individuals with chronic HCV infection.
1.9.
Rationale for Ledipasvir/Sofosbuvir Fixed Dose Combination (FDC) Dose 
Selection
A fixed-dose combination tablet (FDC) of ledipasvir/sofosbuvir 90/400 mg with or without RBV 
has demonstrated favorable safety and efficacy profiles in over 3000 HCV-infected subjects 
across different patient populations in Phase 2 and 3 trials. This FDC represent the marketed 
doses of ledipasvir and sofosbuvir (Harvoni®, LDV/SOF) approved in the US and Europe for the
treatment of chronic HCV infection including treatment naïve and experienced patients with 
GT1.
In support of dosing LDV/SOF to HCV-infected subjects with severe renal impairment, available 
pharmacokinetic data has been evaluated to project mean exposures of GS-331007 and SOF that 
may be achieved in these subjects (Table 1-3). Overall, increased GS-331007 exposures are 
expected in the context of LDV/SOF as compared to SOF administered as single agent 
(SOF USPI and LDV/SOF NDA, Module 2.7.2). Minimal safety data is available at these high 
exposures, irrespective of SOF being administered with LDV or as a single agent. The study 
design allows for consistent progression (~2-3 fold increase) of GS-331007 exposure across 
cohorts enabling assessment of exposure vs. safety relationships while potentially providing 
greater efficacy with the two-drug combination. 


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Table 1-3.
Observed and Predicted GS-331007 and SOF Exposure in Subjects 
with Renal Impairment
Mean (%CV, if applicable)
PK Parameter
GS-331007
SOF
AUCtau 
(ng•hr/ml)
Cmax 
(ng/ml)
AUCtau 
(ng•hr/ml)
Cmax
(ng/ml)
Observed Data
GS-US-334-0154 Cohort 1 SOF 200 mg
Week 12 (n = 10)
31,100
(53.9)
1730
(44.9)
1280
(50.3)
904
(66.2)
Predicted Data
Cohort 3:
LDV/SOF 90/400 mg in Severe RIa
111,000
4400
3430
2330
Pharmacokinetic parameters are shown to 3 significant digits
a
Predicted as the LDV/SOF Phase 2/3 population multiplied times the ratio of predicted SOF 400 mg in severe RI to 
SOF Phase 2/3 population.


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2. 
OBJECTIVES 
The prima1y objectives of this study are: 
Final 
Amendment3 
• 
To evaluate the safety of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks and LDV/SOF for 12 weeks as assessed by review of the accumulated safety data 
in each treatment rum 
• 
To evaluate the efficacy of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks and LDV/SOF for 12 weeks measured by the prop01iion of subjects with renal 
insufficiency who have achieved a sustained viral response 12 weeks after treatment 
discontinuation (SVR12) in each treatment ann 
• 
To evaluate the steady state phrum acokinetics ofSOF and its metabolites and LDV upon 
dosing SOF 200 mg or 400 mg or LDV/SOF in subjects with renal insufficiency 
The secondruy objectives of this study ru·e: 
• 
To evaluate the prop01iion of subjects with renal insufficiency who attain SVR at 
4 and 24 weeks after discontinuation of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of plasma HCV RNA during and after treatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV during and after treatment 
discontinuation 
The explorat01y objective of this study is: 
PPO 
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3.
STUDY DESIGN
This is a multicenter, open label study that will evaluate the safety, tolerability and antiviral 
efficacy of SOF with RBV or LDV/ SOF in chronic renal insufficiency and HCV infection
subjects with genotype 1, 3 or genotype 4 HCV infection, including those with compensated 
cirrhosis.
This study will have 3 cohorts.
Approximately 30 subjects with severe renal insufficiency will be enrolled. 

Cohort 1: 10 subjects will receive SOF 200 mg QD + RBV 200 mg QD for 24 weeks.

Cohort 2: Following review of safety, efficacy and PK data through post-treatment Week 4 
of Cohort 1, 10 additional subjects will receive SOF 400 mg QD + RBV 200 mg QD for 
24 weeks.

Cohort 3: Following review of safety and available PK data through Week 12 of Cohort 2, 
10 additional subjects will receive LDV/SOF QD for 12 weeks.
3.1.
Treatment Plan and Regimen
Following screening procedures and Day 1 assessments, eligible subjects will receive 
one of the following treatments:
Cohort 1: SOF 200 mg QD + RBV 200 mg QD for 24 weeks
Cohort 2: SOF 400 mg QD + RBV 200 mg QD for 24 weeks
Cohort 3: LDV/SOF QD for 12 weeks
Additional information about study drug administration can be found in Section 5.
3.2.
Visit Schedule
All subjects will complete screening, on-treatment and post-treatment assessments. Screening 
assessments will be completed within 42 days of the Day 1 visit. All subjects will complete the 
Week 4 Post-Treatment visit. Weeks 12 and 24 Post-Treatment visits will be dependent on 
subject viral load.
The assessments performed at each visit are described in Section 6.


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3.3.
Virologic Response-Based Stopping Criteria
The following stopping criteria will be used for subjects on treatment:

Confirmed HCV RNA ≥LLOQ after 2 consecutive HCV RNA <LLOQ

Confirmed >1 log10 increase from nadir 

Confirmed HCV RNA ≥LLOQ after 8 weeks of treatment
Confirmation should be performed as soon as possible but within 2 weeks after determination of 
initial observation.
Cardiac Function-Based Stopping Criterion
The following stopping criterion will be used for subjects on treatment:

Left ventricular ejection fraction ≤40%
3.4.
Treatment Discontinuation Criteria
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication must be discontinued in the following instances:

Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises the
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest.

Pregnancy of female subject, or female partner of male subject.

Efficacy failure as defined in Section 3.3.

Declining cardiac function, defined as left ventricular ejection fraction ≤40%.

Significant protocol violation including non-compliance with study assessments. 

Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy or other reason.

Discontinuation of the study at the request of Gilead, regulatory agency or an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
Subjects who discontinue treatment earlier than the assigned 12 or 24-week treatment duration 
will complete an Early Termination Visit (Section 6.7).


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 30 subjects will be treated in this study.
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) Chronic HCV infection documented by either:
a) a positive anti-HCV antibody test or positive HCV RNA or positive HCV genotyping test 
at least 6 months prior to the Day 1 visit, or
b) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV infection
4) Infection with HCV GT 1, 3 or 4 as determined at Screening, as applicable to cohort
5) Subjects must have the following laboratory parameters at Screening: 
a) HCV RNA ≥104 IU/mL
b) ALT ≤10 the upper limit of normal (ULN)
c) AST ≤10 ULN
d) Hemoglobin ≥9 g/dL 
e) Albumin ≥3.0 g/dL
f)
Direct bilirubin ≤1.5 ULN
g) HbA1c ≤10%


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h) Creatinine clearance (CLcr) 30 mL/min, as calculated by the Cockcroft-Gault equation 
{2202} using ideal body weight (IBW).
Male:
CLcr (mL/min) = [140 −age (years)] IBW (kg)
72 Scr
Female:
CLcr (mL/min) = [140 −age (years)] IBW(kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
Ideal body weight (IBW) is estimated by the following equations: 
Males:
IBW (kg) = 50 kg + 2.3 kg for each inch over 5 feet
Females:
IBW (kg) = 45.5 kg + 2.3 kg for each inch over 5 feet
a.
Subjects with CLcr 30-40 mL/min are eligible if they have a prior CLcr ≤30 mL/min
within 6 months of Screening
6) INR ≤1.5 ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR.
7) A negative serum pregnancy test for female subjects of childbearing potential 
(see Appendix 2 for definition). 
8) Male subjects and female subjects of childbearing potential (see Appendix 2 for definition) 
must agree to use protocol specified method(s) of contraception as described in Appendix 2.
9) Lactating females must agree to discontinue nursing before administration of study drug.
10) Subject must be of generally good health as determined by the Investigator. 
11) Subject must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments.
12) Cirrhosis Determination (For all cohorts)

Cirrhosis is defined as any one of the following:
Liver biopsy showing cirrhosis
Fibroscan (in countries where locally approved) showing cirrhosis or results 
> 12.5 kPa
FibroTest® score of > 0.75 AND an AST: platelet (APRI) ratio of > 2 during 
Screening


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
Absence of cirrhosis is defined as any one of the following:
Liver biopsy within 2 years of Screening showing absence of cirrhosis
Fibroscan (in countries where locally approved) with a result of ≤12.5 kPa within 
≤6 months of Day 1
FibroTest® score of ≤ 0.48 AND APRI of ≤1 during Screening
In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria, 
a liver biopsy is required.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) BMI < 18
2) Prior exposure to an direct-acting antiviral targeting HCV NS5B (all cohorts) or HCV NS5A 
(Cohort 3 only)
3) Prior null response to PEG+RBV therapy (Cohorts 1 and 2) or for patients with cirrhosis, 
prior treatment failure with IFN-based therapy not resulting from treatment intolerance
(Cohort 3)
4) Male with pregnant female partner (Cohorts 1 and 2 only)
5) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency, cholangitis)
6) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)
7) Unstable psychiatric condition 
8) Significant cardiac disease including or resulting in:
a) Cardiomyopathy
b) Left ventricular ejection fraction ≤50%
c) Hospital admission for myocardial infarction, heart failure within 1 year of Screening 
d) Pulmonary hypertension within 1 year of Screening
9) Clinically significant abnormality on ECG at Screening, including a QTcF > 500 msec, or 
> 450 msec in patients who concomitantly use methadone.


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10) History of clinically significant hemoglobinopathy (Cohorts 1 and 2 only)
11) History of porphyria (Cohorts 1 and 2 only)
12) Malignancy within the 5 years prior to screening, with the exception of specific cancers that 
are cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation for 
possible malignancy are not eligible.
13) Chronic use of systemically administered immunosuppressive agents 
(e.g., prednisone equivalent > 10 mg/day)
14) Clinically-relevant drug or alcohol abuse within 12 months of Screening
15) Current or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, 
encephalopathy or variceal hemorrhage)
16) History of clinically-significant illness or any other major medical disorder that may interfere 
with subject treatment, assessment or compliance with the protocol
17) History of a primary gastrointestinal disorder (or post operative condition) that could 
interfere with the absorption of the study drug 
18) Excessive alcohol ingestion, defined as > 3 glasses/day (1 glass is equivalent to: 
beer [284 mL], wine [125 mL], or distilled spirits [25 mL]) for females and > 4 glasses/day 
for males)
19) Inability to collect blood for safety, PK, and efficacy throughout the study
20) Donation or loss of more than 400 mL blood within 2 months prior to Day 1 
21) Use of any prohibited concomitant medications as described in Section 5.8 within 21 days of 
the Day 1 visit
22) Known hypersensitivity to RBV (Cohorts 1 and 2 only), the study investigational medicinal 
product, the metabolites, or formulation excipients
23) Receipt of any investigational product within a time period equal to 10 half-lives of the 
product, if known, or a minimum of 4 weeks prior to study drug administration
24) Subjects with hepatocellular carcinoma (HCC) are excluded from the study. In cirrhotic 
patients, liver imaging (e.g., ultrasound) within 6 months of Day 1 is required to exclude 
hepatocellular carcinoma (HCC)


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Sofosbuvir (SOF)
5.1.1.
Formulation
SOF tablets, 100 mg, are yellow, round, film-coated, plain-faced tablets. 
SOF tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets debossed with “GSI” on 
one side and “7977” on the other side. 
In addition to the active ingredient, SOF tablets contain the following inactive ingredients: 
mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, and yellow iron oxide.
5.1.2.
Packaging and Labeling
SOF tablets, 100 mg, are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 28 tablets and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child-resistant screw cap with an induction-sealed, aluminum-faced liner.
SOF tablets, 400 mg, are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains either 28 or 30 tablets and a silica gel desiccant canister or sachet and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child-resistant screw 
cap with an induction-sealed, aluminum-faced liner.
SOF bottles to be distributed to centers in the US and other countries shall be labeled to meet all 
applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 of 
Good Manufacturing Practices: Manufacture of investigational medicinal products 
(February 2010) and/or other local regulations as applicable.
5.1.3.
Storage and Handling
SOF bottles should be stored at a 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.
Sufficient quantities of SOF 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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5.1.4.
Sofosbuvir (SOF) Dosage and Administration
SOF will be administered as 200 mg or 400 mg po daily. SOF (100 mg or 400 mg) tablets will be 
supplied by Gilead Sciences for all subjects.
5.2.
Ribavirin (RBV)
5.2.1.
Formulation
RBV tablets, 200 mg, are blue, capsule-shaped, film-coated tablets debossed with “3RP” on one 
side and “200” on the other side. In addition to the active ingredient, RBV tablets contain the 
following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose 
sodium, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc,
FD&C blue #2.
5.2.2.
Packaging and Labeling
The RBV tablets are packaged in white, HDPE bottles. Each bottle contains 168 tablets and 
rayon coil packing material and is enclosed with a white, continuous thread, child-resistant screw 
cap with an induction-sealed, aluminum-faced liner.
RBV bottles to be distributed to centers in the US and other countries shall be labeled to meet all 
applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 of Good 
Manufacturing Practices: Manufacture of investigational medicinal products (February 2013) 
and/or other local regulations as applicable.
5.2.3.
Storage and Handling
RBV tablets should be stored at 25 C (77 F); excursions are permitted between 15 and 30 C 
(59 and 86 F).
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling RBV.
5.2.4.
RBV Dosage and Administration
RBV will be administered as 200 mg po daily. RBV should be dosed with food and with SOF to 
maximize adherence. RBV dose may be managed at the discretion of the Investigator in 
communication with the Medical Monitor.
RBV tablets (200 mg) will be supplied by Gilead Sciences for all subjects.


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5.3.
Co-administration of Sofosbuvir (SOF) and Ribavirin (RBV)
Each subject will be given instructions to maintain approximately the same daily dosing interval 
between study drug doses.  
If a subject forgets to take the medication at the correct time, it may be taken later in the day; 
however, no more than 400 mg dose of SOF should be taken on any calendar day. The subject 
should resume the standing dosing schedule on the next day.  Study medications should not be 
cut or split. No food restrictions apply to SOF; however, SOF should be taken with RBV and 
with food for optimal adherence.
On the day of clinic visits, subjects will be instructed to take their study medication on the day 
prior to clinic visits, 20-28 hours before the administration of the study medication at the clinic.
Subjects should bring their medication with them to the clinic and take their study medication
after all pre-dose assessments are completed. 
5.4.
Ledipasvir/ Sofosbuvir (LDV/SOF)
5.4.1.
Formulation
Ledipasvir 90mg/ sofosbuvir 400mg fixed dose combination (FDC) tablets are orange, 
diamond-shaped, film-coated tablets containing 400 mg of SOF and 90 mg of LDV. The tablets 
are debossed with “GSI” on one side and “7985” on the other side. The LDV/SOF
(90mg/400mg) tablets contain the following inactive ingredients: lactose monohydrate, 
copovidone, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, 
FD&C yellow # 6 /sunset yellow FCF aluminium lake.
5.4.2.
Packaging and Labeling
Ledipasvir 90 mg/ sofosbuvir 400 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle will contain 28 or 30 tablets, a silica gel desiccant and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child-resistant screw 
cap with an induction-sealed, aluminum-faced liner. 
LDV/SOF bottles to be distributed to centers in the US and other countries shall be labeled to 
meet all applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 
of Good Manufacturing Practices: Manufacture of investigational medicinal products 
(February 2010) and/or other local regulations as applicable.
5.4.3.
Storage and Handling
LDV/SOF bottles should be stored at controlled room temperature until required for 
administration. Controlled room temperature is defined as 25 C (77 F); excursions are 
permitted between 15 C and 30 C (59 F to 86 F).


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All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling LDV/SOF tablets.
Sufficient quantities of LDV/SOF tablets to complete the entire study will be shipped to the 
investigator or qualified designee from Gilead Sciences Clinical Supply Management
(or its designee).
5.4.4.
LDV/SOF Dosage and Administration
LDV/SOF will be administered as one 90 mg/400 mg tablet po daily with or without food for 
12 weeks. LDV/SOF tablets will be supplied by Gilead Sciences for all subjects.
5.5.
Study Drug Compliance
On Day 1, subjects will be administered study drugs and the assigned bottles will be dispensed to 
them along with a dosing diary to be used to document at home dosing. Subjects will be 
instructed to return dosing diaries and any unused study drug in the original container at each 
visit following Day 1 for study drug compliance assessment.
Returned medication will be reconciled by the investigator in order to monitor the subject’s 
compliance with the medication regimen.
5.6.
Dispensing and Accountability of Study Drugs
The Investigator (or designee, e.g., study center pharmacist) will acknowledge receipt of the 
study drugs (after reviewing the shipment’s content and condition) from Gilead Sciences 
(or designee). The Investigator will maintain an accurate inventory of all study drugs. Each dose 
of the study drug(s) administered at the study center will be administered by qualified study 
center personnel. All doses of study drug(s) administered to subjects in the clinic under the 
supervision of staff will be accurately recorded on the Investigational Product Inventory Logs 
provided by Gilead Sciences (or on equivalent documentation maintained by the study center), 
which indicates the date and quantity of all doses of study drug(s) dispensed to individual 
subjects. The requirements of all applicable Federal and State drug dispensing laws will apply to 
all doses of study drugs dispensed by the Investigator (or designee). At the end of the study, all 
unused study drugs (both bulk and individual subject returns) will be returned to a location 
designated by Gilead Sciences.
5.7.
Study Drug Return or Disposal
At the start of the study, the study monitor will evaluate each study center’s study drug disposal 
procedures and provide appropriate instruction for return or destruction of unused study drug 
supplies. If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, 


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the site may destroy used and unused study drug supplies performed in accordance with the 
site’s (hospital/pharmacy) SOP. If the site does not have acceptable procedures in place for 
drug destruction, arrangements will be made between the site and Gilead Sciences 
(or Gilead Sciences’ representative) for return of unused study drug supplies. Where possible, 
study drug will be destroyed at the site.  If drug is destroyed on site, the investigator must 
maintain accurate records for all study drug destroyed. All study drug records must be 
maintained at the site and copies must be submitted to Gilead Sciences at the end of the study.
5.8.
Concomitant Medications
Concomitant medications taken within 30 days of Screening, up to and including the date of the 
visit four weeks after discontinuation of study treatment, need to be recorded in the source 
documents and eCRFs.
5.8.1.
Cohorts 1 and 2
The following medications are prohibited from 21 days prior to the Day 1 visit through the end 
of treatment:

Drugs disallowed per prescribing information of RBV (COPEGUS®)

Concomitant use of certain medications or herbal/natural supplements (inducers of 
drug transporters i.e. P-gp) with study drug(s) may result in pharmacokinetic interactions 
resulting in decreases in exposure of study drug(s).  Representative medications which are 
excluded from 21 days prior to Day 1 through the end of treatment are listed below:
Drug
Agents Disallowed
Concomitant use with study drug may 
potentially result in changes of study 
drug concentration as listed below
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Decrease in concentration of study drug
Antimycobacterials
Rifampin, rifabutin, rifapentine
Decrease in concentration of study drug
Herbal/Natural Supplements
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-Tang)
Decrease in concentration of study drug
Other
Modafinil
Decrease in concentration of study drug
5.8.2.
Cohort 3
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters ie, P-gp) with study drug(s) may result in PK interactions resulting in increases 
or decreases in exposure of study drug(s). Examples of representative medications which are 
prohibited from 21 days prior to Baseline/Day 1 through the end of treatment are listed below:


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Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton-Pump Inhibitors, 
H2-Receptor Antagonists, Antacids
Antiarrhythmics b
Quinidine
Anticonvulsantsc
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Antimycobacterialsc
Rifabutin, Rifapentine, Rifampin
Cardiac Medications b
Digoxin
Herbal/Natural Supplementsc
St. John’s Wort, Echinaccea, Milk 
thistle (i.e., silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase Inhibitorsd
Rosuvastatin
Pravastatin, Pitavastatin
a
It is recommended to separate antacid and LDV/SOF administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF at a dose that does not exceed doses comparable to 
famotidine 40 mg twice daily.  Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with LDV/SOF. Proton-pump inhibitors should not be taken before LDV/SOF. 
b
May result in an increase in the concentration of study drugs and/or concomitant medications. Coadministration of 
LDV/SOF with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration 
monitoring of digoxin is recommended when coadministered with LDV/SOF. 
c
May result in a decrease in the concentrations of study drugs.
d
Use with study drugs may result in an increase in the concentration of the HMG-CoA Reductase Inhibitors. Monitor for 
signs and symptoms of muscle weakness or myopathy, including rhabdomyolysis.
5.8.3.
All Cohorts
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 
prohibited in the study.
Should it become medically necessary for patients to start treatment with any excluded 
concomitant medication, the sponsor must be consulted prior to initiation of the new medication 
and the subject’s continued participation must be discussed with the Gilead Medical Monitor.
5.8.3.1.
Medications Associated with QT Prolongation
Medications that are known to cause or are associated with QT prolongation and/or a risk of 
causing torsades de pointes should be avoided in patients with risk factors for developing long 
QT intervals or those receiving other QT-prolonging medications. These medications include, 
but may not be limited to those listed below (see table below) and must be approved by the 
Gilead Medical Monitor prior to study enrollment or coadministration during the study.


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Representative List of Medications Known or Associated with QT Prolongation
QT Prolonging Medication Class
Known or Strongly Suspected to cause 
QT Prolongation
Weaker Association with QT Prolongation
Antibiotics/Anti-infectives:
Macrolide Antibiotics
azithromycin, clarithromycin, erythromycin, 
roxithromycin, telithromycin
Quinolone Antibiotics
gatifloxacin, gemifloxacin, levofloxacin, 
moxifloxacin, ofloxacin, sparfloxacin
ciprofloxacin
Certain antimalarials/pneumocystis prophylaxis; others
artenimool+piperaquine, bedaquiline, chloroquine, 
halofantrine, pentamidine
trimethoprim-sulfa, quinine sulfate
Antipsychotics:
Phenothyazine Antipsychotics
chlorpromazine, mesoridazine, thioridazine
Other Antipsychotics
clozapine, haloperidol, iloperidone, olanzepine, 
paliperidone, pimozide, quetiapine, risperidone, 
sertindole, ziprasidone
amisulpride,
Anit-mania Bipolar Disorders:
lithium
Anti-depressants:
Serotonin re-uptake inhibitors
citalopram, escitalopram, venlafaxine
fluoxetine, paroxetine, sertraline
Tricyclic anti-depressants
amitriptyline, clomipramine, desipramine, 
doxepin, imipramine, nortriptyline, 
protriptyline trimipramine,
Tetracyclic anti-depressants
mirtazepine
trazodone


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QT Prolonging Medication Class
Known or Strongly Suspected to cause 
QT Prolongation
Weaker Association with QT Prolongation
Cardiology Medications:
Class I (Na+) and III (K+) anti-arrhythmics
amiodarone, disopyramide, dofetilide, 
dronedarone, flecainide, ibutilide, mexiletine, 
procainamide, quinidine
Class II (β blockers) and IV (Ca2+) anti-arrythmics
isradipine, sotalol (Class II/III)
Certain anti-anginals/ calcium blocker
bepridil, nicardipine, ranolazine
Anesthetics, Pain Medications and Additional 
Treatment:
levomethadyl, methadone
general anesthetics 
(e.g., enflurane, halothane, isoflurane, 
sevoflurane)
Anti-nausea:
domperidone, droperidol, dolasetron, granisetron, 
ondansentron, promethazine
Azole anti-fungals (systemic use only)
ketoconazole, voriconazole
fluconazole, itraconazole
Others:
alfuzosin, amantadine, astemizole, cisapride, 
famotidine, felbamate, fosphenytoin, galantamine, 
indapamide, moexipril/HCTZ, octreotide, 
oxytocin, pasireotide, perflutren lipid 
microspheres, probucol, sibutramine, terfenadine,   
tizanidine, tolterodine, vardenafil
chloral hydrate, diphenhydramine, 
solifenacin


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Should it become medically necessary for patients to start treatment with any excluded 
concomitant medication, the sponsor must be consulted prior to initiation of the new medication 
and the subject’s continued participation must be discussed with the Gilead Medical Monitor.
5.8.3.2.
Hematopoietic Growth Factors
Erythropoiesis stimulating agents (ESAs) should not be used during Screening solely to elevate 
hematology laboratory parameters to facilitate entry into the study.  Patients taking ESAs for 
anemia related to chronic kidney disease may enter the study. Granulocyte colony-stimulating 
agents and thrombopoietic growth factors should not be used while the subject is receiving study 
treatment.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in
Table 6-1 and Table 6-2 and described in the following text. 
Any deviation from protocol procedures should be noted in the subject’s clinical chart and 
appropriate eCRFs. In addition, the Sponsor should be promptly notified of any protocol 
deviations. 
The study center will not be released to initiate dosing until:

The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) reviewed and 
approved the study and the informed consent document;

All requested regulatory documents have been submitted to and approved by 
Gilead Sciences;

A Master Services Agreement and/or Study Agreement is executed;

The study initiation meeting has been conducted by the Gilead Sciences clinical monitor 
(or designee).
The initiation meeting will include a review of the protocol, the Investigator’s Brochure, and 
Investigator responsibilities.
Documentation of the personally signed and dated informed consent of each subject, using the 
study-specific informed consent form (ICF), is required before initiating the screening process. 
Generic screening consent forms should not be used in lieu of the study-specific ICF.
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment and throughout the study.
Once consent has been obtained, all screening tests and procedures have been assessed, and
study eligibility has been confirmed, subjects will be enrolled and assigned a unique subject 
identification number.
Subjects will receive the study treatment as described in Section 5.


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Table 6-1.
Schedule of Assessments for Cohorts 1 and 2
Study 
Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Written Informed 
Consent
X
Medical History 
X
HCV RNA 
Genotype
X
IL28B 
Genotyping
X
HbA1c
X
HCV, HBV, 
HIV Serology
X
TSH
X
Physical Exam, 
including 
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram 
X
X
X
Height
X
Weight
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Study 
Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Coagulation 
(PT, PTT, and 
INR)
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA Viral 
Load
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA 
Sequencing 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy 
Teste
X
X
X
X
X
X
X
X
X
X
X
X
Creatinine 
Clearance
X
Optional 
Pharmacogenetic 
Samplek
X
Intensive PK
Xf
Xf
Trough PK 
Sampleg
X
X
X
X
X
X
X
X
X
Archive Plasma 
Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
Administration
X
Weeks 1-24


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Study 
Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Review Dosing 
Diary/Perform 
Accountabilityh
X
X
X
X
X
X
X
X
X
X
AEs/
Concomitant 
Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Screening evaluations must be completed within 42 days prior to Day 1.
b
Day 1 tests and procedures must be completed prior to administration of the first dose of study drugs 
c
Within 72 hours of permanently discontinuing study drug.
d
Full PE at Day 1 and ET visits only; symptom-directed PE at all other timepoints. Vital signs include blood pressure, pulse, respiration rate, and temperature
e
Females of childbearing potential only. To confirm eligibility at Day 1, a urine pregnancy test may be collected for subjects able to pass urine. For subjects unable to pass 
urine, a serum pregnancy test at Day 1 must be performed at a local lab prior to dosing to confirm eligibility along with sample collected and send to central lab. During 
post-treatment of the study, serum or urine pregnancy testing will occur every month during non-clinic post treatment visits. The subject will be contacted by telephone to 
confirm that pregnancy testing has been performed post-treatment during non-clinic visits.
f
Intensive plasma PK evaluations will be assessed at the following timepoints: 0 (predose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose.
g
Trough plasma PK samples will be drawn prior to dosing. 
h
Dosing Diaries will be completed for all non-observed doses and will be reviewed at every visit. Unused study drug will be returned to perform study drug accountability in 
the original container at each visit following Day 1 for study drug compliance assessment.
i
A window of ± 2 days is allowed for the treatment visits on weeks 1, 2, and 12.  A window of ± 4 days is allowed for the treatment visits weeks, 4-10, and 16-24. Subjects 
who cannot complete their study visit per the visit schedule should ensure they do not run out of study drug prior to their next study visit.  Compliance is critical to ensure 
adequate drug exposure.
j
A window of ± 7 days is allowed for the post treatment visits.
k
The sample should be collected on Day 1 prior to dosing, but may be collected at any time during the study or at a separate post-study visit, if necessary.


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Table 6-2.
Schedule of Assessments for Cohort 3
Study Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
4
Week
12
Week
24
Written Informed Consent
X
Medical History 
X
HCV RNA Genotype
X
IL28B Genotyping
X
HbA1c
X
HCV, HBV, HIV Serology
X
TSH
X
Physical Exam, including 
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
Echocardiogram 
X
X
Height
X
Weight
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
(PT, PTT, and INR)
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA Viral Load
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA Sequencing 
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy Teste
X
X
X
X
X
X
X
X
X
Creatinine Clearance
X


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Study Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
4
Week
12
Week
24
Optional Pharmacogenetic 
Samplek
X
Intensive PK
Xf
Xf
Trough PK Sampleg
X
X
X
X
X
X
Archive Plasma Sample
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Administration
X
Weeks 1-12
Review Dosing Diary/
Perform Accountabilityh
X
X
X
X
X
X
X
AEs/Concomitant Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Screening evaluations must be completed within 42 days prior to Day 1.
b
Day 1 tests and procedures must be completed prior to administration of the first dose of study drugs 
c
Within 72 hours of permanently discontinuing study drug.
d
Full PE at Day 1 and ET visits only; symptom-directed PE at all other timepoints. Vital signs include blood pressure, pulse, respiration rate, and temperature
e
Females of childbearing potential only. To confirm eligibility at Day 1, a urine pregnancy test may be collected for subjects able to pass urine. For subjects unable to pass 
urine, a serum pregnancy test at Day 1 must be performed at a local lab prior to dosing to confirm eligibility along with sample collected and send to central lab. During post-
treatment of the study, serum or urine pregnancy testing will occur every month during non-clinic post treatment visits. The subject will be contacted by telephone to confirm 
that pregnancy testing has been performed post-treatment during non-clinic visits.
f
Intensive plasma PK evaluations will be assessed at the following timepoints: 0 (predose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose once either on 
Week 2 OR 4, per investigator discretion.
g
Trough plasma PK samples will be drawn prior to dosing. 
h
Dosing Diaries will be completed for all non-observed doses and will be reviewed at every visit. Unused study drug will be returned to perform study drug accountability in 
the original container at each visit following Day 1 for study drug compliance assessment.
i
A window of ± 2 days is allowed for the treatment visits on weeks 1, 2, and 12.  A window of ± 4 days is allowed for the treatment visits weeks, and 4-10. Subjects who 
cannot complete their study visit per the visit schedule should ensure they do not run out of study drug prior to their next study visit.  Compliance is critical to ensure adequate 
drug exposure.
j
A window of ± 7 days is allowed for the post treatment visits. 
k
The sample should be collected on Day 1 prior to dosing, but may be collected at any time during the study or at a separate post-study visit, if necessary.


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6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Prospective subjects should be screened within 42 days prior to first dose on Day 1. If the subject 
does not begin the treatment phase within this 42-day window, all screening evaluation 
procedures must be repeated. No more than one repeat screen visit is allowed for each subject, 
unless prior written approval has been provided by the Sponsor.
Written informed consent must be obtained from each subject before initiation of any screening 
procedure. After a subject has provided informed consent, the investigator and other study 
personnel will determine if the subject is eligible for participation in the study. This assessment 
will include a review of the inclusion/exclusion criteria and completion of all screening 
procedures as outlined in Table 6-1 and Table 6-2.
Once eligibility is confirmed, the study site will complete an eligibility worksheet for each 
screened subject and submit for Sponsor review. The sponsor will assign a unique subject 
number for each eligible subject and provide the subject number information to the site prior to 
Day 1 visit. 
6.2.2.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history will be collected on all subjects during 
screening. Information related to HCV infection will be collected. In addition, a cirrhosis 
determination will be made as follows:
Cirrhosis determination

Cirrhosis is defined as any one of the following:
Liver biopsy showing cirrhosis
Fibroscan (in countries where locally approved) showing cirrhosis or results > 12.5 kPa
within 6 months of Day 1
FibroTest® score of > 0.75 AND an AST:platelet (APRI) ratio of > 2 during Screening

Absence of cirrhosis is defined as any one of the following:
Liver biopsy within 2 years of Screening showing absence of cirrhosis
Fibroscan (in countries where locally approved) with a result of ≤12.5 kPa 
within ≤6 months of Day 1
FibroTest® score of ≤ 0.48 AND APRI of ≤1 during Screening


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In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria, 
a liver biopsy is required.
In addition, a determination of cardiac function will be made as follows:

Echocardiogram demonstrating left ventricular ejection fraction > 50% performed prior to 
Day 1 visit. Enrollment allowed based on local read of study if central read is not available.
6.3.
Day 1 Assessments
Subjects meeting all eligibility criteria following the screening evaluation will return to the study 
site within 42 days for Day 1 assessments as outlined in Table 6-1 and Table 6-2.
6.3.1.
Dosing Diary
Subjects will be provided with self-administration instructions and study drug diaries to record 
the exact date, time and number of tablets of study drug administration. The site staff will record 
the information from the study drug dosing diary into the eCRF. In the event that the dosing 
diary is not available, the site may obtain dosing information via subject interview and record 
this information in the source notes
6.4.
Treatment Assessments
6.4.1.
Cohorts 1 and 2
Study visits will occur at the end of Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24.
Study procedures and assessments are outlined in Table 6-1.
6.4.2.
Cohort 3
Study visits will occur at the end of Weeks 1, 2, 4, 6, 8, 10, and 12
Study procedures and assessments are outlined in Table 6-2.
6.5.
Safety Assessments
Safety will be evaluated throughout the study. Refer to Table 6-1 and Table 6-2 for a schedule of 
assessments.
6.5.1.
Safety ECGs
Subjects should rest quietly in the supine position for a minimum of 10 minutes prior to each 
scheduled ECG acquisition and should remain in that position until the recording is complete. 
There must be no environmental distractions (television, radio, conversation, etc.) while the 
subjects are resting prior to and during the recordings.


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ECGs will be recorded at a sampling frequency of 500+ Hz, at a speed of 25 mm/sec and at a 
standard duration of 10 seconds. All ECGs will be obtained using instruments that analyze data 
using the same algorithms and produce the same data for interpretation. When ECGs are 
performed on an ECG machine, site standard operating procedures (SOPs) will be used.
ECG measurements will be collected pre-dose at time-points as per Table 6-1 and Table 6-2.
The Investigator or other qualified individuals at the study center will review ECGs to assess for 
changes in ECG intervals and morphology as compared to pre-dose ECGs. Collection of 
additional ECGs for routine safety monitoring at additional time-points or days is at the 
discretion of the Investigator based on GCP.
6.5.2.
Safety Echocardiograms
Safety echocardiograms will be performed as outlined in Table 6-1 and Table 6-2. A window of 
± 10 days is allowed for the on-treatment visits. These safety echocardiograms will be performed
locally and sent to a central location for standardized reading.
6.5.3.
Physical Examination
Complete physical examinations or a symptom directed physical examination will be conducted 
pre-dose as outlined in Table 6-1 and Table 6-2. A complete physical examination must include 
source documentation of general appearance, and the following body systems: head, neck and 
thyroid; eyes, ears, nose, throat, mouth and tongue; chest (excluding breasts); respiratory; 
cardiovascular; lymph nodes, abdomen; skin, hair, nails; musculoskeletal; neurological. 
6.5.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature and will be conducted pre-dose as outlined in Table 6-1 and Table 6-2.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.


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6.5.5.
BMI
Height and weight will be collected at the times shown in the schedule of assessments 
Table 6-1 and Table 6-2.
BMI is calculated by the following equation.
BMI =
weight (pounds) 703
(height in inches)2
or
weight in kilograms
(height in meters)2
6.5.6.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {2202} using 
ideal body weight (IBW). 
Male:
CLcr (mL/min) = [140 −age (years)] IBW (kg)
72 Scr
Female:
CLcr (mL/min) = [140 −age (years)] IBW (kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
Ideal body weight (IBW) is estimated by the following equations: 
Males: 
IBW (kg) = 50 kg + 2.3 kg for each inch over 5 feet
Females: 
IBW (kg) = 45.5 kg + 2.3 kg for each inch over 5 feet
6.5.7.
Clinical Laboratory Tests/Assessments
In addition to the PK blood samples that will be collected, blood samples will be collected 
pre-dose as outlined in the schedule of assessments, Table 6-1 and Table 6-2 for the following 
laboratory analyses:
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, MCV, and 
Coagulation Panel (PT, PTT, and INR).
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Creatinine, Total Bilirubin (reflex to Direct Bilirubin), Glucose, 
Total Protein, Bicarbonate, BUN, Calcium, Chloride, Phosphorus, Magnesium, Potassium,
Sodium, and FibroTest®.


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Thyroid-stimulating hormone (TSH)
Haemoglobin A1C (HbA1c)
Virological Tests: Serologies for HCV, HBV and HIV. HCV RNA will be measured using 
COBAS® AmpliPrep/COBAS® TaqMan® HCV Test. HCV genotype and subtype will be 
determined using the Siemens VERSANTHCV Genotype INNO-LiPA 2.0 Assay. Gilead 
reserves the right to use alternate assays for HCV RNA and HCV genotype should the above 
assays become unavailable or are not definitive.
Viral RNA Sequencing/Phenotyping plasma samples will be collected to confirm virologic 
breakthrough. Untested samples may be archived.
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: All females of childbearing potential will have serum or urine pregnancy 
testing every 4 weeks during the dosing period and for a minimum of 6 months following the last 
dose of RBV. If required by local regulations, additional pregnancy tests may be collected. In the 
event of a positive urine pregnancy result, subjects will be instructed to stop study drugs 
immediately and return to the clinic as soon as possible for a serum pregnancy test.
Pregnancy tests must be completed for all females of childbearing potential (see Appendix 2
for definition) as specified in Table 6-1 and Table 6-2. When feasible for subjects, a urine 
pregnancy test may also be taken. During post treatment of the study, subject will be contacted 
by telephone monthly to confirm that the serum or urine pregnancy testing has been performed 
post-treatment during non-clinic visits. Alternatively, if required by local regulations or preferred 
by the investigator or subject, the subject may return to the clinic for urine or serum pregnancy 
tests post treatment.
6.5.8.
Adverse Events/Concomitant Medications/Protocol Restrictions
Evaluation for adverse events, review of concomitant medications, and review of protocol 
restrictions will occur at the times shown in the schedule of assessments Table 6-1 and
Table 6-2. See Section 7 for more information regarding adverse events and Section 5 for more 
information about concomitant medications.
6.6.
Pharmacokinetic (PK) Assessments
Subjects will be instructed to take their SOF or LDV/SOF dose on the day prior to clinic visits, 
20-28 hours before the clinic visit. On the day of clinic visits, subjects should bring their 
medication with them to the clinic and take their dose after the trough PK sample is collected, or 
after the predose intensive PK sample is taken.
The exact time of the dose taken prior to collection of the PK sample and the exact time the PK 
sample is drawn will be recorded on the appropriate eCRF.


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Intensive PK Assessments:
Cohorts 1 and 2:
Serial plasma PK samples will be collected on week 2 and 12 at the following timepoints:

0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours post-dose. 
Cohort 3:
Serial blood samples will be collected once either on week 2 OR 4 (per investigator discretion) at 
the following timepoints:

0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours post-dose.
Plasma concentrations of SOF and its metabolites and LDV will be determined and PK 
parameters will be estimated as appropriate. Plasma concentrations of RBV may be determined, 
as applicable.
Trough PK Assessments:
Trough PK plasma samples for analyses of SOF, its metabolites, RBV and LDV concentrations 
will be collected at all other on treatment visits beginning at the Week 1 visit as applicable.
PK Parameters for SOF, its metabolites, LDV and RBV will be estimated as appropriate. 
6.7.
Early Termination (ET)/Unscheduled Visit
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The 
assessments at the unscheduled visits are at the investigator’s discretion. At all unscheduled 
visits initiated for the purpose of confirming virologic failure a Viral RNA 
Sequencing/Phenotyping Sample must be collected. 
The Sponsor (e.g. Medical Monitor and Clinical Program Manager)/CRO must be informed, as 
soon as possible, when a subject prematurely discontinues treatment. The primary reason for 
premature treatment discontinuation must be provided to the Sponsor/CRO.
If a subject discontinues treatment early for any reason then the following assessments for the 
Early Termination (ET) Visit must be performed: 

Perform complete physical examination

Obtain body weight

Obtain vital signs

Assessment of AEs and concomitant medications


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• 
Pregnancy prevention counseling 
• 
Obtain blood samples for: 
-
Hematology & Chemistiy 
-
Coagulation (PT, PTT, and INR) 
-
HCVRNA 
-
Viral Sequencing I Phenotyping Sample 
-
TroughPK 
-
Semm pregnancy test (females of childbearing potential only) 
Final 
Amendment3 
• 
Review study dmg adherence with subject including recording the date and time of the 
subject's last dose of study dmg prior to the PK draw (subject should retum all study dmgs at 
this visit) 
All subjects will attend the 4-Week Post-Treatment Visit. 
6.8. 
Post-Treatment Assessments 
Subjects with HCV RNA < LLOQ at the 4-Week Post-Treatment Visit will attend the 12-Week 
Post-Treatment Visit. 
Subjects with HCV RNA ~ LLOQ do not need to retum for additional visits and they will be 
tenninated early from the study. 
Subjects with HCV RNA < LLOQ at the Post-Treatment Week 12 Visit will retum at the 
post-u·eatment Week 24 Visit. 
6.9. 
Optional Samples for Pharmacogenetic Testing 
PPD 
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6.10.
Archived Plasma Sample
Archive plasma samples will be collected at the study visits, indicated in Table 6-1 and 
Table 6-2. Archive plasma samples are being collected for possible additional analyses, 
including but not limited to, study drug or metabolite measurements, viral load, safety/efficacy 
assessments, HCV gene sequencing, HCV resistance testing and other possible predictors of 
response as determined by Gilead.
In the event of a subject’s death or loss of competence, the subject’s specimens and data will 
continue to be used as part of the future biomarker research.
If a subject wishes to withdraw the testing of his or her specimens for future research, the 
investigator must inform the Gilead Sciences Medical Monitor in writing of the subject’s wishes.
6.11.
Blood Storage
Archived plasma samples will be collected for future testing. These samples will be frozen and 
stored. The stored plasma samples may be used by the Sponsor or its research partner for future 
clinical laboratory testing to provide additional clinical data. At the conclusion of this study, 
these samples may be retained in storage by Gilead Sciences, Inc. at its research partner facility 
for a period up to 10 years.


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


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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


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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30-days of the 
last dose of study IMP, regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period, 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:
Gilead DSPH:
Fax:
E-mail:
+1-650-522-5477
safety_fc@gilead.com

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.


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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to expedite 
to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), 
or suspected unexpected serious adverse reactions (SUSARs). In accordance with the 
EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide 
regulatory agencies and the relevant IEC in concerned Member States of applicable SUSARs as 
outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. 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. 
7.5.
Toxicity Management
7.5.1.
Stopping Rules for Toxicity
Subjects who meet any of the following criteria should be instructed to immediately stop all 
study drugs and return for an Early Termination Visit:

Confirmed elevation of ALT and/or AST > 5× Day 1 or nadir, confirmed by immediate 
repeat testing

Confirmed elevation of ALT > 3× Day 1 and total bilirubin > 2 × ULN

Confirmed elevation of ALT >15 x ULN

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event assessed as related to treatment 

Echocardiogram demonstrating left ventricular ejection fraction ≤40%
7.5.2.
Sofosbuvir (SOF) or LDV/SOF 
Administration of SOF or LDV/SOF may be discontinued due to a clinical or laboratory event.  
There is no option for sofosbuvir or LDV/SOF dose reduction. In the event that SOF is stopped, 
RBV should also be discontinued. 


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7.5.3.
Ribavirin (RBV)
Dose reduction or interruption of RBV due to toxicity should be performed based on the clinical 
experience of the Investigator. RBV may be temporarily discontinued due to toxicity without 
stopping SOF. However, if RBV is permanently discontinued due to toxicity, SOF should also be 
discontinued.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.
A pregnancy report is used to report any pregnancy following maternal or paternal exposure to 
the medicinal product.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (ie, signs the informed consent) and throughout the study, including the 
post study drug follow-up period, to the Gilead DSPH using the pregnancy report form within 
24 hours of becoming aware of the pregnancy. Refer to Section 7.3 and the eCRF completion 
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The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.3 and 7.4. 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. 
Clinical staff should also report any relevant pregnancies to the Ribavirin Pregnancy Registry 
at 1-800-593-2214 (see also http://www.ribavirinpregnancyregistry.com).
Refer to Appendix 2 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of medications prohibited by this protocol should not be reported as 
“misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The prima1y objectives of this study are as follows: 
Final 
Amendment3 
• 
To evaluate the safety of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks and LDV/SOF for 12 weeks as assessed by review of the accumulated safety data 
in each treatment mm 
• 
To evaluate the efficacy of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks and LDV/SOF for 12 weeks measured by the prop01iion of subjects with renal 
insufficiency who have achieved a sustained viral response 12 weeks after treatment 
discontinuation (SVR12) in each treatment ann 
• 
To evaluate the steady state phmmacokinetics ofSOF and its metabolites and LDV upon 
dosing SOF 200 mg or 400 mg or LDV/SOF in subjects with renal insufficiency 
The secondmy objectives ofthis study m·e as follows: 
• 
To evaluate the prop01iion of subjects with renal insufficiency who attain SVR at 
4 and 24 weeks after discontinuation of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of plasma HCV RNA during and after treatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV during and after treatment 
discontinuation 
The explorat01y objective of this study is: 
PPO 
8.1.2. 
Primary Endpoint 
The prima1y safety endpoints include incidences of AEs, laborat01y, 12-lead ECG, and vital sign 
abn01malities. 
The prima1y PK endpoints are pm·ameters AUCtau, Cmax, and Ctau for analytes SOF, its 
metabolites, LDV and RBV as applicable. 
The prima1y efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after discontinuation 
of therapy). 
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8.1.3.
Secondary Endpoint
Secondary PK endpoints are parameters AUClast, Clast, Tmax, Tlast, λz, and t1/2 for analytes SOF, its 
metabolites, LDV and RBV as applicable.
Secondary efficacy endpoints include the proportion of subjects with SVR4 and SVR24, the 
proportion of subjects with virologic failure including viral breakthrough and relapse.
8.1.4.
Other Endpoints of Interest
Additional efficacy evaluations may include HCV RNA change from baseline; ALT 
normalization, andviral kinetic parameters.
8.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using SASsoftware (SAS Institute, Cary, North Carolina, USA).
The study drugs in this study include SOF, RBV and LDV/SOF. Last dose of study drug refers to 
the last dose of any of the study drugs in a treatment group and will be used in the definition of 
treatment-emergent AEs and laboratory abnormalities as well as the efficacy endpoints of SVR 
at various post-treatment time points.
All analyses will be presented by treatment cohort. Subjects who receive study drug other than 
that to which they were assigned will be analyzed according to the study drug received.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which includes 
subjects who were enrolled and received at least one dose of study drug. 
8.2.1.2.
Safety
The primary analysis set for safety analyses will be the Safety Analysis Set which includes
subjects who received at least one dose of study drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose of 
study drug through the date of the last dose of study drug plus 30 days.
8.2.1.3.
Pharmacokinetics
The PK analysis set will include all subjects who are enrolled and have received at least one dose 
of study drug and for whom PK concentration data of interested analytes (SOF, its metabolites,
LDV or RBV) are available. The PK analysis set will be used for analyses of general PK.


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8.2.2.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. In general, values for 
missing data will not be imputed. 
For the analysis of post-baseline categorical efficacy endpoints, if a data point is missing and is 
immediately preceded and followed in time by values that are deemed successes, then the 
missing data point will be termed a success; otherwise the data point will be termed a failure.
Any subject with missing data due to premature discontinuation of the study medication will be 
considered a failure at the time points on, or following, the date of discontinuation. If no HCV 
RNA values are obtained after the last dose of study medication, the subject will be considered a 
treatment failure for the SVR endpoints. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject received study medication, the subject will be included in a summary of adverse 
events according to the treatment received; otherwise, if the subject is not dosed then they 
will be excluded from the summary.

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 predose value, then the subject will be excluded from the calculation of summary 
statistics for the predose value and the change from predose values.
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pretreatment laboratory value is 
available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) for the 
summary of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing baseline result will 
be replaced with a screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for 
calculation of summary statistics for the actual HCV RNA values and the change from baseline 
values by study visit. The reported values will be provided in the HCV RNA listing.
For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed to 
the logarithmic (base 10) scale (log10 IU/mL).
PK concentration values below the lower limit of quantitation (BLQ) will be treated as zero for 
determination of summary and order statistics. Individual values that are BLQ will be presented 
as “BLQ” in the concentration data listing. For the presentation of summary and order statistics, 
if at least 1 subject has a concentration value BLQ for the time point, then the minimum value 
will be displayed as “BLQ.” If more than 50% of the subjects have a concentration data value 


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BLQ for the time point, then the minimum and median values will be displayed as “BLQ.” If 
more than 75% of the subjects have a concentration data value of BLQ for a given time point, 
then the minimum. 1st quartile [q1], median, and 3rd quartile [Q3] values will be displayed as 
“BLQ.” If all subjects have concentration data values BLQ for the time point, then all order 
statistics (minimum, first quartile [Q1], median, third quartile [Q3], maximum) will be displayed 
as “BLQ”.
Exposure parameters that are selected for statistical analysis will be natural log-transformed. 
Concentration values that are BLQ will be excluded for any ratio or natural log-transformed 
statistical analysis.
8.2.3.
Interim Analysis
Interim analyses will be performed to support external multidisciplinary data monitoring 
committee meetings (Section 8.9).
8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline characteristics will be summarized using standard descriptive 
methods by treatment cohort.
Demographic data will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include body weight/body mass index, HCV RNA level 
(log10 IU/mL), IL28B genotype, baseline ALT level, creatinine clearance estimated by 
Cockcroft-Gault, and additional endpoints as necessary.
8.4.
Efficacy Analysis
8.4.1.
Primary Analysis
The primary efficacy endpoint is SVR12 in the FAS population. The primary analysis will be 
performed after all enrolled subjects have been followed through 12 weeks post-treatment or 
discontinued from study.
A point estimate with a 2-sided 95% exact confidence interval (CI) using the exact binomial 
distribution (Clopper-Pearson method) will be constructed for the SVR12 rate by treatment 
cohort.
No statistical hypothesis testing will be performed.
8.4.2.
Secondary Analysis
The proportion of subjects with HCV RNA below the LLOQ over time (including SVR12) will 
be presented by treatment cohort in tabular and graphical form. 
Descriptive summaries and listings will be provided for additional efficacy evaluations including 
the proportion of subjects who experience virologic failure, ALT normalization, serum HCV 
RNA actual values and change from baseline. 


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Details on efficacy analyses will be described in the statistical analysis plan (SAP). 
8.5. 
Safety Analysis 
Safety will be evaluated by assessment of clinical laborat01y tests, physical examinations, vital 
signs measmements, at various time points dming the study, and by the documentation of AEs. 
All safety data collected on or after the first dose of study dmg adminisu·ation up to 30 days after 
the last dose of study dmg will be summarized according to the study dmg received. Safety 
endpoints will be summarized as the number (prop01tion) of subjects with events or 
abnonnalities for categorical data or as an 8-number summaty (n, mean, standard deviation, 
minimum, Ql, median, Q3, maximum) for continuous data. 
8.5.1. 
Extent of Exposure 
A subject's extent of exposme to study dmg will be generated from the study dmg 
adminisu·ation page of the CRF. Exposme data will be summarized by u·eatment coh01t . 
8.5.2. 
Adverse Events 
Clinical and laborat01y AEs will be coded using the Medical Dictionruy for Regulat01y 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Tetm (HLGT), 
High-Level Tetm (HLT), Prefened Tetm (PT), and Lower-Level Tetm (LLT) will be attached to 
the clinical database. 
Events will be summarized on the basis of the date of onset for the event. A u·eatlnent-emergent 
adverse event will be defined as any new or worsening adverse event that begins on or after the 
date of first dose of study dmg up to the date of last dose of study dmg plus 30 days. 
Summaries (number and percentage of subjects) ofu·eatlnent-emergent adverse events 
(by SOC and prefen ed te1m) will be provided by u·eatlnent coh01t: 
• 
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 AEs that caused change in dose or temporary interruption of study drug,

All SAEs (including death), and

All study drug-related SAEs
All AEs collected during the course of the study will be presented in data listings.
8.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, minimum, Q1, median, Q3, 
maximum) by study visit along with corresponding change from baseline.
Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme 
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 baseline at any 
time post-baseline up to the date of last dose of study drug plus 30 days will be summarized by 
treatment cohort. 
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pretreatment laboratory value is 
available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) for the 
summary of graded laboratory abnormalities. Thus, any post-baseline graded abnormality 
(i.e., at least Grade 1) will be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
8.6.
Pharmacokinetic Analysis
Plasma concentrations of the study drug over time will be listed and summarized using 
descriptive statistics. PK parameters (e.g., AUCtau, Cmax, and Ctau) will be listed and summarized 
for study drug (i.e., SOF and its metabolites, LDV and RBV) using descriptive statistics 
(e.g., sample size, arithmetic mean, geometric mean, % coefficient of variation [%CV], SD, 
minimum, Q1, median, Q3, maximum). 
8.7.
Stopping Rules for Individual Groups
There are no predetermined futility criteria which would require enrollment to be halted or 
treatment discontinued.


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8.8.
Sample Size
Due to the exploratory nature of this study, no formal power or sample size calculations were 
performed to determine treatment group size. The total sample size of 30 is largely based on 
feasibility.
8.9.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety, efficacy, and PK data for each cohort of the study 
before proceeding to the next. Specifically, all of the data through post-treatment week 4 from 
the SOF 200 mg group (Cohort 1) will be reviewed before screening, enrollment and dosing for 
the SOF 400 mg group (Cohort 2). A similar review and initiation process will occur between  
SOF 400 mg (Cohort 2) and LDV/SOF dose group (Cohort 3), with review of safety and PK data 
through Week 12 from Cohort 2 prior to initiating Cohort 3. The DMC will provide 
recommendations to Gilead whether the nature, frequency, and severity of adverse effects 
associated with study treatment warrant the early termination of the study in the best interests of 
the participants, whether the study should continue as planned, or the study should continue with 
modifications. The DMC may also provide recommendations as needed regarding the need for 
additional meetings or an alternative meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.


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


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investigator must use the most current IRB- or IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB or IEC or
local requirements. The consent form will inform subjects about pharmacogenomic testing and 
sample retention, and their right to receive clinically relevant pharmacogenomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB or IEC, or laboratory. Laboratory 
specimens must be labeled in such as way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The 
investigator must keep a screening log showing codes, names, and addresses for all subjects 
screened and for all subjects enrolled in the trial. Subject data will be processed in accordance 
with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully 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 should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);


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
Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. Subsequent to data entry, a study monitor will perform source data verification 
within the EDC system. Original entries as well as any changes to data fields will be stored in the 


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


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead Sciences. All protocol modifications must be submitted to the Competent 
Authorities, IRB or IEC in accordance with local requirements. Approval must be obtained 
before changes can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). 
Gilead will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be
prepared in certain cases. 
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

the results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years

The investigator will submit to Gilead any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).

The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.


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9.3.2.
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.
9.3.3.
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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10.
REFERENCES
2202
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16:31-41.
12557
Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. 
Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 
weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of 
chronic infection with hepatitis C virus. International Hepatitis Interventional 
Therapy Group (IHIT). Lancet 1998;352 (9138):1426-32.
12558
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et 
al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for 
chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 
1998;339 (21):1485-92.
15572
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
Laboratories Inc., Nutley, NJ. Revised: January 2010.
15668
Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
Characteristics. Roche Products Limited, Welwyn Garden City, United Kingdom. 
Revised: March 2010.
19705
Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus 
infection in Europe. J Hepatol 2008;48 (1):148-62.
23275
Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. 
Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J 
Med 2013;368 (1):34-44.
24149
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
Laboratories Inc., Nutley, NJ. Revised: February 2013.
24713
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, 
Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients 
without treatment options. N Engl J Med 2013;368 (20):1867-77.
24715
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et 
al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J 
Med 2013;368 (20):1878-87.
27832
Gilead Sciences Limited. SOVALDI 400 mg film-coated tablets. Summary of 
Product Characteristics.  County Cork Ireland. January 2014.  2014:


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31179
Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. 
US Prescribing Information.  Foster City, CA October 2014:
32081
Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US 
Prescribing Information.  Foster City, CA. November 2014:


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2b, Open-Label Study of200 mg or 400 mg Sofosbuvir+RBV for 24 Weeks in 
Genotype 1 or 3 and Ledipasvir/Sofosbuvir (LDV/SOF) Fixed-Dose Combination (FDC) Tablet 
for 12 weeks in Genotype 1 or 4 HCY-lnfected Subjects with Renal Insufficiency 
GS-US-334-0154, Amendment 3, 23 February 2015 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
0~u gv-C{..,.I{ t - ~ 
~< f 
f.I-1.P 
Theo Sarif, MD (Printed) 
Medical Monitor 
Date 
Z.viC 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 75 
23 February 2015 


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Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Background
For Cohorts 1 and 2
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects have 
been demonstrated in all animal species tested. Pregnancy must be excluded before the start of 
treatment with study drugs and prevented thereafter by reliable contraceptive methods. 
Pregnancy tests will be performed regularly throughout this study. Furthermore, RBV is known 
to accumulate intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, 
extreme care must be taken to avoid pregnancy during RBV therapy and for up to 6 months 
following completion of treatment (7 months for males). Please refer to the latest version of the 
product insert for additional information. 
Non-clinical toxicity studies of SOF demonstrated no adverse effect on fertility or embryo-fetal 
development. However, there are no clinical studies of SOF in pregnant women. Please refer to 
the latest version of the investigator’s brochure for additional information. 
For Cohort 3
Non-clinical toxicity studies of LDV/SOF demonstrated no adverse effect on embryo-fetal 
development. However, there are no clinical studies of LDV/SOF in pregnant women Please 
refer to the latest version of the Investigator’s Brochure for additional information.
2) Definition of Female of Childbearing Potential and Contraceptive Requirements for 
Female Subjects (and their male partners)
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 6 months after last dose of RBV
(Cohorts 1 and 2) or until 30 days after the last dose of study drug in the absence of RBV 
(Cohort 3):


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
Complete abstinence from intercourse. Abstinence is an acceptable method of contraception 
only when it is in line with the subject's preferred and usual lifestyle. Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
Or

Consistent and correct use of 1 of the following methods of birth control listed below, in 
addition to a male partner who correctly uses a condom, from the date of Screening until 
6 months after the last dose of RBV (Cohorts 1 and 2) or 30 days after last dose of study drug 
in the absence of RBV (Cohort 3): 
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent
tubal sterilization
vasectomy in male partner
implants of levonorgestrel
injectable progesterone
oral contraceptives (either combined or progesterone only)
contraceptive vaginal ring 
transdermal contraceptive patch
3) Contraceptive Requirements for Male Subjects (and their female partners)
All male study participants must agree to consistently and correctly use a condom from 
Baseline until 7 months after the last dose of RBV (Cohorts 1 and 2) or until 90 days after 
administration of the last dose of study drug in the absence of RBV (Cohort 3). If their female 
partner is of childbearing potential (as defined above), their female partner must use 1 of the 
methods of birth control listed above from the date of Screening until 7 months after last dose of 
RBV (Cohorts 1 and 2) or until 90 days after administration of the last dose of study drug in the 
absence of RBV (Cohort 3).
Male subjects must agree to refrain from sperm donation for at least 7 months after the last dose 
of RBV (Cohorts 1 and 2) or for at least 90 days after the last dose of study drug in the absence 
of RBV (Cohort 3).


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4) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 6 months (7 months for partners of male subjects) of 
last RBV dose or within 30 days (90 days for partners of male subjects) of last LDV/SOF dose.
Subjects who become pregnant or who suspect that they are pregnant must report the information 
to the investigator and discontinue study drug immediately. Subjects whose partner has become 
pregnant or suspects she is pregnant must report the information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 7.6.2.


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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18 June 2012
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
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L


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


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


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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
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol/L to LLN
57 to 87 μmol/L
27 to 57 μmol/L
27 μmol/L
Creatinine 
1.50 to 2.00 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol/L
177 to 265 μmol/L
265 to 530 μmol/L
530 μmol/L
Bicarbonate
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L
LDL
(Fasting)
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL


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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) 
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
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social & 
functional activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference 
with usual social & 
functional activities 
Sensory alteration or 
paresthesia causing inability 
to perform usual social & 
functional activities
Disabling sensory alteration 
or paresthesia causing 
inability to perform basic 
self-care functions


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


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


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


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


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Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 100
23 February 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


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

Prot_002.pdf: 
Study Title: 
Sponsor: 
IND No.: 
EudraCT No: 
Indication: 
Protocol ID: 
Gilead Sciences Study 
Director 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2b, Open-Label Study of200 mg or 400 mg 
Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 
HCV-Infected Subjects with Renal Insufficiency 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
106,739 
2013-002897-30 
Hepatitis C Vims Infection 
GS-US-3 34-0154 
Name: 
Telephone: 
Fax: 
E-mail: 
PPD 
PPD 
PPD 
t-'t-'U 
Original: 
11 July 2013 
Amendment 1: 
05 September 2013 
Amendment 2: 
20 Febmmy 2014 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pmiiculm·ly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Institutional Review Bom·d or Independent Ethics Committee. The inf01mation is 
only to be used by you in connection with authorized clinical studies of the investigational 
dmg described in the protocol. You will not disclose any of the infonnation to others without 
written authorization from Gilead Sciences, Inc., except to the extent necessmy to obtain 
inf01med consent from those persons to whom the dmg may be administered. 


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Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
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20 February 2014
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.
Sofosbuvir (formerly GS-7977)......................................................................................................13
1.3.
Ribavirin (RBV)..............................................................................................................................13
1.4.
Rationale for the Current Study ......................................................................................................14
1.5.
Rationale for SOF Dose Selection ..................................................................................................15
1.6.
Rationale for RBV Dose Selection .................................................................................................16
2.
OBJECTIVES..............................................................................................................................................17
3.
STUDY DESIGN ........................................................................................................................................18
3.1.
Treatment Plan and Regimen..........................................................................................................18
3.2.
Visit Schedule .................................................................................................................................18
3.3.
Virologic Response-Based Stopping Criteria..................................................................................19
3.3.1.
Cardiac Function-Based Stopping Criterion .................................................................19
3.4.
Treatment Discontinuation Criteria.................................................................................................19
3.5.
Registry Studies ..............................................................................................................................20
3.5.1.
Sequence Registry Study...............................................................................................20
3.5.2.
SVR Registry Study ......................................................................................................20
4.
SUBJECT POPULATION...........................................................................................................................21
4.1.
Number of Subjects and Subject Selection .....................................................................................21
4.2.
Inclusion Criteria ............................................................................................................................21
4.3.
Exclusion Criteria ...........................................................................................................................22
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ....................................................................................25
5.1.
Sofosbuvir (SOF) ............................................................................................................................25
5.1.1.
Formulation...................................................................................................................25
5.1.2.
Packaging and Labeling ................................................................................................25
5.1.3.
Storage and Handling....................................................................................................25
5.1.4.
Sofosbuvir (SOF) Dosage and Administration..............................................................26
5.2.
Ribavirin (RBV)..............................................................................................................................26
5.2.1.
Formulation...................................................................................................................26
5.2.2.
Packaging and Labeling ................................................................................................26
5.2.3.
Storage and Handling....................................................................................................26
5.2.4.
RBV Dosage and Administration..................................................................................27
5.3.
Co-administration of Sofosbuvir (SOF) and Ribavirin (RBV) .......................................................27
5.4.
Study Drug Compliance..................................................................................................................27
5.5.
Dispensing and Accountability of Study Drugs..............................................................................27
5.6.
Study Drug Return or Disposal.......................................................................................................28
5.7.
Concomitant Medications ...............................................................................................................28
5.7.1.
Medications Associated with QT Prolongation.............................................................29
5.7.2.
Hematopoietic Growth Factors .....................................................................................31


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Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
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20 February 2014
6.
STUDY PROCEDURES .............................................................................................................................32
6.1.
Subject Enrollment and Treatment Assignment..............................................................................32
6.2.
Pretreatment Assessments...............................................................................................................36
6.2.1.
Screening Visit..............................................................................................................36
6.2.2.
Medical History.............................................................................................................36
6.3.
Day 1 Assessments..........................................................................................................................37
6.3.1.
Dosing Diary.................................................................................................................37
6.4.
Treatment Assessments...................................................................................................................37
6.5.
Safety Assessments.........................................................................................................................37
6.5.1.
Safety ECGs..................................................................................................................37
6.5.2.
Safety echocardiograms ................................................................................................38
6.5.3.
Physical Examination....................................................................................................38
6.5.4.
Vital Signs.....................................................................................................................38
6.5.5.
BMI...............................................................................................................................38
6.5.6.
Creatinine Clearance .....................................................................................................38
6.5.7.
Clinical Laboratory Tests/Assessments.........................................................................39
6.5.8.
Adverse Events/ Concomitant Medications/ Protocol Restrictions...............................40
6.6.
Pharmacokinetic (PK) Assessments................................................................................................40
6.7.
Early Termination (ET)/Unscheduled Visit ....................................................................................41
6.8.
Post-Treatment Assessments...........................................................................................................42
6.9.
Optional Samples for Pharmacogenetic Testing .............................................................................42
6.10.
Archived Plasma Sample ................................................................................................................42
6.11.
Blood Storage..................................................................................................................................42
7.
ADVERSE EVENTS MANAGEMENT.....................................................................................................43
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events..........................43
7.1.1.
Adverse Events..............................................................................................................43
7.1.2.
Serious Adverse Events.................................................................................................43
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events..............................................................44
7.2.
Assessment of Adverse Events and Serious Adverse Events..........................................................44
7.2.1.
Assessment of Causality for Study Drugs and Procedures............................................45
7.2.2.
Assessment of Severity .................................................................................................45
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead................................................................................................................45
7.4.
Gilead Reporting Requirements......................................................................................................47
7.5.
Toxicity Management .....................................................................................................................47
7.5.1.
Stopping Rules for Toxicity..........................................................................................47
7.5.2.
Sofosbuvir (SOF) ..........................................................................................................48
7.5.3.
Ribavirin (RBV)............................................................................................................48
7.6.
Special Situations Reports ..............................................................................................................48
7.6.1.
Definitions of Special Situations...................................................................................48
7.6.2.
Instructions for Reporting Special Situations................................................................49
8.
STATISTICAL CONSIDERATIONS.........................................................................................................51
8.1.
Analysis Objectives and Endpoints.................................................................................................51
8.1.1.
Analysis Objectives.......................................................................................................51
8.1.2.
Primary Endpoint ..........................................................................................................51
8.1.3.
Secondary Endpoint ......................................................................................................52
8.1.4.
Other Endpoints of Interest ...........................................................................................52
8.2.
Analysis Conventions .....................................................................................................................52
8.2.1.
Analysis Sets.................................................................................................................52
8.2.2.
Data Handling Conventions ..........................................................................................53


Sofosbuvir
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 4
20 February 2014
8.2.3.
Interim Analysis............................................................................................................54
8.3.
Demographic Data and Baseline Characteristics ............................................................................54
8.4.
Efficacy Analysis............................................................................................................................54
8.4.1.
Primary Analysis...........................................................................................................54
8.4.2.
Secondary Analysis.......................................................................................................54
8.5.
Safety Analysis ...............................................................................................................................55
8.5.1.
Extent of Exposure........................................................................................................55
8.5.2.
Adverse Events..............................................................................................................55
8.5.3.
Laboratory Evaluations .................................................................................................56
8.6.
Pharmacokinetic Analysis...............................................................................................................56
8.7.
Stopping Rules for Individual Groups ............................................................................................57
8.8.
Sample Size.....................................................................................................................................57
8.9.
Data Monitoring Committee ...........................................................................................................57
9.
RESPONSIBILITIES ..................................................................................................................................58
9.1.
Investigator Responsibilities ...........................................................................................................58
9.1.1.
Good Clinical Practice ..................................................................................................58
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) Approval..............................................................................................................58
9.1.3.
Informed Consent..........................................................................................................59
9.1.4.
Confidentiality ..............................................................................................................59
9.1.5.
Study Files and Retention of Records...........................................................................59
9.1.6.
Case Report Forms........................................................................................................61
9.1.7.
Drug Accountability......................................................................................................61
9.1.8.
Inspections ....................................................................................................................61
9.1.9.
Protocol Compliance.....................................................................................................62
9.2.
Sponsor Responsibilities.................................................................................................................62
9.2.1.
Protocol Modifications..................................................................................................62
9.2.2.
Study Report and Publications ......................................................................................62
9.3.
Joint Investigator/Sponsor Responsibilities ....................................................................................62
9.3.1.
Access to Information for Monitoring...........................................................................62
9.3.2.
Access to Information for Auditing or Inspections .......................................................63
9.3.3.
Study Discontinuation...................................................................................................63
10.
REFERENCES ............................................................................................................................................64
11.
APPENDICES .............................................................................................................................................66
Appendix 1.
Investigator Signature Page...........................................................................................67
Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements ..................................................................68
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities .............................................................................................70
LIST OF IN-TEXT TABLES
Table 6-1.
Schedule of Assessments ..............................................................................................33


Sofosbuvir
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 5
20 February 2014
PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2b, Open-Label Study of 200 mg or 400 mg 
Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 HCV-Infected 
Subjects with Renal Insufficiency
IND Number:
Eudra CT Number:
106,739
2013-002897-30
Study Centers 
Planned:
Multiple sites in New Zealand, Europe, North America and South 
America
Number of Subjects 
Planned:
Approximately 40 subjects
Target Population:
Adults with chronic renal insufficiency and HCV infection
Treatment Duration:
24 weeks
Objectives:
The primary objectives of this study are:

To evaluate the safety of sofosbuvir (SOF) 200 mg or 400 mg
+ ribavirin (RBV) for 24 weeks as assessed by review of the 
accumulated safety data in each treatment arm

To evaluate the efficacy of sofosbuvir (SOF) 200 mg or 
400 mg + ribavirin (RBV) for 24 weeks measured by the 
proportion of subjects with renal insufficiency who have 
achieved a sustained viral response 12 weeks after treatment 
discontinuation (SVR12) in each treatment arm

To evaluate the steady state pharmacokinetics of SOF and its 
metabolites upon dosing SOF 200 mg or 400 mg in subjects
with renal insufficiency 
The secondary objectives of this study are:

To evaluate the proportion of subjects with renal insufficiency 
who attain SVR at 4 and 24 weeks after discontinuation of 
treatment (SVR4 and SVR24)

To evaluate the kinetics of plasma HCV RNA during and after 
treatment discontinuation

To evaluate the emergence of viral resistance to SOF during 
and after treatment discontinuation


Sofosbuvir 
Protocol GS-US-334-0154 
Gilead Sciences, Inc. 
Study Design: 
Registry Studies: 
CONFIDENTIAL 
The explorat01y objective of this study is: 
This study will have 2 pmis. 
Final 
Amendment2 
Pmi 1 will enroll approximately 20 subjects with severe renal 
insufficiency. 
• 
10 subjects will receive SOF 200 mg QD + RBV 200 mg QD 
for 24 weeks. 
• 
Following review of safety, efficacy and PK data through 
post-tr·eatrnent Week 4 of the Pmi 1 SOF 200 mg group, 
10 additional subjects will receive SOF 400 mg QD + RBV 
200 mg QD for 24 weeks. 
Pmi 2 will enroll approximately 20 subjects on dialysis following 
review of safety, efficacy and PK data through post-tr·eatrnent 
Week 4 of Pmi 1 SOF 400 mg group. 
• 
10 subjects will receive SOF 200 mg QD + RBV 200 mg QD 
for 24 weeks. 
• 
Following review of safety, efficacy and PK data through 
post-tr·eatrnent Week 4 of the Pmi 2 SOF 200 mg group, 
10 additional subjects will receive SOF 400 mg QD + RBV 
200 mg QD for 24 weeks. 
Sequence Registry Study 
Subjects who do not achieve SVR will be eligible for enrollment in 
the Sequence Registry Study where available and approved. The 
pmpose of the Sequence Registry Study will be to monitor the 
persistence of resistant mutations for up to 3 yem·s. The Sequence 
Registry Study is described in a sepm·ate protocol 
(GS-US-248-0123). 
SVR Registry Study 
All subjects who achieve SVR will be eligible for enrollment in the 
SVR Registry Study where available and approved. The pmpose of 
the SVR Registry Study will be to evaluate dmability of SVR for 
up to 3 yem·s post-tr·eat:Inent. The SVR Regisby Study is described 
in a sepm·ate protocol (GS-US-248-0122). 
Page6 
20 FebiUaiy2014 


Sofosbuvir
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Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 7
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Diagnosis and Main 
Eligibility Criteria:
Adults (≥ 18 years) with chronic genotype 1 or genotype 3 HCV 
infection. Reference Sections 4.2 and 4.3 for detailed Inclusion and 
Exclusion criteria.
Study Procedures/
Frequency:
Screening assessments will be completed within 42 days of the 
Day 1 visit. 
Study visits will occur at Screening, Day 1, and at the end of 
Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20 and 24 and at Post-Treatment 
Weeks 4, 12, and 24. Screening assessments will include physical 
examination, height, weight, vital signs, 12-lead ECG, 
echocardiogram, concomitant medications, safety laboratory tests, 
HCV RNA, serology (HIV, HCV, HBV), hemoglobin A1c 
(HbA1c), serum β-hCG (females of child bearing potential only), 
IL28B genotyping 
On-treatment assessments will include adverse events (AEs), 
concomitant medications, study medication pill count, physical 
examination, vital signs, 12-lead ECGs, echocardiogram, safety 
laboratory tests, HCV RNA, pharmacokinetic samples, and serum 
pregnancy tests (females of child bearing potential only). 
Post-treatment assessments will include AEs, concomitant 
medications, vital signs, safety laboratory tests, HCV RNA, and 
serum pregnancy tests (females of child bearing potential only).
Samples for viral RNA sequencing will be collected at Day 1 and 
every visit thereafter. Samples will be collected during treatment 
visits for PK analysis of study drug(s).
PK assessments
Intensive PK Assessments
Serial blood samples will be collected on week 2 and 12 at the 
following timepoints:
0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours 
post-dose.
Plasma concentrations of SOF and its metabolites will be 
determined and PK parameters will be estimated as appropriate. 
Plasma concentrations of RBV may be determined, if necessary.
Trough PK Assessments:
Trough PK plasma samples for analyses of SOF, its metabolites 
and RBV concentrations will be collected at all other on treatment 
visits beginning at the Week 1 visit.
PK Parameters for SOF, its metabolites, and RBV will be 
estimated as appropriate. 


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Test Product, Dose, 
and Mode of 
Administration: 
Optional Genetic Sample Collection 
PPD 
Archived Plasma Sample 
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Archive plasma samples are being collected for possible additional 
analyses, including but not limited to, study dmg or metabolite 
measurements, viral load, safety/efficacy assessments, HCV gene 
sequencing, HCV resistance testing and other possible predictors 
of response as detennined by Gilead. 
Sofosbuvir is manufactured as 100 mg and 400 mg tablets for oral 
administration. Subjects enrolled to take the 200 mg dose will take 
2 x 100 mg tablets for a total dose of 200 mg orally QD in the 
moming with RBV and with food. Subjects enrolled to take the 
400 mg dose will take 1x400 mg tablet for a total dose of 400 mg 
orally QD in the moming with RBV and with food. 
RBV will be supplied as a 200 mg tablet for oral administration by 
Gilead Sciences. Subjects will take 1 x 200 mg tablet in the 
moming with SOF and with food. 
Reference Therapy: 
None 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
PK: 
CONFIDENTIAL 
AEs will be collected through 4 weeks post-treatment. Safety labs 
and SAEs will be collected throughout the study. Safety will be 
evaluated by assessment of clinical laborat01y tests, ECG, 
echocardiogram, periodic physical examinations including vital 
signs at various time points during the study, and by the 
documentation of adverse events. 
Efficacy will be evaluated using scheduled assessments of HCV 
RNA perf01m ed using CO BAS® AmpliPrep/COBAS® TaqMan® 
HCV Test. 
Plasma PK parameters will be calculated for sofosbuvir and its 
metabolites GS-566500 and GS-331007 and RBV, as applicable. 
Examples are AUCiast, AUCtau, Cmax, Clast, Ctau, and t112. 
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Statistical Methods:
Safety data will be listed by subject and summarized by treatment 
in each renal function subgroup (study part) using frequency of 
event/abnormality or descriptive statistics (e.g., sample size, 
arithmetic mean, geometric mean, % coefficient of variation [CV], 
standard deviation [SD], minimum, Q1, median, Q3, and 
maximum).
The steady state PK plasma concentrations and parameters will be 
listed by subject and summarized by treatment and study part using 
descriptive statistics for each analyte (SOF, GS-566500, 
GS-331007, and RBV, as appropriate). 
In the efficacy analysis, no statistical hypothesis testing will be 
performed and no formal inference will be made on primary 
efficacy endpoint SVR12. A point-estimate with two-sided 95% 
exact confidence interval (CI) using the binomial distribution 
(Clopper-Pearson method) will be constructed for the SVR12 rate 
by treatment and study part. Similar analysis will be also 
performed for secondary endpoints SVR4 and SVR24.
To evaluate the kinetics of circulating HCV RNA during and after 
treatment discontinuation, viral load data will be listed by subject 
and summarized by treatment and visit in each study part using 
descriptive statistics.
Due to the exploratory nature of this study, no formal power or 
sample size calculations were performed to determine treatment 
group size. The total sample size of 40 (i.e., 10 enrolled to obtain 
8 evaluable for each dose level group in each study part) is largely 
based on feasibility.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
β-hCG
β-human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase  (also SGOT)
AUC
area under the curve
AUCtau
area under the plasma concentration versus time curve over the dosing 
interval (tau)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BW
body weight
CLcr
Creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear 
(PBMC) concentration of drug
Ctau
observed drug concentration at the end of the dosing interval (tau)
CRF
case report form(s)
CRO
Contract (or clinical) research organization 
dL
Deciliter
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
ESRD
End Stage Renal Disease
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
HBV
Hepatitis B virus
HCV
Hepatitis C virus


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
HDPE
high-density polyethylene
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
High-Level Term
IBW
Ideal Body Weight
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL28B
IL28B gene
IND
Investigational New Drug (Application)
IRB
institutional review board
IUD
intrauterine device
IV
Intravenous
kg
Kilogram
L
Liter
LDH
Lactase dehydrogenase
LLN
lower limit of the normal range
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MH
Mantel-Haenszel
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PBMC
peripheral blood mononuclear cell(s)
PEG
Pegylated interferon
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
QD
once daily (use only in tables)
QTcF
QT interval corrected using Fridericia’s formula
RBC
Red blood cell count 
RBV
Ribavirin
RNA
ribonucleic acid
RVR
rapid virologic response 
SADR
Serious adverse drug reaction


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
SAE
serious adverse event
SD
Standard deviation
SOC
Standard of Care
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TND
Target not detected
TSH
Thyroid stimulating hormone
t½
An estimate of the terinal elimination half-life of the drug in 
serum/plasma/PBMC, calculated by dividing the natural log of 2 by the 
terminal elimination rate contstant (λz)
ULN
upper limit of the normal range
US
United States
WBC
white blood cell count


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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) is responsible for a large proportion of chronic liver disease 
worldwide and accounts for 70% of cases of chronic hepatitis in industrialized countries. The 
global prevalence of chronic hepatitis C is estimated to average 3% {19705}. The most
common genotype worldwide is genotype 1 followed by genotypes 2 and 3 {19705}. 
Although there is evidence that the incidence of viral infection may be decreasing, the 
prevalence of liver disease caused by HCV is on the rise, primarily due to the lag between the 
onset of infection and the clinical manifestation of liver disease {19705}. The prevalence of 
chronic HCV is significantly higher among patients with chronic renal failure, and HCV 
itself is associated with impaired renal function. Treatment of these individuals is therefore 
recommended but is often complicated by the substantial increase in hematologic toxicities 
associated with the use of ribavirin in the setting of low creatinine clearance {23275}.
Standard of care for genotype 1 HCV infection involves 24-48 weeks of an HCV protease 
inhibitor in combination with pegylated interferon-alfa (PEG)+ribavirin (RBV). The 
recommended first-line treatment for subjects with genotype 2 or genotype 3 chronic 
hepatitis C is PEG+ RBV for 24 weeks {13693}, {17940}. There are minimal data regarding 
the optimal regimen for patients with severe renal disease (e.g., Cr clearance<30 mL/min) or 
end stage renal disease on maintenance hemodialysis. Interferon monotherapy for 48 weeks 
which provides an SVR rate of approximately 40% in clinical trials is often deemed the 
treatment of choice. Due to the side effects and lengthy duration of current treatment, there is 
substantial need for a short, simple, interferon-free regimen, particularly in patients who are 
more susceptible to drug toxicities, such as those with renal insufficiency. 
1.2.
Sofosbuvir (formerly GS-7977)
Sovaldi® (sofosbuvir) is a potent nucleotide analogue that inhibits HCV RNA replication in 
vitro and has demonstrated high rates of sustained viral response (SVR) when administered 
with RBV, with or without pegylated interferon, to subjects with chronic genotype 1-6 HCV 
infection {27503}, {23275}, {24713}, {24715}, {27832}.  Sovaldi® has been approved in the 
United States (GT1-4) and in the European Union (GT1-6) for the treatment of chronic HCV 
infection including treatment naïve and experienced patients and HIV/HCV co-infected 
patients.
For further information on the clinical pharmacology, virology, safety and efficacy of 
sofosbuvir (SOF), please refer to the current version of the Investigator’s Brochure and US 
and EU prescribing information.
1.3.
Ribavirin (RBV)
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of 
RNA and DNA viruses {15572}, {15668}. Ribavirin monotherapy has little or no effect on the 
replication of HCV but can result in short term normalization of serum ALT activity. When 


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combined with interferon or PEG therapy, RBV decreases substantially the relapse rate seen 
after cessation of interferon therapy {12557}, {12558}.
Ribavirin is a known teratogen (FDA category X). Furthermore, RBV is known to 
accumulate intracellularly where it is cleared slowly, and is also excreted in semen. 
Therefore, extreme care must be taken to avoid pregnancy during RBV therapy and for up to 
6 months following completion of treatment. A comprehensive review of RBV is contained 
in the package insert/SmPC.
1.4.
Rationale for the Current Study
This study will evaluate the safety, efficacy and pharmacokinetics of treatment with 
SOF+RBV for 24 weeks in subjects with chronic genotype 1 or 3 HCV infection and severe 
renal impairment.
Liver disease caused by HCV causes significant morbidity and mortality among patients with 
end-stage renal disease, particularly those treated with dialysis. Although treatment for 
chronic HCV has evolved over the last decade resulting in response rates of approximately 
70%, treatment with PEG and RBV is not recommended in ESRD patients {24913}. 
Interferon monotherapy, however, is associated with poor tolerability, a 48 week treatment 
duration, and efficacy of approximately 40%. Furthermore, once patients have failed this 
course of treatment, they have no further treatment options and are at risk for progression of 
liver disease, cirrhosis, and hepatocellular carcinoma.
To date, SOF+RBV has demonstrated safety and efficacy in a broad range of subjects with 
chronic HCV infection in Phase 2 and Phase 3 clinical trials. However, subjects with Cr 
clearance <60 mL/min have been excluded from these studies due to the recommendation 
that RBV not be administered to patients with Cr clearance <50 mL/min. In addition, study 
P7977-0915 has shown the major circulating metabolite of SOF, GS-331007, is renally 
cleared and a single dose study conducted in subjects with severe renal impairment or 
end-stage renal disease on hemodialysis demonstrated exposures approximately 1.6-fold and 
14 to 22-fold higher, respectively, than those observed in matched controls with normal renal 
function. Whilst dose reduction of SOF would reduce these exposures, viral efficacy is 
dependent on SOF exposures such that lower SOF doses or intermittent administration could 
be associated with reduced efficacy. Thus, this exploratory study of safety and efficacy of 
standard (400 mg) and reduced (200 mg) doses of SOF in combination with low-dose RBV 
in a small number of subjects will provide important data regarding dosing recommendations 
for use of SOF in this patient population with a high unmet medical need.
Phase 3 studies of SOF+RBV for 12 or 16 weeks in treatment-naïve and 
treatment-experienced genotype 3 HCV-infected subjects demonstrated SVR12 rates of 56% 
and 62%, respectively. Increasing treatment duration to 24 weeks may further improve 
response rates. In Phase 2 studies of SOF+RBV for 12 or 24 weeks in treatment-naïve 
genotype 1 HCV-infected subjects, SVR rates have varied from 47% to 84% depending on 
the study and patient population. In both genotypes 1 and 3, lower doses of RBV have been 
associated with reduced efficacy of the regimen. Given the safety need for a reduced RBV 


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dose in the current study (Section 1.6), treatment with SOF+RBV will be administered for 
24 weeks to maximize efficacy. Subjects with genotypes 1 or 3 HCV infection have been 
selected for this study since they represent the largest group of HCV-infected individuals in 
the regions where this study will be conducted and because the 24 week treatment regimen is 
appropriate. In contrast, genotype 2 HCV-infected subjects have been shown to have high 
response rates following 12 weeks of SOF+RBV therapy. If SOF+RBV is well tolerated for 
24 weeks in patients with severe renal insufficiency, safety for 12 weeks in this smaller HCV 
population may be inferred.
1.5.
Rationale for SOF Dose Selection 
Sofosbuvir 400 mg, once daily, when dosed in combination with RBV with or without PEG 
has demonstrated broad genotypic efficacy and a favorable safety profile in over 
3300 HCV-infected subjects across multiple patient populations in Phase 2 and 3 trials.  This 
dose (400 mg) is the proposed to be marketed dose of sofosbuvir for the treatment of 
HCV-infection.  
In study P7977-0915, a single dose PK study in subjects with varying degrees of renal 
impairment, exposure (AUCinf) of sofosbuvir and the renally eliminated metabolite, 
GS-331007, were 2.7- and 5.5-fold higher respectively in subjects with severe renal 
impairment compared to matched controls with normal renal function.  A significant dose 
reduction (eg, 2- to 4-fold) of sofosbuvir would be necessary to provide comparable 
GS-331007 exposures in subjects with severe renal impairment and those with normal renal 
function. Data from dose-finding and Phase 2 studies demonstrated that sofosbuvir, dosed 
once daily, was necessary to provide the active anabolite at the site of action (circulating 
GS-331007 cannot be phosphorylated to the active anabolite); therefore, dose interval 
modifications may not be appropriate. The efficacy of a substantially reduced dose of 
sofosbuvir in subjects with severe renal impairment has not been established.  
Part 1 of this study will evaluate the safety, efficacy and pharmacokinetics of 2 doses of 
sofosbuvir in subjects with severe renal impairment; the reduced dose of 200 mg sofosbuvir 
is expected to provide sofosbuvir systemic exposures that are comparable to the 400 mg dose 
in subjects with normal renal function and GS-331007 exposures that are approximately 
2.2-fold above those observed in subjects with normal renal function at the 400 mg dose.
Safety, efficacy and pharmacokinetic data from the 200 mg and then the 400 mg dose of 
sofosbuvir in Part 1 will inform the initiation of Part 2.  In Part 2, the safety, efficacy and 
pharmacokinetics of SOF at a dose of 200 mg and then 400 mg will be evaluated in subjects 
with End Stage Renal Disease (ESRD) on dialysis.  In study P7977-0915, exposure (AUCinf) 
of sofosbuvir and GS-331007, were 1.6 fold and 14 to 22-fold higher respectively in subjects 
with ESRD compared to matched controls with normal renal function.  Dose reduction of 
sofosbuvir to mitigate increased GS-331007 exposure in subjects with ESRD may result in 
suboptimal sofosbuvir exposure.  As such, in this patient population with a high unmet 
medical need, to balance both safety and efficacy, the 200 mg and 400 mg dose will be 
evaluated in Part 2 in subjects with ESRD.


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1.6.
Rationale for RBV Dose Selection
Ribavirin increases treatment response rates when administered with interferon or PEG. In 
addition, reducing the RBV dose from 1000-1200 mg/day to 600 or 800 mg/day when given 
in combination with SOF reduced SVR rates, as did SOF monotherapy. It is therefore 
desirable to keep RBV as part of the SOF treatment regimen. Since RBV is cleared renally 
and its main toxicity is hemolytic anemia which is poorly tolerated in patients with advanced 
renal insufficiency who are usually anemic at baseline and have little bone marrow reserve, 
the starting dose of RBV must be substantially lower than 1000-1200 mg/day. For this study, 
a dose of 200 mg/day has been selected based on investigator input in light of the high 
frequency of hemotoxicity of RBV and the general desire to optimize the efficacy of the 
treatment regimen {24149}.
To date there has been no safety signal identified that is attributable to SOF when 
administered as part of a combination regimen. Furthermore, SOF does not exacerbate the 
toxicities associated with RBV, most notably hemolytic anemia. Clinical data with SOF in 
severe renal insufficiency and in subjects requiring hemodialysis is limited to a single dose 
study in non-HCV infected subjects. No specific safety signals were identified. The current 
study is designed to assess the safety and efficacy of therapeutic treatment with SOF+RBV in 
a small number of subjects with severe renal insufficiency. The 2-part stepwise design will 
allow a full review of the risk/benefit of both doses and treatment arms in patients with Cr 
clearance <30 mL/min before proceeding to the cohort of patients on dialysis who are 
predicted to have higher SOF and GS-331007 exposures. 
The potential benefit of successful treatment of HCV in these subjects is substantial. Few 
patients with severe renal insufficiency can tolerate combination therapy with PEG+RBV 
due to profound anemia. SVR rates to interferon monotherapy administered for 48 weeks are 
less than 50%. Interferon-free treatment for 24 weeks could provide substantial 
improvements in safety, tolerability and efficacy for individuals with chronic HCV infection 
and end stage renal disease.


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2. 
OBJECTIVES 
The prima1y objectives of this study are: 
Final 
Amendment2 
• 
To evaluate the safety of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks as assessed by review of the accumulated safety data in each treatment ann 
• 
To evaluate the efficacy of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks measured by the proportion of subjects with renal insufficiency who have 
achieved a sustained viral response 12 weeks after treatment discontinuation (SVR12) in 
each treatment rum 
• 
To evaluate the steady state phrumacokinetics of SOF and its metabolites upon dosing 
SOF 200 mg or 400 mg in subjects with renal insufficiency 
The secondruy objectives of this study ru·e: 
• 
To evaluate the prop01iion of subjects with renal insufficiency who attain SVR at 4 and 
24 weeks after discontinuation of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of plasma HCV RNA during and after treatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF during and after treatment 
discontinuation 
The explorat01y objective of this study is: 
IT 
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3.
STUDY DESIGN
This is a multicenter, open label study that will evaluate the safety, tolerability and antiviral 
efficacy of SOF with RBV in chronic renal insufficiency and HCV infection subjects with 
genotype 1 or genotype 3 HCV infection, including those with compensated cirrhosis.
This study will have 2 parts. 
Part 1 will enroll approximately 20 subjects with severe renal insufficiency. 

10 subjects will receive SOF 200 mg QD + RBV 200 mg QD for 24 weeks.

Following review of safety, efficacy and PK data through post-treatment Week 4 of the 
Part 1 SOF 200 mg group, 10 additional subjects will receive SOF 400 mg QD + RBV 
200 mg QD for 24 weeks.
Part 2 will enroll approximately 20 subjects on dialysis following review of safety, efficacy 
and PK data through post-treatment Week 4 of Part 1 SOF 400 mg group.  

10 subjects will receive SOF 200 mg QD + RBV 200 mg QD for 24 weeks.

Following review of safety, efficacy and PK data through post-treatment Week 4 of the 
Part 2 SOF 200 mg group, 10 additional subjects will receive SOF 400 mg QD + RBV 
200 mg QD for 24 weeks.
3.1.
Treatment Plan and Regimen
In Part 1, following screening procedures and Day 1 assessments, eligible subjects will 
receive either SOF 200 mg or 400 mg QD + RBV 200 mg QD for 24 weeks.
In Part 2, following screening procedures and Day 1 assessments, eligible subjects receive 
either SOF 200 mg or 400 mg QD + RBV 200 mg QD for 24 weeks. 
Additional information about study drug administration can be found in Section 5.
3.2.
Visit Schedule
All subjects will complete screening, on-treatment and post-treatment assessments. Screening 
assessments will be completed within 42 days of the Day 1 visit. All subjects will complete 
the Week 4 Post-Treatment visit. Weeks 12 and 24 Post-Treatment visits will be dependent 
on subject viral load.
The assessments performed at each visit are described in Section 6.


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3.3.
Virologic Response-Based Stopping Criteria
The following stopping criteria will be used for subjects on treatment:

Confirmed HCV RNA ≥LLOQ after 2 consecutive HCV RNA <LLOQ

Confirmed >1 log10  increase from nadir 

Confirmed HCV RNA ≥LLOQ after 8 weeks of treatment
Confirmation should be performed as soon as possible but within 2 weeks after determination 
of initial observation.
3.3.1.
Cardiac Function-Based Stopping Criterion
The following stopping criterion will be used for subjects on treatment:

Left ventricular ejection fraction ≤40%
3.4.
Treatment Discontinuation Criteria
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication must be discontinued in the following instances:

Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises 
the ability to continue study-specific procedures or is considered to not be in the subject’s 
best interest.

Pregnancy of female subject, or female partner of male subject.

Efficacy failure as defined in Section 3.4.

Declining cardiac function, defined as left ventricular ejection fraction ≤40%.

Significant protocol violation including non-compliance with study assessments. 

Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy or other reason.

Discontinuation of the study at the request of Gilead, regulatory agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC).
Subjects who discontinue treatment earlier than the assigned 24-week treatment duration will 
complete an Early Termination Visit (Section 6.7).


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3.5.
Registry Studies
3.5.1.
Sequence Registry Study
Subjects who do not achieve SVR will be eligible for enrollment in the Sequence Registry 
Study where available and approved. The purpose of the Sequence Registry Study will be to 
monitor the persistence of resistant mutations for up to 3 years. The Sequence Registry Study 
is described in a separate protocol (GS-US-248-0123).
3.5.2.
SVR Registry Study
All subjects who achieve SVR will be eligible for enrollment in the SVR Registry Study
where available and approved. The purpose of the SVR Registry Study will be to evaluate 
durability of SVR for up to 3 years post-treatment. The SVR Registry Study is described in a 
separate protocol (GS-US-248-0122).


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 40 subjects will be treated in this study.
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) Chronic HCV infection documented by either:
a) a positive anti-HCV antibody test or positive HCV RNA or positive HCV genotyping 
test at least 6 months prior to the Day 1 visit, or
b) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV 
infection
4) Infection with HCV GT 1 or 3 as determined at Screening
5) Subjects must have the following laboratory parameters at Screening: 
a) HCV RNA 104 IU/mL
b) ALT 10 the upper limit of normal  (ULN)
c) AST 10 ULN
d) Hemoglobin  9 g/dL 
e) Albumin 3.0 g/dL
f)
Direct bilirubin 1.5 x ULN
g) HbA1c 10%


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h) Creatinine clearance (CLcr) 30 mL/min, as calculated by the Cockcroft-Gault 
equation {2202} using ideal body weight (IBW). For Part 1 subjects, CLcr  
≤30 mL/min and not on dialysis, and for Part 2 subjects,on dialysis 
Male:
CLcr (mL/min) = [140 - age (years)] IBW(kg)
72 Scr
Female:
CLcr (mL/min) = [140 - age (years)] IBW(kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
Ideal body weight (IBW) is estimated by the following equations: 
      Males:                   
IBW (kg) = 50 kg + 2.3 kg for each inch over 5 feet
Females: 
            IBW (kg) = 45.5 kg + 2.3 kg for each inch over 5 feet
a.
Subjects with CLcr 30-40 mL/min are eligible if they have a prior 
CLcr 30 mL/min within 6 months of Screening
6) INR 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR.
7) A negative serum pregnancy test for female subjects of childbearing potential (see 
Appendix 2 for definition). 
8) Male subjects and female subjects of childbearing potential (see Appendix 2 for 
definition) must agree to use protocol specified method(s) of contraception as described 
in Appendix 2.
9) Lactating females must agree to discontinue nursing before administration of study drug.
10) Subject must be of generally good health as determined by the Investigator. 
11) Subject must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) BMI < 18
2) Prior exposure to an direct-acting antiviral targeting the HCV NS5B polymerase


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3) Prior null response to PEG+RBV therapy 
4) Male with pregnant female partner
5) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency, cholangitis)
6) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)
7) Unstable psychiatric condition 
8) Significant cardiac disease including or resulting in:
a) Cardiomyopathy
b) Left ventricular ejection fraction ≤50%
c) Hospital admission for myocardial infarction, heart failure within 1 year of Screening 
d) Pulmonary hypertension within 1 year of Screening
9) Clinically significant abnormality on ECG at Screening, including a QTcF >500 msec, or 
>450 msec in patients who concomitantly use methadone.
10) History of clinically significant hemoglobinopathy
11) History of porphyria
12) Malignancy within the 5 years prior to screening, with the exception of specific cancers 
that are cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation 
for possible malignancy are not eligible.
13) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone 
equivalent > 10 mg/day)
14) Clinically-relevant drug or alcohol abuse within 12 months of Screening
15) Current or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, 
encephalopathy or variceal hemorrhage)
16) History of clinically-significant illness or any other major medical disorder that may 
interfere with subject treatment, assessment or compliance with the protocol
17) History of a primary gastrointestinal disorder (or post operative condition) that could 
interfere with the absorption of the study drug 


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18) Excessive alcohol ingestion, defined as 3 glasses/day (1 glass is equivalent to: beer 
[284 mL], wine [125 mL], or distilled spirits [25 mL]) for females and 4 glasses/day for 
males)
19) Inability to collect blood for safety, PK, and efficacy throughout the study
20) Donation or loss of more than 400 mL blood within 2 months prior to Day 1 
21) Use of any prohibited concomitant medications as described in Section 5.7 within 
21 days of the Day 1 visit
22) Known hypersensitivity to RBV, the study investigational medicinal product, the 
metabolites, or formulation excipients
23) Receipt of any investigational product within a time period equal to 10 half-lives of the 
product, if known, or a minimum of 4 weeks prior to study drug administration
24) Subjects with hepatocellular carcinoma (HCC) are excluded from the study. In cirrhotic 
patients, liver imaging (e.g., ultrasound) within 6 months of Day 1 is required to exclude 
hepatocellular carcinoma (HCC)


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Sofosbuvir (SOF)
5.1.1.
Formulation
SOF tablets, 100 mg, are yellow, round, film-coated, plain-faced tablets. 
SOF tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets debossed with “GSI” on 
one side and “7977” on the other side. 
In addition to the active ingredient, SOF tablets contain the following inactive ingredients: 
mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, and yellow iron 
oxide.
5.1.2.
Packaging and Labeling
SOF tablets, 100 mg, are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 28 tablets and polyester packing material. Each bottle is enclosed with a 
white, continuous thread, child-resistant screw cap with an induction-sealed, aluminum-faced 
liner.
SOF tablets, 400 mg, are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 30 tablets and a silica gel desiccant canister or sachet and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant screw cap 
with an induction-sealed, aluminum-faced liner.
SOF bottles to be distributed to centers in the US and other countries shall be labeled to meet 
all applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 of 
Good Manufacturing Practices: Manufacture of investigational medicinal products 
(February 2010) and/or other local regulations as applicable.
5.1.3.
Storage and Handling
SOF bottles should be stored at a controlled room temperature until required for 
administration. Controlled room temperature is defined as 25 C (77 F); excursions are 
permitted between 15 C and 30 C (59 F to 86 F).
All drug products should be stored in a securely locked area, accessible only to authorized 
site personnel. To ensure the stability of the study drug and to ensure proper product 
identification, the drug product should not be stored in a container other than the container in 
which they are supplied. Consideration should be given to handling, preparation, and 
disposal through measures that minimize drug contact with the body. Appropriate 
precautions should be followed to avoid direct eye contact or exposure through inhalation 
when handling SOF.


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Sufficient quantities of SOF tablets to complete the entire study will be shipped to the 
investigator or qualified designee from Gilead Sciences Materials & Logistics (or its 
designee).
5.1.4.
Sofosbuvir (SOF) Dosage and Administration 
SOF will be administered as 200 mg or 400 mg po daily. SOF (100 mg or 400 mg) tablets
will be supplied by Gilead Sciences for all subjects.
5.2.
Ribavirin (RBV)
5.2.1.
Formulation
RBV tablets, 200 mg, are blue, capsule-shaped, film-coated tablets debossed with “3RP” on 
one side and “200” on the other side. In addition to the active ingredient, RBV tablets contain 
the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, 
croscarmellose sodium, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, 
macrogol, talc, FD&C blue #2.
5.2.2.
Packaging and Labeling
The RBV tablets are packaged in white, HDPE bottles. Each bottle contains 168 tablets and 
rayon coil packing material and is enclosed with a white, continuous thread, child-resistant 
screw cap with an induction-sealed, aluminum-faced liner.  
RBV bottles to be distributed to centers in the US and other countries shall be labeled to meet 
all applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 of 
Good Manufacturing Practices: Manufacture of investigational medicinal products 
(February 2013) and/or other local regulations as applicable.
5.2.3.
Storage and Handling
RBV tablets should be stored at 25 C (77 F); excursions are permitted between 15 and 
30 C (59 and 86 F).
All drug products should be stored in a securely locked area, accessible only to authorized 
site personnel. To ensure the stability of the study drug and to ensure proper product 
identification, the drug product should not be stored in a container other than the container in 
which they are supplied. Consideration should be given to handling, preparation, and 
disposal through measures that minimize drug contact with the body. Appropriate 
precautions should be followed to avoid direct eye contact or exposure through inhalation 
when handling RBV.


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5.2.4.
RBV Dosage and Administration 
RBV will be administered as 200 mg po daily. RBV should be dosed with food and with SOF 
to maximize adherence. RBV dose may be managed at the discretion of the Investigator in 
communication with the Medical Monitor.
RBV tablets (200 mg) will be supplied by Gilead Sciences for all subjects.
5.3.
Co-administration of Sofosbuvir (SOF) and Ribavirin (RBV)
Each subject will be given instructions to maintain approximately the same daily dosing 
interval between study drug doses.  
If a subject forgets to take the medication at the correct time, it may be taken later in the day; 
however, no more than 400 mg dose of SOF should be taken on any calendar day. The 
subject should resume the standing dosing schedule on the next day.  Study medications 
should not be cut or split.  No food restrictions apply to SOF; however, SOF should be taken 
with RBV and with food for optimal adherence.
On the day of clinic visits, subjects will be instructed to take their study medication on the 
day prior to clinic visits, 20-28 hours before the administration of the study medication at the 
clinic. Subjects should bring their medication with them to the clinic and take their study 
medication after all pre-dose assessments are completed. 
5.4.
Study Drug Compliance
On Day 1, subjects will be administered study drugs and the assigned bottles will be 
dispensed to them along with a dosing diary to be used to document at home dosing. Subjects 
will be instructed to return dosing diaries and any unused study drug in the original container 
at each visit following Day 1 for study drug compliance assessment.
Returned medication will be reconciled by the investigator in order to monitor the subject’s 
compliance with the medication regimen.
5.5.
Dispensing and Accountability of Study Drugs
The Investigator (or designee, e.g., study center pharmacist) will acknowledge receipt of the 
study drugs (after reviewing the shipment’s content and condition) from Gilead Sciences (or 
designee). The Investigator will maintain an accurate inventory of all study drugs. Each dose 
of the study drug(s) administered at the study center will be administered by qualified study 
center personnel. All doses of study drug(s) administered to subjects in the clinic under the 
supervision of staff will be accurately recorded on the Investigational Product Inventory Logs 
provided by Gilead Sciences (or on equivalent documentation maintained by the study 
center), which indicates the date and quantity of all doses of study drug(s) dispensed to 
individual subjects. The requirements of all applicable Federal and State drug dispensing 
laws will apply to all doses of study drugs dispensed by the Investigator (or designee). At the 


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end of the study, all unused study drugs (both bulk and individual subject returns) will be 
returned to a location designated by Gilead Sciences.
5.6.
Study Drug Return or Disposal
At the start of the study, the study monitor will evaluate each study center’s study drug 
disposal procedures and provide appropriate instruction for return or destruction of unused 
study drug supplies. If the site has an appropriate Standard Operating Procedure (SOP) for 
drug destruction, the site may destroy used and unused study drug supplies performed in 
accordance with the site’s (hospital/pharmacy) SOP. If the site does not have acceptable 
procedures in place for drug destruction, arrangements will be made between the site and 
Gilead Sciences (or Gilead Sciences’ representative) for return of unused study drug 
supplies. Where possible, study drug will be destroyed at the site.  If drug is destroyed on 
site, the investigator must maintain accurate records for all study drug destroyed. All study 
drug records must be maintained at the site and copies must be submitted to Gilead Sciences 
at the end of the study.
5.7.
Concomitant Medications
Concomitant medications taken within 30 days of Screening, up to and including the date of 
the visit four weeks after discontinuation of study treatment, need to be recorded in the 
source documents and eCRFs.
The following medications are prohibited from 21 days prior to the Day 1 visit through the 
end of treatment:

Drugs disallowed per prescribing information of RBV (COPEGUS®)

Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters i.e. P-gp) with study drug(s) may result in pharmacokinetic interactions 
resulting in decreases in exposure of study drug(s).  Representative medications which 
are excluded from 21 days prior to Day 1 through the end of treatment are listed below:
Drug
Agents Disallowed
Concomitant use with study drug may 
potentially result in changes of study 
drug concentration as listed below
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Decrease in concentration of study drug
Antimycobacterials
Rifampin, rifabutin, rifapentine
Decrease in concentration of study drug
Herbal/Natural 
Supplements
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-
to (or Xiao-Shai-Hu-Tang)
Decrease in concentration of study drug
Other
Modafinil
Decrease in concentration of study drug


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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 
prohibited in the study.
Should it become medically necessary for patients to start treatment with any excluded 
concomitant medication, the sponsor must be consulted prior to initiation of the new 
medication and the subject’s continued participation must be discussed with the Gilead 
Medical Monitor.
5.7.1.
Medications Associated with QT Prolongation
Medications that are known to cause or are associated with QT prolongation and/or a risk of 
causing torsades de pointes should be avoided in patients with risk factors for developing 
long QT intervals or those receiving other QT-prolonging medications.  These medications 
include, but may not be limited to those listed below (see table below) and must be approved 
by the Gilead Medical Monitor prior to study enrollment or coadministration during the 
study.  


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Representative List of Medications Known or Associated with QT Prolongation
QT Prolonging Medication Class
Known or Strongly Suspected to cause 
QT Prolongation
Weaker Association with 
QT Prolongation
Antibiotics/Anti-infectives:
Macrolide Antibiotics
azithromycin, clarithromycin, 
erythromycin, roxithromycin, 
telithromycin
Quinolone Antibiotics
gatifloxacin, gemifloxacin, levofloxacin, 
moxifloxacin, ofloxacin, sparfloxacin
ciprofloxacin
Certain 
antimalarials/pneumocystis 
prophylaxis; others
artenimool+piperaquine, bedaquiline, 
chloroquine, halofantrine, pentamidine
trimethoprim-sulfa, quinine 
sulfate
Antipsychotics:
Phenothyazine 
Antipsychotics
chlorpromazine, mesoridazine, 
thioridazine
Other Antipsychotics
clozapine, haloperidol, iloperidone, 
olanzepine, paliperidone, pimozide, 
quetiapine, risperidone, sertindole, 
ziprasidone
amisulpride,
Anit-mania Bipolar Disorders:
lithium
Anti-depressants:
Serotonin re-uptake 
inhibitors
citalopram, escitalopram, venlafaxine
fluoxetine, paroxetine, 
sertraline
Tricyclic anti-depressants
amitriptyline, 
clomipramine, 
desipramine, doxepin, 
imipramine, nortriptyline, 
protriptyline trimipramine,
Tetracyclic anti-
depressants
mirtazepine
trazodone
Cardiology Medications:
Class I (Na+) and III (K+) 
anti-arrhythmics
amiodarone, disopyramide, dofetilide, 
dronedarone, flecainide, ibutilide, 
mexiletine, procainamide, quinidine
Class II (β blockers) and 
IV (Ca2+) anti-arrythmics
isradipine, sotalol (Class II/III)
Certain anti-anginals/ 
calcium blocker
bepridil, nicardipine, ranolazine
Anesthetics, Pain Medications 
and Additional Treatment:
levomethadyl, methadone
general anesthetics (e.g., 
enflurane, halothane, 
isoflurane, sevoflurane)


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QT Prolonging Medication Class
Known or Strongly Suspected to cause 
QT Prolongation
Weaker Association with 
QT Prolongation
Anti-nausea:
domperidone, droperidol, dolasetron, 
granisetron, ondansentron, promethazine
Azole anti-fungals (systemic use 
only)
ketoconazole, voriconazole
fluconazole, itraconazole
Others:
alfuzosin, amantadine, astemizole, 
cisapride, famotidine, felbamate, 
fosphenytoin, galantamine, indapamide, 
moexipril/HCTZ, octreotide, oxytocin, 
pasireotide, perflutren lipid microspheres, 
probucol, sibutramine, terfenadine,   
tizanidine, tolterodine, vardenafil
chloral hydrate, 
diphenhydramine, 
solifenacin
Should it become medically necessary for patients to start treatment with any excluded 
concomitant medication, the sponsor must be consulted prior to initiation of the new 
medication and the subject’s continued participation must be discussed with the Gilead 
Medical Monitor.
5.7.2.
Hematopoietic Growth Factors
Erythropoiesis stimulating agents (ESAs) should not be used during Screening solely to 
elevate hematology laboratory parameters to facilitate entry into the study.  Patients taking 
ESAs for anemia related to chronic kidney disease may enter the study. Granulocyte colony-
stimulating agents and thrombopoietic growth factors should not be used while the subject is 
receiving study treatment. 


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in
Table 6-1 and described in the following text. 
Any deviation from protocol procedures should be noted in the subject’s clinical chart and 
appropriate eCRFs. In addition, the Sponsor should be promptly notified of any protocol
deviations. 
The study center will not be released to initiate dosing until:

The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) reviewed 
and approved the study and the informed consent document;

All requested regulatory documents have been submitted to and approved by 
Gilead Sciences;

A Master Services Agreement and/or Study Agreement is executed;

The study initiation meeting has been conducted by the Gilead Sciences clinical monitor 
(or designee).
The initiation meeting will include a review of the protocol, the Investigator’s Brochure, and 
Investigator responsibilities.
Documentation of the personally signed and dated informed consent of each subject, using 
the study-specific informed consent form (ICF), is required before initiating the screening 
process. Generic screening consent forms should not be used in lieu of the study-specific 
ICF.
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that subjects are eligible to participate in 
the study prior to enrollment and throughout the study.
Once consent has been obtained, all screening tests and procedures have been assessed, and 
study eligibility has been confirmed, subjects will be enrolled and assigned a unique subject 
identification number.
Subjects will receive the study treatment as described in Section 5.


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Table 6-1.
Schedule of Assessments
Study Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment 
Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Written Informed 
Consent
X
Medical History 
X
HCV RNA 
Genotype
X
IL28B Genotyping
X
HbA1c  
X
HCV, HBV, HIV 
Serology
X
TSH
X
Physical Exam, 
including Vital 
Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram 
X
X
X
Height
X
Weight
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Study Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment 
Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Coagulation (PT, 
PTT, and INR)
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA Viral 
Load
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA 
Sequencing 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy 
Teste
X
X
X
X
X
X
X
X
X
X
X
X
Creatinine 
Clearance
X
Optional 
Pharmacogenetic 
Sample
X
Intensive PK
Xf
Xf
Trough PK Sampleg
X
X
X
X
X
X
X
X
X
Archive Plasma 
Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
Administration
X
Weeks 1 -24


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Study Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment 
Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Review Dosing 
Diary/Perform 
Accountabilityh
X
X
X
X
X
X
X
X
X
X
AEs/
Concomitant Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Screening evaluations must be completed within 42 days prior to Day 1.
b
Day 1 tests and procedures must be completed prior to administration of the first dose of study drugs 
c
Within 72 hours of permanently discontinuing study drug.
d
Full PE at Day 1 and ET visits only; symptom-directed PE at all other timepoints. Vital signs include blood pressure, pulse, respiration rate, and temperature
e
Females of childbearing potential only. To confirm eligibility at Day 1, a urine pregnancy test may be collected for subjects able to pass urine. For subjects unable to pass 
urine, a serum pregnancy test at Day 1 must be performed at a local lab prior to dosing to confirm eligibility along with sample collected and send to central lab. During post-
treatment of the study, serum or urine pregnancy testing will occur every month during non-clinic post treatment visits. The subject will be contacted by telephone to confirm 
that pregnancy testing has been performed post-treatment during non-clinic visits.
f
Intensive plasma PK evaluations will be assessed at the following timepoints: 0 (predose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose. In Part 2 (ESRD 
subjects on dialysis), the Week 2 and 12 visits (intensive PK assessments) must be conducted the same number of days after the previous dialysis session.
g
Trough plasma PK samples will be drawn prior to dosing. 
h
Dosing Diaries will be completed for all non-observed doses and will be reviewed at every visit. Unused study drug will be returned to perform study drug accountability in 
the original container at each visit following Day 1 for study drug compliance assessment.
i
A window of ± 2 days is allowed for the treatment visits on weeks 1, 2, and 12.  A window of ± 4 days is allowed for the treatment visits weeks, 4-10, and 16-24. Subjects 
who cannot complete their study visit per the visit schedule should ensure they do not run out of study drug prior to their next study visit.  Compliance is critical to ensure 
adequate drug exposure.
j
A window of ± 7 days is allowed for the post treatment visits.


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6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Prospective subjects should be screened within 42 days prior to first dose on Day 1. If the 
subject does not begin the treatment phase within this 42-day window, all screening 
evaluation procedures must be repeated. No more than one repeat screen visit is allowed for 
each subject, unless prior written approval has been provided by the Sponsor.
Written informed consent must be obtained from each subject before initiation of any
screening procedure. After a subject has provided informed consent, the investigator and 
other study personnel will determine if the subject is eligible for participation in the study.  
This assessment will include a review of the inclusion/exclusion criteria and completion of 
all screening procedures as outlined in Table 6-1.
Once eligibility is confirmed, the study site will complete an eligibility worksheet for each 
screened subject and submit for Sponsor review. The sponsor will assign a unique subject 
number for each eligible subject and provide the subject number information to the site prior 
to Day 1 visit. 
6.2.2.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and 
whether condition(s) is currently ongoing, and medication history will be collected on all 
subjects during screening. Information related to HCV infection will be collected. In 
addition, a cirrhosis determination will be made as follows:
Cirrhosis determination

Cirrhosis is defined as any one of the following:
— Liver biopsy showing cirrhosis
— Fibroscan (in countries where locally approved) showing cirrhosis or results 
> 12.5 kPa
— FibroTest® score of > 0.75 AND an AST:platelet (APRI) ratio of > 2 during 
Screening

Absence of cirrhosis is defined as any one of the following:
— Liver biopsy within 2 years of Screening showing absence of cirrhosis
— Fibroscan (in countries where locally approved) with a result of ≤12.5 kPa within 
≤6 months of Day 1
— FibroTest® score of ≤ 0.48 AND APRI of ≤1 during Screening


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In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above 
criteria, a liver biopsy is required.
In addition, a determination of cardiac function will be made as follows:

Echocardiogram demonstrating left ventricular ejection fraction > 50% performed prior 
to Day 1 visit.  Enrollment allowed based on local read of study if central read is not 
available.   
6.3.
Day 1 Assessments
Subjects meeting all eligibility criteria following the screening evaluation will return to the 
study site within 42 days for Day 1 assessments as outlined in Table 6-1.
6.3.1.
Dosing Diary
Subjects will be provided with self-administration instructions and study drug diaries to 
record the exact date, time and number of tablets of study drug administration.  The site staff 
will record the information from the study drug dosing diary into the eCRF.  In the event that 
the dosing diary is not available, the site may obtain dosing information via subject interview 
and record this information in the source notes
6.4.
Treatment Assessments
Study visits will occur at the end of Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24.
Study procedures and assessments are outlined in Table 6-1. 
6.5.
Safety Assessments
Safety will be evaluated throughout the study. Refer to Table 6-1 for a schedule of 
assessments.
6.5.1.
Safety ECGs
Subjects should rest quietly in the supine position for a minimum of 10 minutes prior to each 
scheduled ECG acquisition and should remain in that position until the recording is complete. 
There must be no environmental distractions (television, radio, conversation, etc.) while the 
subjects are resting prior to and during the recordings.
ECGs will be recorded at a sampling frequency of 500+ Hz, at a speed of 25 mm/sec and at a 
standard duration of 10 seconds. All ECGs will be obtained using instruments that analyze 
data using the same algorithms and produce the same data for interpretation. When ECGs are 
performed on an ECG machine, site standard operating procedures (SOPs) will be used.
ECG measurements will be collected pre-dose at time-points as per Table 6-1.
The Investigator or other qualified individuals at the study center will review ECGs to assess 
for changes in ECG intervals and morphology as compared to pre-dose ECGs. Collection of 


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additional ECGs for routine safety monitoring at additional time-points or days is at the 
discretion of the Investigator based on GCP.
6.5.2.
Safety echocardiograms
Safety echocardiograms will be performed as outlined in Table 6-1.  A window of ± 10 days 
is allowed for the on-treatment visits. These safety echocardiograms will be performed
locally and sent to a central location for standardized reading.  For Part B, echocardiograms 
will be performed up to 36 hours following dialysis.
6.5.3.
Physical Examination
Complete physical examinations or a symptom directed physical examination will be 
conducted pre-dose as outlined in Table 6-1. A complete physical examination must include 
source documentation of general appearance, and the following body systems: head, neck 
and thyroid; eyes, ears, nose, throat, mouth and tongue; chest (excluding breasts); respiratory; 
cardiovascular; lymph nodes, abdomen; skin, hair, nails; musculoskeletal; neurological. 
6.5.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, 
respiratory rate, and temperature and will be conducted pre-dose as outlined in Table 6-1.
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.
6.5.5.
BMI
Height and weight will be collected at the times shown in the schedule of assessments 
Table 6-1.
BMI is calculated by the following equation.
BMI = weight (pounds) 703           or            weight in kilograms
   (height in inches)2                                (height in meters)2
6.5.6.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {2202} using ideal body 
weight (IBW). 


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Male:
CLcr (mL/min) = [140 - age (years)] IBW(kg)
72 Scr
Female:
CLcr (mL/min) = [140 - age (years)] IBW(kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
Ideal body weight (IBW) is estimated by the following equations: 
      Males:                   
IBW (kg) = 50 kg + 2.3 kg for each inch over 5 feet
Females: 
            IBW (kg) = 45.5 kg + 2.3 kg for each inch over 5 feet
6.5.7.
Clinical Laboratory Tests/Assessments
In addition to the PK blood samples that will be collected, blood samples will be collected 
pre-dose as outlined in the schedule of assessments, Table 6-1 for the following laboratory 
analyses:
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, MCV, 
and Coagulation Panel (PT, PTT, and INR).
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase 
(AST/SGOT), Albumin, Alkaline phosphatase, Creatinine, Total Bilirubin (reflex to Direct 
Bilirubin), Glucose, Total Protein, Bicarbonate, BUN, Calcium, Chloride, Phosphorus, 
Magnesium, Potassium, Sodium, and FibroTest®.
Thyroid-stimulating hormone (TSH)
Haemoglobin A1C (HbA1c)
Virological Tests: Serologies for HCV, HBV and HIV. HCV RNA will be measured using 
COBAS® AmpliPrep/COBAS® TaqMan® HCV Test. HCV genotype and subtype will be 
determined using the Siemens VERSANTHCV Genotype INNO-LiPA 2.0 Assay. Gilead 
reserves the right to use alternate assays for HCV RNA and HCV genotype should the above 
assays become unavailable or are not definitive.
Viral RNA Sequencing / Phenotyping plasma samples will be collected to confirm virologic 
breakthrough. Untested samples may be archived.
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 


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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: All females of childbearing potential will have serum or urine pregnancy 
testing every 4 weeks during the dosing period and for a minimum of 6 months following the 
last dose of RBV. If required by local regulations, additional pregnancy tests may be 
collected. In the event of a positive urine pregnancy result, subjects will be instructed to stop 
study drugs immediately and return to the clinic as soon as possible for a serum pregnancy 
test.
Pregnancy tests must be completed for all females of childbearing potential (see Appendix 2
for definition) as specified in Table 6-1. When feasible for subjects, a urine pregnancy test 
may also be taken. During post treatment of the study, subject will be contacted by telephone 
monthly to confirm that the serum or urine pregnancy testing has been performed 
post-treatment during non-clinic visits.. Alternatively, if required by local regulations or 
preferred by the investigator or subject, the subject may return to the clinic for urine or serum 
pregnancy tests post treatment.
6.5.8.
Adverse Events/ Concomitant Medications/ Protocol Restrictions
Evaluation for adverse events, review of concomitant medications, and review of protocol 
restrictions will occur at the times shown in the schedule of assessments Table 6-1. See 
Section 7 for more information regarding adverse events and Section 5 for more information 
about concomitant medications.
6.6.
Pharmacokinetic (PK) Assessments
Subjects will be instructed to take their SOF dose on the day prior to clinic visits, 
20-28 hours before the clinic visit. On the day of clinic visits, subjects should bring their 
medication with them to the clinic and take their dose after the trough PK sample is 
collected, or after the predose intensive PK sample is taken.
In Part 2 (ESRD subjects on dialysis), the Week 2 and 12 visits (intensive PK assessments) 
must be conducted the same number of days after the previous dialysis session.
The exact time of the dose taken prior to collection of the PK sample and the exact time the 
PK sample is drawn will be recorded on the appropriate eCRF.
Intensive PK Assessments:
Intensive plasma PK samples will be collected on week 2 and 12 at the following timepoints: 
0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours post-dose. 
Plasma concentrations of SOF and its metabolites will be determined and PK parameters will 
be estimated as appropriate. Plasma concentrations of RBV may be determined, if necessary.


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Trough PK Assessments:
Trough PK plasma samples for analyses of SOF, its metabolites and RBV concentrations will 
be collected at all other on treatment visits beginning at the Week 1 visit.
PK Parameters for SOF, its metabolites, and RBV will be estimated as appropriate. 
6.7.
Early Termination (ET)/Unscheduled Visit 
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. 
The assessments at the unscheduled visits are at the investigator’s discretion. At all 
unscheduled visits initiated for the purpose of confirming virologic failure a Viral RNA 
Sequencing / Phenotyping Sample must be collected. 
The Sponsor (e.g. Medical Monitor and Clinical Program Manager)/CRO must be informed, 
as soon as possible, when a subject prematurely discontinues treatment.  The primary reason 
for premature treatment discontinuation must be provided to the Sponsor/CRO.  
If a subject discontinues treatment early for any reason then the following assessments for the 
Early Termination (ET) Visit must be performed: 

Perform complete physical examination

Obtain body weight

Obtain vital signs

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Obtain blood samples for:
— Hematology & Chemistry
— Coagulation (PT, PTT, and INR)
— HCV RNA
— Viral Sequencing / Phenotyping Sample 
— Trough PK
— Serum pregnancy test (females of childbearing potential only)

Review study drug adherence with subject including recording the date and time of the 
subject’s last dose of study drug prior to the PK draw (subject should return all study 
drugs at this visit)
All subjects will attend the 4-Week Post-Treatment Visit.


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Post-Treatment Assessments 
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Subjects with HCV RNA < LLOQ at the 4-Week Post-Treatment Visit will attend the 
12-Week Post-Treatment Visit. 
Subjects with HCV RNA ~ LLOQ do not need to retum for additional visits and they will be 
tenninated early from the study. 
Subjects with HCV RNA < LLOQ at the Post-Treatment Week 12 Visit will retum at the 
post-treatment Week 24 Visit. 
6.9. 
Optional Samples for Pharmacogenetic Testing 
PPD 
6.10. 
Archived Plasma Sample 
Archive plasma samples will be collected at the study visits, indicated in Table 6-1. Archive 
plasma samples are being collected for possible additional analyses, including but not limited 
to, study dmg or metabolite measurements, viral load, safety/efficacy assessments, HCV 
gene sequencing, HCV resistance testing and other possible predictors of response as 
determined by Gilead. 
In the event of a subject's death or loss of competence, the subject's specimens and data. will 
continue to be used as pmi of the future biomm·ker research. 
If a subject wishes to withdraw the testing of his or her specimens for future research, the 
investigator must inf01m the Gilead Sciences Medical Monitor in writing of the subject's 
wishes. 
6.11. 
Blood Storage 
Archived plasma samples will be collected for future testing. These samples will be frozen 
and stored. The stored plasma samples may be used by the Sponsor or its research pminer for 
future clinical laborat01y testing to provide additional clinical data. At the conclusion of this 
study, these samples may be retained in storage by Gilead Sciences, Inc. at its resem·ch 
pminer facility for a period up to 10 yem·s. 
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7.
ADVERSE EVENTS MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with the treatment. An AE can therefore be any unfavorable and/or unintended sign, 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. AEs may also include pre- or post-treatment 
complications that occur as a result of protocol specified procedures, lack of efficacy, 
overdose, drug abuse/misuse reports, or occupational exposure. Preexisting events that 
increase in severity or change in nature during or as a consequence of participation in the 
clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and 
transfusion. The condition that led to the procedure may be an adverse event and must be 
reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before 
the screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not 
an AE. It is considered to be pre-existing and should be documented on the medical 
history CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the 
following:

Death


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
Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer 
to an event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; and development of drug 
dependency or drug abuse. For the avoidance of doubt, infections resulting from 
contaminated medicinal product will be considered a medically important event and
subject to expedited reporting requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event 
information and assessments.


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7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to
IMP therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, 
an alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally 
related in the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or 
biopsy) should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study 
procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading 
Scale for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs 
associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in 
agreement with the grading of the laboratory abnormality.
7.3.
Investigator Requirements and Instructions for Reporting Adverse 
Events and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of 
events should be reported on the case report form (CRF/eCRF): all SAEs and adverse events 
related to protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30-days after last administration of study IMP must be reported to the CRF/eCRF 
database as instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined 
follow up period.


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All SAEs, regardless of cause or relationship, that occms after the subject first consents to 
pmiicipate in the study (ie, signing the infonned consent) and throughout the dmation of the 
study, including the protocol-required post treatment follow-up period, must be reported to 
the CRF/eCRF database and Gilead Dmg Safety and Public Health (DSPH) as instructed. 
This also includes any SAEs resulting from protocol-associated procedmes perf01med after 
inf01med consent is signed. 
Any SAEs and deaths that occm after the post tr·eatment follow-up visit but within 30-days of 
the last dose of study IMP, regardless of causality, should also be rep01ied. 
Investigators m·e not obligated to actively seek SAEs after the protocol defined follow up 
period, however, if the investigator lemns of any SAEs that occm after study pmticipation 
has concluded and the event is deemed relevant to the use ofiMP, he/she should promptly 
document 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. 
Electr·onic Serious Adverse Event ( eSAE) Rep01iing Process 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit the SAE 
inf01mation to Gilead DSPH within 24 homs of the investigator's knowledge of the 
event. Detailed instructions can be fmmd in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE infonnation electr·onically, ie, the 
eCRF database is not ftmctioning, record the SAE on the paper serious adverse event 
rep01iing f01m and submit within 24 homs to: 
Gilead DSPH: 
Fax: 
+ 1-650-522-5477 
E-mail: 
safety_ fc@gilead.com 
Gilead Sciences Medical 
Name: 
Luisa Stamm, MD, PhD 
Monitor: 
Phone: 
PPD 
Fax: 
PPD 
E-mail: 
1-'1-'U 
I 
• 
As soon as it is possible to do so, any SAE rep01ted via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been rep01ied via a paper fonn because the eCRF database has been 
locked, no ftnther action is necessaty. 
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
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and 
other documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate 
safety reports.

Any medications necessary for treatment of the SAE must be recorded onto the 
concomitant medication section of the subject’s CRF/eCRF and the event description 
section of the SAE form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to 
expedite to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions 
(SADRs), or suspected unexpected serious adverse reactions (SUSARs). In accordance with 
the EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify 
worldwide regulatory agencies and the relevant IEC in concerned Member States of 
applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. 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. 
7.5.
Toxicity Management 
7.5.1.
Stopping Rules for Toxicity
Subjects who meet any of the following criteria should be instructed to immediately stop all 
study drugs and return for an Early Termination Visit:

Confirmed elevation of ALT and/or AST > 5x Day 1 or nadir, confirmed by immediate 
repeat testing

Confirmed elevation of ALT >3x Day 1 and total bilirubin >2 x ULN

Confirmed elevation of ALT >15 x ULN

Any Grade 3 or greater rash associated with constitutional symptoms


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
Any Grade 4 event assessed as related to treatment 

Echocardiogram demonstrating left ventricular ejection fraction ≤40%
7.5.2.
Sofosbuvir (SOF)
Administration of SOF may be discontinued due to a clinical or laboratory event.  In the 
event that SOF is stopped, RBV should also be discontinued. 
7.5.3.
Ribavirin (RBV)
Dose reduction or interruption of RBV due to toxicity should be performed based on the 
clinical experience of the Investigator. RBV may be permanently discontinued due to toxicity 
without stopping SOF. 
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, and 
pregnancy reports regardless of an associated AE.  Also includes reports of adverse reactions 
in infants following exposure from breastfeeding, and reports of adverse reactions associated 
with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following maternal or paternal exposure 
to the medicinal product.
Medication error is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by 
a subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not 
in accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a 
medicinal product given per administration or cumulatively which is above the maximum 
recommended dose as per protocol or in the product labelling (as it applies to the daily dose 
of the subject in question). In cases of a discrepancy in drug accountability, overdose will be 
established only when it is clear that the subject has taken the excess dose(s). Overdose 
cannot be established when the subject cannot account for the discrepancy except in cases in 
which the investigator has reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the 
manufacture, packaging, or distribution of the medicinal product.  


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7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first 
consents to participate in the study (ie, signs the informed consent) and throughout the study, 
including the post study drug follow-up period, to the Gilead DSPH using the pregnancy 
report form within 24 hours of becoming aware of the pregnancy. Refer to Section 7.3 and 
the eCRF completion guidelines for full instructions on the mechanism of pregnancy 
reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate 
a pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as 
an SAE. The underlying medical reason for this procedure should be recorded as the AE 
term.
A spontaneous abortion is always considered to be an SAE and will be reported as described 
in Sections 7.1.1 and 7.1.2 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. 
Clinical staff should also report any pregnancies to the Ribavirin Pregnancy Registry at 
1-800-593-2214 (see also http://www.ribavirinpregnancyregistry.com).
Refer to Appendix 2 for Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the 


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situation. These reports must consist of situations that involve study IMP, but do not apply to 
concomitant medications. Except for situations that result in AEs, special situations involving 
concomitant medications will not be reported. Any inappropriate use of medications 
prohibited by this protocol should not be reported as “misuse,” but may be more 
appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or 
SAEs at the same time using the AE eCRF and/or the SAE report form. Details of the 
symptoms and signs, clinical management, and outcome will be reported, when available.


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The prima1y objectives of this study are as follows: 
Final 
Amendment2 
• 
To evaluate the safety of SOF 200 mg or 400 mg + RBV for 24 weeks as assessed by 
review of the accumulated safety data in each treatment rum 
• 
To evaluate the efficacy of SOF 200 mg or 400 mg + RBV for 24 weeks measured by the 
prop01iion of subjects with renal insufficiency who have achieved a SVR12 after 
treatment discontinuation in each treatment ann 
• 
To evaluate the steady state PK of SOF and its metabolites upon dosing SOF 200 mg or 
400 mg in subjects with renal insufficiency 
The secondruy objectives of this study ru·e as follows: 
• 
To evaluate the prop01iion of subjects with renal insufficiency who attain SVR4 and 
SVR24 weeks after discontinuation of treatment 
• 
To evaluate the kinetics of plasma HCV RNA during and after treatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF during and after treatment 
discontinuation 
The explorat01y objective ofthis study is: 
PPO 
8.1.2. 
Primary Endpoint 
The prima1y safety endpoints include incidences of AEs, laborat01y, 12-lead ECG, and vital 
sign abn01m alities. 
The prima1y PK endpoints ru·e pru·ameters AUCtau, Cmax, and Ctau for analytes SOF, its 
metabolites, and RBV as applicable. 
The prima1y efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after discontinuation 
of therapy). 
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8.1.3.
Secondary Endpoint
Secondary PK endpoints are parameters AUClast, Clast, Tmax, Tlast, λz, and t1/2 for analytes SOF,
its metabolites, and RBV as applicable.
Secondary efficacy endpoints include the proportion of subjects with SVR4 and SVR24, the 
proportion of subjects with virologic failure including viral breakthrough and relapse.
8.1.4.
Other Endpoints of Interest
Additional efficacy evaluations may include HCV RNA change from baseline; ALT 
normalization; viral kinetic parameters, and the health related quality of life endpoints.
8.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses 
will be performed using SASsoftware (SAS Institute, Cary, North Carolina, USA).
The study drugs in this study include SOF and RBV. Last dose of study drug refers to the last 
dose of any of the study drugs in a treatment group and will be used in the definition of 
treatment-emergent AEs and laboratory abnormalities as well as the efficacy endpoints of 
SVR at various post-treatment time points.
All analyses will be presented by treatment in each renal function subgroup (study part). 
Subjects who receive study drug other than that to which they were assigned will be analyzed 
according to the study drug received.
8.2.1.
Analysis Sets
8.2.1.1
Efficacy
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which 
includes subjects who were enrolled and received at least one dose of study drug. 
8.2.1.2
Safety
The primary analysis set for safety analyses will be the Safety Analysis Set which includes
subjects who received at least one dose of study drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose of 
study drug through the date of the last dose of study drug plus 30 days.
8.2.1.3
Pharmacokinetics
The PK analysis set will include all subjects who are enrolled and have received at least 
one dose of study drug and for whom PK concentration data of interested analytes (SOF, its 
metabolites, or RBV) are available. The PK analysis set will be used for analyses of general 
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8.2.2.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. In general, values 
for missing data will not be imputed. 
For the analysis of post-baseline categorical efficacy endpoints, if a data point is missing and 
is immediately preceded and followed in time by values that are deemed successes, then the 
missing data point will be termed a success; otherwise the data point will be termed a failure.
Any subject with missing data due to premature discontinuation of the study medication will 
be considered a failure at the time points on, or following, the date of discontinuation. If no 
HCV RNA values are obtained after the last dose of study medication, the subject will be 
considered a treatment failure for the SVR endpoints. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject received study medication, the subject will be included in a summary of 
adverse events according to the treatment received; otherwise, if the subject is not dosed 
then they will be excluded from the summary.

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 predose value, then the subject will be excluded from the 
calculation of summary statistics for the predose value and the change from predose 
values.
Values for missing safety laboratory data will not be imputed; however, a missing baseline 
result will be replaced with a screening result, if available. If no pretreatment laboratory 
value is available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) 
for the summary of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for 
calculation of summary statistics for the actual HCV RNA values and the change from 
baseline values by study visit. The reported values will be provided in the HCV RNA listing.
For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed 
to the logarithmic (base 10) scale (log10 IU/mL).
PK concentration values below the lower limit of quantitation (BLQ) will be treated as zero
for determination of summary and order statistics. Individual values that are BLQ will be 
presented as “BLQ” in the concentration data listing. For the presentation of summary and 
order statistics, if at least 1 subject has a concentration value BLQ for the time point, then the 


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minimum value will be displayed as “BLQ.” If more than 50% of the subjects have a 
concentration data value BLQ for the time point, then the minimum and median values will 
be displayed as “BLQ.” If more than 75% of the subjects have a concentration data value of 
BLQ for a given time point, then the minimum. 1st quartile [q1], median, and 3rd quartile 
[Q3] values will be displayed as “BLQ.” If all subjects have concentration data values BLQ 
for the time point, then all order statistics (minimum, first quartile [Q1], median, third 
quartile [Q3], maximum) will be displayed as “BLQ”.
Exposure parameters that are selected for statistical analysis will be natural log-transformed. 
Concentration values that are BLQ will be excluded for any ratio or natural log-transformed 
statistical analysis.
8.2.3.
Interim Analysis
Interim analyses will be performed to support external multidisciplinary data monitoring 
committee meetings (Section 8.9).
8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline characteristics will be summarized using standard descriptive 
methods by treatment in each study part.
Demographic data will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include body weight/body mass index, HCV RNA level 
(log10 IU/mL), IL28B genotype, baseline ALT level, creatinine clearance estimated by 
Cockcroft-Gault, and additional endpoints as necessary.
8.4.
Efficacy Analysis
8.4.1.
Primary Analysis
The primary efficacy endpoint is SVR12 in the FAS population. The primary analysis will be 
performed after all enrolled subjects have been followed through 12 weeks post-treatment or 
discontinued from study.
A point estimate with a 2-sided 95% exact confidence interval (CI) using the exact binomial 
distribution (Clopper-Pearson method) will be constructed for the SVR12 rate by treatment 
and study part.
No statistical hypothesis testing will be performed.
8.4.2.
Secondary Analysis
The proportion of subjects with HCV RNA below the LLOQ over time (including SVR12) 
will be presented by treatment and study part in tabular and graphical form. 


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Descriptive summaries and listings will be provided for additional efficacy evaluations 
including the prop01iion of subjects who experience virologic failme, ALT n01malization, 
semm HCV RNA actual values and change from baseline, other endpoints of interest 
including AL T nonnalization and health related quality of life endpoints. 
PD 
Details on efficacy analyses will be described in the statistical analysis plan (SAP). 
8.5. 
Safety Analysis 
Safety will be evaluated by assessment of clinical laborat01y tests, physical examinations, 
vital signs measmements, at various time points dming the study, and by the docmnentation 
ofAEs. 
All safety data collected on or after the first dose of study dmg adminisu·ation up to 30 days 
after the last dose of study dmg will be summarized according to the study dmg received. 
Safety endpoints will be summarized as the number (prop01iion) of subjects with events or 
abn01malities for categorical data or as an 8-number summaty (n, mean, standard deviation, 
minimum, Ql, median, Q3, maximum) for continuous data. 
8.5.1. 
Extent of Exposure 
A subject's extent of exposme to study dmg will be generated from the study dmg 
adminisu·ation page of the CRF. Exposme data will be summarized by u·eatment and study 
pati. 
8.5.2. 
Adverse Events 
Clinical and laborat01y AEs will be coded using the Medical Dictionaty 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 
u·eatlnent-emergent adverse event will be defined as any new or worsening adverse event that 
begins on or after the date of first dose of study dmg up to the date of last dose of study dmg 
plus 30 days. 
Summaries (number and percentage of subjects) ofu·eatlnent-emergent adverse events (by 
SOC and prefen ed tetm ) will be provided by u·eatlnent and study part: 
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
All AEs,

All study drug-related AEs,

Combined Grade 2, 3 and 4 AEs,

Combined Grade 3 and 4 AEs,

Combined Grade 2, 3 and 4 study drug-related AEs,

Combined Grade 3 and 4 study drug-related AEs,

All AEs that caused permanent discontinuation from study drug,

All AEs that caused change in dose or temporary interruption of study drug,

All SAEs (including death), and

All study drug-related SAEs
All AEs collected during the course of the study will be presented in data listings.
8.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, minimum, Q1, median, Q3, 
maximum) by study visit along with corresponding change from baseline.
Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme 
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 baseline at 
any time post-baseline up to the date of last dose of study drug plus 30 days will be 
summarized by treatment and study part. 
Values for missing safety laboratory data will not be imputed; however, a missing baseline 
result will be replaced with a screening result, if available. If no pretreatment laboratory 
value is available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) 
for the summary of graded laboratory abnormalities. Thus, any post-baseline graded 
abnormality (i.e., at least Grade 1) will be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
8.6.
Pharmacokinetic Analysis
Plasma concentrations of the study drug over time will be listed and summarized using 
descriptive statistics. PK parameters (e.g., AUCtau, Cmax, and Ctau) will be listed and 
summarized for study drug (i.e., SOF and its metabolites, and RBV) using descriptive 


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statistics (e.g., sample size, arithmetic mean, geometric mean, % coefficient of variation
[%CV], SD, minimum, Q1, median, Q3, maximum). 
8.7.
Stopping Rules for Individual Groups
There are no predetermined futility criteria which would require enrollment to be halted or 
treatment discontinued.
8.8.
Sample Size
Due to the exploratory nature of this study, no formal power or sample size calculations were 
performed to determine treatment group size. The total sample size of 40 ( i.e., 10 enrolled to 
obtain 8 evaluable for each dose level group in each study part) is largely based on 
feasibility.
8.9.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of 
the study and perform interim reviews of safety, efficacy, and PK data through post-
treatment week 4 for each part and dose of the study before proceeding to the next.
Specifically, all of the data from the Part 1 SOF 200 mg group will be reviewed before 
screening, enrollment and dosing will occur for the Part 1 SOF 400 mg group and the same 
review and initiation process will occur between Part 1 SOF 400 mg and Part 2 SOF 200 mg 
and also between Part 2 SOF 200 mg and Part 2 SOF 400 mg.   The DMC will provide 
recommendations to Gilead whether the nature, frequency, and severity of adverse effects 
associated with study treatment warrant the early termination of the study in the best interests 
of the participants, whether the study should continue as planned, or the study should 
continue with modifications. The DMC may also provide recommendations as needed 
regarding the need for additional meetings or an alternative meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, 
including possible early study termination, Gilead retains final decision-making authority on 
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of 
the Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the study subject. These standards are consistent with the European 
Union Clinical Trials Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or 
proprietary interests in the investigational drug under study. This documentation must be 
provided prior to the investigator’s (and any subinvestigator’s) participation in the study. The 
investigator and subinvestigator agree to notify Gilead of any change in reportable interests 
during the study and for 1 year following completion of the study. Study completion is 
defined as the date when the last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the 
subject (such as advertisements, subject information sheets, or descriptions of the study used 
to obtain informed consent) to an IRB or IEC. The investigator will not begin any study 
subject activities until approval from the IRB or IEC has been documented and provided as a 
letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval 
from the IRB or IEC any modifications made to the protocol or any accompanying material 
to be provided to the subject after initial IRB or IEC approval, with the exception of those 
necessary to reduce immediate risk to study subjects.


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9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB- or IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be 
appropriately signed and dated by the subject or the subject’s legally authorized 
representative and the person conducting the consent discussion, and also by an impartial 
witness if required by IRB or IEC or local requirements. The consent form will inform 
subjects about pharmacogenomic testing and sample retention, and their right to receive 
clinically relevant pharmacogenomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties. Only subject initials, date of birth, 
another unique identifier (as allowed by local law) and an identification code will be 
recorded on any form or biological sample submitted to the Sponsor, IRB or IEC, or 
laboratory. Laboratory specimens must be labeled in such as way as to protect subject 
identity while allowing the results to be recorded to the proper subject. Refer to specific 
laboratory instructions. NOTE: The investigator must keep a screening log showing codes, 
names, and addresses for all subjects screened and for all subjects enrolled in the trial. 
Subject data will be processed in accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to 
the investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study 
information, remain the sole and exclusive property of Gilead during the conduct of the study 
and thereafter. This information is not to be disclosed to any third party (except employees or 
agents directly involved in the conduct of the study or as required by law) without prior 
written consent from Gilead. The investigator further agrees to take all reasonable 
precautions to prevent the disclosure by any employee or agent of the study site to any third 
party or otherwise into the public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into at least the following two categories: (1) investigator’s 
study file, and (2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB or IEC and governmental approval with correspondence, informed consent, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence.


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The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and 
return;

Record of all adverse events and other safety parameters (start and end date, and 
including causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing 
application in an ICH region (ie, United States, Europe, or Japan) and until there are no 
pending or planned marketing applications in an ICH region; or, if no application is filed or if 
the application is not approved for such indication, until 2 years after the investigation is 
discontinued and regulatory authorities have been notified. Investigators may be required to 
retain documents longer if specified by regulatory requirements, by local regulations, or by 
an agreement with Gilead. The investigator must notify Gilead before destroying any clinical 
study records.
Should the investigator wish to assign the study records to another party or move them to 
another location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all 
of the documents, special arrangements must be made between the investigator and Gilead to 
store these records securely away from the site so that they can be returned sealed to the 
investigator in case of an inspection. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage away from the site.


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9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should 
be completed on the day of the subject visit to enable the sponsor to perform central 
monitoring of safety data.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system. Original entries as well as any changes to data 
fields will be stored in the audit trail of the system.  Prior to database lock (or any interim 
time points as described in the clinical data management plan), the investigator will use 
his/her log in credentials to confirm that the forms have been reviewed, and that the entries 
accurately reflect the information in the source documents. The eCRF capture the data 
required per the protocol schedule of events and procedures. System-generated or manual 
queries will be issued to the investigative site staff as data discrepancies are identified by the 
monitor or internal Gilead staff, who routinely review the data for completeness, correctness, 
and consistency. The site coordinator is responsible for responding to the queries in a timely 
manner, within the system, either by confirming the data as correct or updating the original 
entry, and providing the reason for the update (e.g. data entry error). At the conclusion of the 
trial, Gilead will provide the site with a read-only archive copy of the data entered by that 
site. This archive must be stored in accordance with the records retention requirements 
outlined in Section 9.1.5.
9.1.7.
Drug Accountability
Gilead recommends that used and unused IMP supplies be returned to the shipping facility 
from which it came for eventual destruction. The study monitor will provide instructions for 
return. If return is not possible, the study monitor will evaluate each study center’s IMP 
disposal procedures and provide appropriate instruction for destruction of unused IMP 
supplies. If the site has an appropriate standard operating procedure (SOP) for drug 
destruction as determined by Gilead QA, the site may destroy used (empty or partially 
empty) and unused IMP supplies in accordance with that site’s approved SOP. A copy of the 
site’s approved SOP will be obtained for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the IMP. Upon study completion, 
copies of the IMP accountability records must be filed at the site. Another copy will be 
returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs or IECs or to regulatory authority or health 
authority inspectors.


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9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, 
may be made only by Gilead Sciences. All protocol modifications must be submitted to the 
Competent Authorities, IRB or IEC in accordance with local requirements. Approval must be 
obtained before changes can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). 
Gilead will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report 
may be prepared in certain cases. 
Investigators in this study may communicate, orally present, or publish in scientific journals 
or other scholarly media only after the following conditions have been met:

the results of the study in their entirety have been publicly disclosed by or with the 
consent of Gilead in an abstract, manuscript, or presentation form or the study has been 
completed at all study sites for at least 2 years

The investigator will submit to Gilead any proposed publication or presentation along 
with the respective scientific journal or presentation forum at least 30 days before 
submission of the publication or presentation. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).

The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to 
withhold publication or presentation for an additional 60 days in order to obtain patent 
protection if deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to 
the investigator’s source documentation in order to verify the accuracy of the data recorded 
in the CRF/eCRF.


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The monitor is responsible for routine review of the CRF/eCRF at regular intervals 
throughout the study to verify adherence to the protocol and the completeness, consistency, 
and accuracy of the data being entered on them. The monitor should have access to any 
subject records needed to verify the entries on the CRF/eCRF. The investigator agrees to 
cooperate with the monitor to ensure that any problems detected through any type of 
monitoring (central, on site) are resolved.
9.3.2.
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.
9.3.3.
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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10.
REFERENCES
2202
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16:31-41.
12557
Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. 
Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks 
versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic 
infection with hepatitis C virus. International Hepatitis Interventional Therapy 
Group (IHIT). Lancet 1998;352 (9138):1426-32.
12558
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et 
al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for 
chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 
1998;339 (21):1485-92.
13693
Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and 
treatment of hepatitis C: an update. Hepatology 2009;49 (4):1335-74.
15572
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
Laboratories Inc., Nutley, NJ. Revised: January 2010.
15668
Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
Characteristics. Roche Products Limited, Welwyn Garden City, United Kingdom. 
Revised: March 2010.
17940
Craxi A. EASL clinical practice guidelines: management of hepatitis C virus 
infection, European association for the study of the liver. J Hepatol 2011;55:245-
64.
19705
Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus 
infection in Europe. J Hepatol 2008;48 (1):148-62.
23275
Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. 
Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J 
Med 2013;368 (1):34-44.
24149
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
Laboratories Inc., Nutley, NJ. Revised: February 2013.
24713
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, 
Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without 
treatment options. N Engl J Med 2013;368 (20):1867-77.


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24715
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et 
al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 
2013;368 (20):1878-87.
24913
Abboud O, Becker G, Bellorin-Font E, Field M, Johnson R, Li PK, et al. KDIGO 
clinical practice guidelines on hepatitis C in chronic kidney disease acknowledged 
by ISN. Nature clinical practice 2008;4 (12):648-9.
27503
SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing Information. Gilead 
Sciences, Inc. Foster City, CA. December 2013.  
27832
Sovaldi 400 mg film-coated tablets. Summary of Product Characteristics. Gilead 
Sciences Limited. County Cork Ireland. January 2014.  


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2b, Open-Label Study of200 mg or 400 mg Sofosbuvir+RBV for 24 Weeks in 
Genotype 1 or 3 HCV-lnfected Subjects with Renal Insufficiency 
GS-US-334-0154, Amendment 2, 20 February 2014 
This protocol bas been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
V1 
PrN A 8 42.-A-J t¥ A-rl-P Far 
Luisa Stamm, MD, PhD (Printed) LuLs. A 
Medical Monitor 
.S lAMM 
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 staff to conduct tbis 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. 
l 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 
CONFIDENT1AL 
Page67 
20 Febroary 2014 


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Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
11.1.1.
Background
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects 
have been demonstrated in all animal species tested. Pregnancy must be excluded before the 
start of treatment with study drugs and prevented thereafter by reliable contraceptive 
methods. Pregnancy tests will be performed regularly throughout this study. Furthermore, 
RBV is known to accumulate intracellularly where it is cleared slowly, and is also excreted in 
semen. Therefore, extreme care must be taken to avoid pregnancy during RBV therapy and 
for up to 6 months following completion of treatment (7 months for males). Please refer to 
the latest version of the product insert for additional information. 
Non-clinical toxicity studies of SOF demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of SOF in pregnant 
women. Please refer to the latest version of the investigator’s brochure for additional 
information. 
11.1.2.
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 6 months after last dose of 
RBV:

Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) is not permitted.
Or

Consistent and correct use of 1 of the following methods of birth control listed below, in 
addition to a male partner who correctly uses a condom, from the date of Screening until 
6 months after the last dose of RBV: 
— intrauterine device (IUD) with a failure rate of < 1% per year
— female barrier method: cervical cap or diaphragm with spermicidal agent


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— tubal sterilization
— vasectomy in male partner
— implants of levonorgestrel
— injectable progesterone
— oral contraceptives (either combined or progesterone only)
— contraceptive vaginal ring 
— transdermal contraceptive patch
11.1.3.
Contraceptive Requirements for Male Subjects (and their female 
partners)
All male study participants must agree to consistently and correctly use a condom from 
Baseline until 7 months after the last dose of RBV. If their female partner is of childbearing 
potential (as defined above), their female partner must use 1 of the methods of birth control 
listed above from the date of Screening until 7 months after last dose of RBV.
Male subjects must agree to refrain from sperm donation for at least 7 months after the last
dose of RBV.
11.1.4.
Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any 
time during the study, or if they become pregnant within 6 months (7 months for 
partners of male subjects) of last RBV dose. Subjects who become pregnant or who 
suspect that they are pregnant must report the information to the investigator and 
discontinue study drug immediately. Subjects whose partner has become pregnant 
or suspects she is pregnant must report the information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined 
in Section 7.6.2. 


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


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


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Amendment 2
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4  mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L


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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
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


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated


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


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


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


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


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


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


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


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


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


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


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


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


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

Prot_004.pdf: 
Study Title: 
Sponsor: 
IND No.: 
EudraCT No: 
Indication: 
Protocol ID: 
Gilead Sciences 
Study Director 
Gilead Sciences 
Medical Monitor 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2b, Open-Label Study of200 mg or 400 mg 
Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 and 
Ledipasvir/Sofosbuvir (LDV/SOF) Fixed-Dose Combination 
(FDC) Tablet for 12 weeks in Genotype 1 or 4 HCV-Infected 
Subjects with Renal Insufficiency 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
106739 
2013-002897-30 
Hepatitis C Vims Infection 
GS-US-3 34-0154 
Name: 
PPD 
Telephone: 
PPD 
Fax: 
PPD 
E-mail: 
t-'t-'U 
I 
~--------------~ 
Name: 
Telephone: 
Fax: 
E-mail: 
Original: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Amendment 4: 
Theo Sarif, MD 
PD 
PPD 
t-'t-'U 
11 July 2013 
05 September 2013 
20 Febmmy 2014 
23 Febmmy 2015 
23 April 2015 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pmiiculm·ly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 


Sovaldi® (Sofosbuvir)
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................11
1.
INTRODUCTION ..............................................................................................................................................14
1.1.
Background ............................................................................................................................................14
1.2.
Sofosbuvir (formerly GS-7977) .............................................................................................................14
1.3.
Ribavirin (RBV).....................................................................................................................................14
1.4.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................15
1.5.
Preliminary Results of Study GS-US-334-0154, Cohort 1.....................................................................15
1.5.1.
Pharmacokinetics .................................................................................................................15
1.5.2.
Safety....................................................................................................................................16
1.5.3.
Efficacy ................................................................................................................................16
1.6.
Rationale for the Current Study .............................................................................................................16
1.6.1.
Cohorts 1 and 2 ....................................................................................................................17
1.6.2.
Cohort 3................................................................................................................................17
1.7.
Rationale for SOF Dose Selection .........................................................................................................19
1.8.
Rationale for RBV Dose Selection.........................................................................................................19
1.9.
Rationale for Ledipasvir/Sofosbuvir Fixed Dose Combination (FDC) Dose Selection.........................20
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
4.
SUBJECT POPULATION..................................................................................................................................25
4.1.
Number of Subjects and Subject Selection ............................................................................................25
4.2.
Inclusion Criteria....................................................................................................................................25
4.3.
Exclusion Criteria...................................................................................................................................27
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................29
5.1.
Sofosbuvir (SOF) ...................................................................................................................................29
5.1.1.
Formulation..........................................................................................................................29
5.1.2.
Packaging and Labeling .......................................................................................................29
5.1.3.
Storage and Handling...........................................................................................................29
5.1.4.
Sofosbuvir (SOF) Dosage and Administration.....................................................................30
5.2.
Ribavirin (RBV).....................................................................................................................................30
5.2.1.
Formulation..........................................................................................................................30
5.2.2.
Packaging and Labeling .......................................................................................................30
5.2.3.
Storage and Handling...........................................................................................................30
5.2.4.
RBV Dosage and Administration.........................................................................................30
5.3.
Co-administration of Sofosbuvir (SOF) and Ribavirin (RBV) ..............................................................31
5.4.
Ledipasvir/ Sofosbuvir (LDV/SOF).......................................................................................................31
5.4.1.
Formulation..........................................................................................................................31
5.4.2.
Packaging and Labeling .......................................................................................................31
5.4.3.
Storage and Handling...........................................................................................................31
5.4.4.
LDV/SOF Dosage and Administration ................................................................................32


Sovaldi® (Sofosbuvir)
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Gilead Sciences, Inc.
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5.5.
Study Drug Compliance.........................................................................................................................32
5.6.
Dispensing and Accountability of Study Drugs .....................................................................................32
5.7.
Study Drug Return or Disposal ..............................................................................................................33
5.8.
Concomitant Medications ......................................................................................................................33
5.8.1.
Cohorts 1 and 2 ....................................................................................................................33
5.8.2.
Cohort 3................................................................................................................................34
5.8.3.
All Cohorts...........................................................................................................................35
6.
STUDY PROCEDURES ....................................................................................................................................39
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................39
6.2.
Pretreatment Assessments......................................................................................................................45
6.2.1.
Screening Visit .....................................................................................................................45
6.2.2.
Medical History....................................................................................................................45
6.3.
Day 1 Assessments.................................................................................................................................46
6.3.1.
Dosing Diary ........................................................................................................................46
6.4.
Treatment Assessments..........................................................................................................................46
6.4.1.
Cohorts 1 and 2 ....................................................................................................................46
6.4.2.
Cohort 3................................................................................................................................46
6.5.
Safety Assessments ................................................................................................................................46
6.5.1.
Safety ECGs.........................................................................................................................46
6.5.2.
Safety Echocardiograms.......................................................................................................47
6.5.3.
Physical Examination...........................................................................................................47
6.5.4.
Vital Signs............................................................................................................................47
6.5.5.
BMI ......................................................................................................................................48
6.5.6.
Creatinine Clearance ............................................................................................................48
6.5.7.
Clinical Laboratory Tests/Assessments................................................................................48
6.5.8.
Adverse Events/Concomitant Medications/Protocol Restrictions........................................49
6.6.
Pharmacokinetic (PK) Assessments.......................................................................................................49
6.7.
Early Termination (ET)/Unscheduled Visit ...........................................................................................50
6.8.
Post-Treatment Assessments..................................................................................................................51
6.9.
Optional Samples for Pharmacogenetic Testing ....................................................................................51
6.10.
Archived Plasma Sample .......................................................................................................................52
6.11.
Blood Storage.........................................................................................................................................52
7.
ADVERSE EVENTS MANAGEMENT ............................................................................................................53
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................53
7.1.1.
Adverse Events.....................................................................................................................53
7.1.2.
Serious Adverse Events........................................................................................................53
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................54
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................54
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................54
7.2.2.
Assessment of Severity ........................................................................................................55
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................55
7.4.
Gilead Reporting Requirements.............................................................................................................57
7.5.
Toxicity Management ............................................................................................................................57
7.5.1.
Stopping Rules for Toxicity .................................................................................................57
7.5.2.
Sofosbuvir (SOF) or LDV/SOF............................................................................................57
7.5.3.
Ribavirin (RBV)...................................................................................................................58
7.6.
Special Situations Reports......................................................................................................................58
7.6.1.
Definitions of Special Situations..........................................................................................58
7.6.2.
Instructions for Reporting Special Situations.......................................................................58


Sovaldi® (Sofosbuvir)
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
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8.
STATISTICAL CONSIDERATIONS................................................................................................................60
8.1.
Analysis Objectives and Endpoints........................................................................................................60
8.1.1.
Analysis Objectives..............................................................................................................60
8.1.2.
Primary Endpoint .................................................................................................................60
8.1.3.
Secondary Endpoint .............................................................................................................61
8.1.4.
Other Endpoints of Interest ..................................................................................................61
8.2.
Analysis Conventions.............................................................................................................................61
8.2.1.
Analysis Sets ........................................................................................................................61
8.2.2.
Data Handling Conventions .................................................................................................62
8.2.3.
Interim Analysis ...................................................................................................................63
8.3.
Demographic Data and Baseline Characteristics ...................................................................................63
8.4.
Efficacy Analysis ...................................................................................................................................63
8.4.1.
Primary Analysis..................................................................................................................63
8.4.2.
Secondary Analysis..............................................................................................................63
8.5.
Safety Analysis.......................................................................................................................................64
8.5.1.
Extent of Exposure...............................................................................................................64
8.5.2.
Adverse Events.....................................................................................................................64
8.5.3.
Laboratory Evaluations ........................................................................................................65
8.6.
Pharmacokinetic Analysis......................................................................................................................65
8.7.
Stopping Rules for Individual Groups....................................................................................................65
8.8.
Sample Size............................................................................................................................................66
8.9.
Data Monitoring Committee ..................................................................................................................66
9.
RESPONSIBILITIES..........................................................................................................................................67
9.1.
Investigator Responsibilities ..................................................................................................................67
9.1.1.
Good Clinical Practice..........................................................................................................67
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval...............................................................................................................................67
9.1.3.
Informed Consent.................................................................................................................67
9.1.4.
Confidentiality......................................................................................................................68
9.1.5.
Study Files and Retention of Records ..................................................................................68
9.1.6.
Case Report Forms...............................................................................................................69
9.1.7.
Drug Accountability.............................................................................................................70
9.1.8.
Inspections............................................................................................................................70
9.1.9.
Protocol Compliance............................................................................................................70
9.2.
Sponsor Responsibilities ........................................................................................................................71
9.2.1.
Protocol Modifications.........................................................................................................71
9.2.2.
Study Report and Publications .............................................................................................71
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................71
9.3.1.
Access to Information for Monitoring..................................................................................71
9.3.2.
Access to Information for Auditing or Inspections ..............................................................72
9.3.3.
Study Discontinuation..........................................................................................................72
10.
REFERENCES ...................................................................................................................................................73
11.
APPENDICES ....................................................................................................................................................75
Appendix 1.
Investigator Signature Page....................................................................................................76
Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................77
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............80


Sovaldi® (Sofosbuvir)
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 5
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LIST OF IN-TEXT TABLES
Table 1-1.
Preliminary Comparison of the Effect of Severe Renal Impairment on GS-331007 
and SOF Exposure in HCV-infected and Non-HCV-Infected Subjects .................................16
Table 1-2.
SVR4 Rates in Genotype 4 Subjects from Study GS-US-337-1119 ......................................18
Table 1-3.
Observed and Predicted GS-331007 and SOF Exposure in Subjects with Renal 
Impairment .............................................................................................................................21
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................34
Table 6-1.
Schedule of Assessments for Cohorts 1 and 2........................................................................40
Table 6-2.
Schedule of Assessments for Cohort 3 ...................................................................................43


Sovaldi® (Sofosbuvir)
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 6
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title:
A Phase 2b, Open-Label Study of 200 mg or 400 mg
Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 and 
Ledipasvir/Sofosbuvir (LDV/SOF) Fixed-Dose Combination (FDC) 
Tablet for 12 weeks in Genotype 1 or 4 HCV-Infected Subjects with 
Renal Insufficiency
IND Number:
Eudra CT Number:
106739
2013-002897-30
Study Centers Planned:
Multiple sites in New Zealand, Europe, North America and 
South America
Number of Subjects 
Planned:
Approximately 35 subjects
Target Population:
Adults with chronic renal insufficiency and HCV infection
Treatment Duration:
12 weeks or 24 weeks
Objectives:
The primary objectives of this study are:

To evaluate the safety of sofosbuvir (SOF) 200 mg or 400 mg
+ ribavirin (RBV) for 24 weeks and LDV/SOF for 12 weeks as 
assessed by review of the accumulated safety data in each 
treatment arm

To evaluate the efficacy of sofosbuvir (SOF) 200 mg or 400 mg
+ ribavirin (RBV) for 24 weeks and LDV/SOF for 12 weeks
measured by the proportion of subjects with renal insufficiency 
who have achieved a sustained viral response 12 weeks after 
treatment discontinuation (SVR12) in each treatment arm

To evaluate the steady state pharmacokinetics of SOF and its 
metabolites and LDV upon dosing SOF 200 mg or 400 mg or
LDV/SOF in subjects with renal insufficiency 


Sovaldi® (Sofosbuvir) 
Protocol GS-US-334-0154 
Gilead Sciences, Inc. 
Study Design: 
Diagnosis and Main 
Eligibility Criteria: 
Study Procedures/ 
Frequency: 
CONFIDENTIAL 
The secondruy objectives of this study ru·e: 
Final 
Amendment4 
• 
To evaluate the prop01tion of subjects with renal insufficiency 
who attain SVR at 4 and 24 weeks after discontinuation of 
u·eatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of plasma HCV RNA during and after 
u·eatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV 
during and after u·eahnent discontinuation 
The explorat01y objective of this study is: 
This study will emoll approximately 35 subjects with severe renal 
insufficiency. 
• 
Cohort 1: 10 subjects will receive SOF 200 mg QD + 
RBV 200 mg QD for 24 weeks. 
• 
Cohort 2: Following review of safety, efficacy and PK data 
through post-u·eatment Week 4 ofCoh01t 1, 
10 additional subjects will receive SOF 400 mg QD + 
RBV 200 mg QD for 24 weeks. 
• 
Cohort 3: Following review of safety and available PK data 
through Week 12 of Coh01t 2, 15 additional subjects will receive 
LDV/SOF QD for 12 weeks. 
Adults (~ 18 years) with chronic genotype 1 or genotype 3 
(for Coh01ts 1 and 2) or genotype 1 or 4 (for Coh01t 3) HCV 
infection. Reference Sections 4.2 and 4.3 for detailed Inclusion and 
Exclusion criteria. 
Screening assessments will be completed within 42 days of the 
Day 1 visit. 
Study visits will occur at Screening, Day 1, and at the end of 
Weeks 1, 2, 4, 6, 8, 10, 12 (all cohorts), and Weeks 16, 20 and 24 
(Cohorts 1 and 2 only) and at Post-Treatment Weeks 4, 12, and 24 
(all coh01ts). Screening assessments will include physical 
examination, height, weight, vital signs, 12-lead ECG, 
echocru·diogram, concomitant medications, safety laborat01y tests, 
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Sovaldi® (Sofosbuvir)
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
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HCV RNA, serology (HIV, HCV, HBV), hemoglobin A1c (HbA1c), 
serum β-hCG (females of child bearing potential only), IL28B 
genotyping.
On-treatment assessments will include adverse events (AEs), 
concomitant medications, study medication pill count, physical 
examination, vital signs, 12-lead ECGs, echocardiogram, safety 
laboratory tests, HCV RNA, pharmacokinetic samples, and serum 
pregnancy tests (females of child bearing potential only). 
Post-treatment assessments will include AEs, concomitant 
medications, vital signs, safety laboratory tests, HCV RNA, and 
serum pregnancy tests (females of child bearing potential only).
Samples for viral RNA sequencing will be collected at Day 1 and 
every visit thereafter. Samples will be collected during treatment 
visits for PK analysis of study drug(s).
PK assessments
Intensive PK Assessments
Cohorts 1 and 2:
Serial blood samples will be collected on week 2 and 12 at the 
following timepoints:

0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours 
post-dose.
Cohort 3:
Serial blood samples will be collected once either on week 2 or 4 
(per investigator discretion) at the following timepoints:

0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours 
post-dose.
Plasma concentrations of SOF and its metabolites and LDV will be 
determined and PK parameters will be estimated as appropriate. 
Plasma concentrations of RBV may be determined, if necessary.
Trough PK Assessments:
Trough PK plasma samples for analyses of SOF, its metabolites,
RBV (as applicable) and LDV concentrations will be collected at all 
other on treatment visits beginning at the Week 1 visit.
PK Parameters for SOF, its metabolites, LDV and RBV will be 
estimated as appropriate. 


Sovaldi® (Sofosbuvir) 
Protocol GS-US-334-0154 
Gilead Sciences, Inc. 
Test Product, Dose, and 
Mode of Administration: 
Optional Genetic Sample Collection 
PPD 
Archived Plasma Sample 
Final 
Amendment4 
Archive plasma samples are being collected for possible additional 
analyses, including but not limited to, study dmg or metabolite 
measmements, viral load, safety/efficacy assessments, HCV gene 
sequencing, HCV resistance testing and other possible predictors of 
response as detennined by Gilead. 
Sofosbuvir is manufactmed as 100 mg and 400 mg tablets for oral 
adminisu·ation. Subjects emolled to take the 200 mg dose will take 
2 x 100 mg tablets for a total dose of 200 mg orally QD in the 
moming with RBV and with food. Subjects emolled to take the 
400 mg dose will take 1 x 400 mg tablet for a total dose of 400 mg 
orally QD in the moming with RBV and with food. 
RBV will be supplied as a 200 mg tablet for oral adminisu·ation by 
Gilead Sciences. Subjects will take 1 x 200 mg tablet in the moming 
with SOF and with food. 
LDV/SOF is manufactmed as a fixed-dose combination tablet, 
consisting of90 mg LDV and 400 mg SOF, for oral adminisu·ation. 
All subjects will take 1 tablet daily with or without food. 
Reference Therapy: 
None 
Criteria for Evaluation: 
Safety: 
Efficacy: 
CONFIDENTIAL 
AEs, SAEs, and safety labs will be collected throughout the study. 
Safety will be evaluated by assessment of clinicallaborat01y tests, 
ECG, echocardiogram, periodic physical examinations including 
vital signs at various time points dming the study, and by the 
documentation of adverse events. 
Efficacy will be evaluated usini scheduled assessments of HCV 
RNA perf01m ed using COBAS AmpliPrep/COBAS® TaqMan® 
HCV Test. 
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Protocol GS-US-334-0154
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PK:
Plasma PK parameters will be calculated for sofosbuvir and its 
metabolites GS-566500 and GS-331007, LDV and RBV, as 
applicable. Examples are AUClast, AUCtau, Cmax, Clast, Ctau, and t1/2.
Statistical Methods:
Safety data will be listed by subject and summarized by treatment 
cohort using frequency of event/abnormality or descriptive statistics 
(e.g., sample size, arithmetic mean, geometric mean, % coefficient 
of variation [CV], standard deviation [SD], minimum, Q1, median, 
Q3, and maximum).
The steady state PK plasma concentrations and parameters will be 
listed by subject and summarized by treatment cohort using 
descriptive statistics for each analyte (SOF, GS-566500, GS-331007, 
RBV and LDV, as appropriate). 
In the efficacy analysis, no statistical hypothesis testing will be 
performed and no formal inferences will be made on the primary 
efficacy endpoint SVR12. A point-estimate with two-sided 95% 
exact confidence interval (CI) using the binomial distribution 
(Clopper-Pearson method) will be constructed for the SVR12 rate by 
treatment cohort. Similar analysis will be also performed for 
secondary endpoints SVR4 and SVR24.
To evaluate the kinetics of circulating HCV RNA during and after 
treatment discontinuation, viral load data will be listed by subject 
and summarized by treatment cohort and visit using descriptive 
statistics.
Due to the exploratory nature of this study, no formal power or 
sample size calculations were performed to determine treatment 
group size. The total sample size of 35 is largely based on 
feasibility.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


Sovaldi® (Sofosbuvir)
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
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23 April 2015
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
β-hCG
β-human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase  (also SGOT)
AUC
area under the curve
AUCtau
area under the plasma concentration versus time curve over the dosing interval 
(tau)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BW
body weight
CLcr
Creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Ctau
observed drug concentration at the end of the dosing interval (tau)
CRF
case report form(s)
CRO
Contract (or clinical) research organization 
DAA
direct-acting antiviral
dL
Deciliter
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
ESAs
Erythropoiesis stimulating agents
ESRD
End Stage Renal Disease
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
Hb
Hemoglobin
HbA1c
Hemoglobin A1c


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Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 12
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDPE
high-density polyethylene
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
High-Level Term
IBW
Ideal Body Weight
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL28B
IL28B gene
IND
Investigational New Drug (Application)
IRB
institutional review board
IUD
intrauterine device
IV
Intravenous
kg
Kilogram
L
Liter
LDH
Lactase dehydrogenase
LDV
Ledipasvir
LLN
lower limit of the normal range
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MH
Mantel-Haenszel
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PBMC
peripheral blood mononuclear cell(s)
PEG
Pegylated interferon
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
po
Per os (by mouth)
QD
once daily (use only in tables)
QTcF
QT interval corrected using Fridericia’s formula
RBC
Red blood cell count 


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Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
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23 April 2015
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
RBV
Ribavirin
RNA
ribonucleic acid
RVR
rapid virologic response 
SADR
Serious adverse drug reaction
SAE
serious adverse event
SD
Standard deviation
SOC
Standard of Care
SOF
Sofosbuvir
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TND
Target not detected
TSH
Thyroid stimulating hormone
t½
An estimate of the terinal elimination half-life of the drug in 
serum/plasma/PBMC, calculated by dividing the natural log of 2 by the terminal 
elimination rate contstant (λz)
ULN
upper limit of the normal range
US
United States
WBC
white blood cell count


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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) is responsible for a large proportion of chronic liver disease worldwide 
and accounts for 70% of cases of chronic hepatitis in industrialized countries. The global 
prevalence of chronic hepatitis C is estimated to average 3% {23338}. The most common 
genotype worldwide is genotype 1 followed by genotypes 2 and 3 {23338}. Although there is 
evidence that the incidence of viral infection may be decreasing, the prevalence of liver disease 
caused by HCV is on the rise, primarily due to the lag between the onset of infection and the 
clinical manifestation of liver disease {23338}. The prevalence of chronic HCV is significantly 
higher among patients with chronic renal failure, and HCV itself is associated with impaired 
renal function. Treatment of these individuals is therefore recommended but is often complicated 
by the substantial increase in hematologic toxicities associated with the use of ribavirin in the 
setting of low creatinine clearance {23275}.
1.2.
Sofosbuvir (formerly GS-7977)
Sovaldi® (sofosbuvir) is a potent nucleotide analogue that inhibits HCV RNA replication in vitro 
and has demonstrated high rates of sustained viral response (SVR) when administered with RBV, 
with or without pegylated interferon, to subjects with chronic genotype 1-6 HCV infection 
{34475}, {23275}, {24713}, {24715}, {27832}. Sovaldi® has been approved in the United States
(GT1-4) and in the European Union (GT1-6) for the treatment of chronic HCV infection 
including treatment naïve and experienced patients and HIV/HCV co-infected patients.
For further information on the clinical pharmacology, virology, safety and efficacy of sofosbuvir 
(SOF), please refer to the current version of the Investigator’s Brochure and US and EU 
prescribing information.
1.3.
Ribavirin (RBV)
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of RNA 
and DNA viruses {15572}, {15668}. Ribavirin monotherapy has little or no effect on the 
replication of HCV but can result in short term normalization of serum ALT activity. When 
combined with interferon or PEG therapy, RBV decreases substantially the relapse rate seen after 
cessation of interferon therapy {12557}, {12558}.
Ribavirin is a known teratogen (FDA category X). Furthermore, RBV is known to accumulate 
intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, extreme care 
must be taken to avoid pregnancy during RBV therapy and for up to 6 months following 
completion of treatment. A comprehensive review of RBV is contained in the package 
insert/SmPC.


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1.4.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
Harvoni® (ledipasvir/sofosbuvir fixed-dose combination (LDV/SOF) combines 
two HCV specific-direct acting antivirus (DAA) agents into a single tablet for the treatment of 
chronic HCV infection. Sofosbuvir is a nucleotide analog that is a potent and selective inhibitor 
of NS5B-directed HCV replication, irrespective of HCV genotype. Ledipasvir is a novel HCV 
NS5A inhibitor that has demonstrated potent anti-HCV activity against genotypes 1 and 4 HCV 
infection. Harvoni® has been approved in the United States and Europe for the treatment of 
chronic HCV infection including treatment naïve and experienced patients with genotype 1. 
For further information on the clinical pharmacology, virology, safety and efficacy of LDV/SOF, 
please refer to the current version of the Investigator’s Brochure and US prescribing information.
1.5.
Preliminary Results of Study GS-US-334-0154, Cohort 1
Preliminary results are available and presented below for Cohort 1: 10 subjects with estimated 
glomerular filtration rate (eGFR by Cockcroft-Gault) less than 30 mL/min within six months of 
screening, not on dialysis, treated with SOF 200 mg + RBV 200 mg daily for 24 Weeks. A 
review of the integrated safety, PK and efficacy from this first cohort demonstrate that 
SOF 200 mg + RBV 200 mg daily for 24 weeks is safe and relatively well tolerated.
1.5.1.
Pharmacokinetics
Preliminary pharmacokinetic data are available for subjects in Cohort 1 who received 
200 mg SOF + 200 mg RBV for 24 weeks. Exposure (from intensive PK sampling) of SOF and 
its predominant circulating renally eliminated metabolite (GS-331007) were similar at 
Week 2 and Week 12; as such further PK analyses are conducted with the Week 12 data 
(Table 1-1). 
As expected, in the Cohort 1 HCV-infected subjects, severe renal impairment increases 
GS-331007 and SOF exposures. In general, when normalized to subjects with normal renal 
function, the results are comparable to that observed in the non HCV-infected renal impairment 
study (P7977-0915, %GMR in Table 1-1). The only exception was the increase in GS-331007 
Cmax seen in severe renal impaired HCV-infected subjects as opposed to the non-infected subjects 
(%GMR HCV-infected vs. non-infected: 589% vs. 134%). This difference in GS-331007 Cmax is 
likely a result of expected accumulation of GS-331007 upon steady state dosing in the 
Study GS-US-334-0154 as compared to single dose administration in the P7977-0915 study.


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Table 1-1.
Preliminary Comparison of the Effect of Severe Renal Impairment 
on GS-331007 and SOF Exposure in HCV-infected and 
Non-HCV-Infected Subjects
Mean (%CV) PK Parameter
GS-331007
SOF
AUCinf or tau 
(ng•hr/ml)
Cmax
(ng/ml)
AUCinf or tau 
(ng•hr/ml)
Cmax
(ng/ml)
HCV-Infected Subjects
GS-US-334-0154 SOF 200 mg cohort
Week 12 (n = 10)
31,100 (53.9)
1730 (44.9)
1280 (50.3)a
904 (66.2)
Phase 2/3 Population Dose normalized to SOF 200 mg
(SOF n = 838, GS-331007 n = 1695)
3561 (30.7)
291 (36.3)
513 (36.5)
256 (32.5)
%GMR (90% CI)
817
(694, 963)
589
(481, 721)
233
(193, 282)
321
(261, 395)
Non HCV-Infected Subjects (P7977-0915)
%GMR (90% CI)
(Severe Impairment/Normal Function)
551
(313, 968)
134
(98.6, 183)
271
(183, 402)
177
(96.6, 324)
Note: PK parameters are presented as mean (%CV) to three significant digits.
a
n = 9
Source: Ad Hoc Table 6822.2, P7977-0915 Table 11.13
1.5.2.
Safety
Sofosbuvir was generally well-tolerated and safe when administered with RBV in Cohort 1. 
Most adverse events (AEs) were mild to moderate in severity. There were two serious AEs 
(SAEs) of unstable angina and hyperglycaemic hyperosmolar nonketotic syndrome which were 
assessed by the investigators as not related to the study drugs. Neither event led to change in 
study drug administration. The most frequently reported AEs were anemia, headache, pruritus, 
and rash. Renal function and cardiac function were stable during treatment as assessed by eGFR,
safety ECG and echocardiograms, respectively.
1.5.3.
Efficacy
All subjects experienced rapid on-treatment virologic decline similar to those with normal renal 
function and full-dose SOF+RBV. There were no subjects with virologic breakthrough. 
One subject withdrew consent and stopped treatment at Week 12; he did not return for 
post-treatment visits. One subject prematurely discontinued treatment at Week 21. Overall, 
4 of the 10 (40%) subjects achieved SVR4.
1.6.
Rationale for the Current Study
This study will evaluate the safety, efficacy and pharmacokinetics of treatment with SOF+RBV 
for 24 weeks (for genotype 1 or 3) and of treatment with LDV/SOF for 12 weeks (for genotype 1 
or 4) in subjects with chronic HCV infection and severe renal impairment.


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Interferon monotherapy, however, is associated with poor tolerability, a 48 week treatment 
duration, and efficacy of approximately 40%. Furthermore, once patients have failed this course 
of treatment, they have no further treatment options and are at risk for progression of liver 
disease, cirrhosis, and hepatocellular carcinoma.
1.6.1.
Cohorts 1 and 2
To date, SOF+RBV has demonstrated safety and efficacy in a broad range of subjects with 
chronic HCV infection in Phase 2 and Phase 3 clinical trials. However, subjects with 
Cr clearance <60 mL/min have been excluded from these studies due to the recommendation 
that RBV not be administered to patients with Cr clearance <50 mL/min. In addition,
study P7977-0915 has shown the major circulating metabolite of SOF, GS-331007, is renally 
cleared and a single dose study conducted in subjects with severe renal impairment or end-stage 
renal disease on hemodialysis demonstrated exposures approximately 1.6-fold and 14 to 22-fold 
higher, respectively, than those observed in matched controls with normal renal function. Whilst 
dose reduction of SOF would reduce these exposures, viral efficacy is dependent on SOF 
exposures such that lower SOF doses or intermittent administration could be associated with 
reduced efficacy. Thus, this exploratory study of safety and efficacy of standard (400 mg) and 
reduced (200 mg) doses of SOF in combination with low-dose RBV in a small number of 
subjects will provide important data regarding dosing recommendations for use of SOF in this 
patient population with a high unmet medical need.
Phase 3 studies of SOF+RBV for 12 or 16 weeks in treatment-naïve and treatment-experienced 
genotype 3 HCV-infected subjects demonstrated SVR12 rates of 56% and 62%, respectively. 
Increasing treatment duration to 24 weeks may further improve response rates. In Phase 2 studies 
of SOF+RBV for 12 or 24 weeks in treatment-naïve genotype 1 HCV-infected subjects, SVR 
rates have varied from 47% to 84% depending on the study and patient population. In both 
genotypes 1 and 3, lower doses of RBV have been associated with reduced efficacy of the 
regimen. Given the safety need for a reduced RBV dose in the current study (Section 1.8), 
treatment with SOF+RBV will be administered for 24 weeks to maximize efficacy. Subjects with 
genotypes 1 or 3 HCV infection have been selected for this study since they represent the largest 
group of HCV-infected individuals in the regions where this study will be conducted and because 
the 24 week treatment regimen is appropriate. In contrast, genotype 2 HCV-infected subjects 
have been shown to have high response rates following 12 weeks of SOF+RBV therapy. If 
SOF+RBV is well tolerated for 24 weeks in patients with severe renal insufficiency, safety for 
12 weeks in this smaller HCV population may be inferred.
1.6.2.
Cohort 3
To date in subjects with a CLcr > 60 mL/min, LDV/SOF without RBV has an excellent safety 
profile, with efficacy > 93% in all patient populations {34474}. Cohort 3, in which LDV/SOF for 
12 weeks will be the treatment regimen, will generate clinical data in a patient population with a 
regimen which is the Standard of Care (SOC) for genotype 1. 


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Phase 3 trials with LDV/SOF demonstrated the addition of RBV to LDV/SOF for the treatment 
of HCV in genotype 1 subjects did not increase efficacy. As such, Cohort 3 will not include RBV 
which is of particular benefit for this patient population in which chronic anemia is common; the 
preliminary data from Cohort 1 with SOF 200mg + RBV indicate that anemia was the most 
frequent AE and led to increased epoetin use.
In Cohort 3, the safety, efficacy and pharmacokinetics of LDV/SOF 90/400 mg will be evaluated 
in subjects with severe renal impairment. Data from GS-US-344-0108 demonstrated that severe 
renal impairment had no effect on LDV exposure. As described above for Cohorts 1 and 2, 
impaired renal function significantly increases GS-331007 exposure. As such, progression of 
GS-331007 exposure across cohorts was a major consideration in determining the appropriate 
design for this study (see Section 1.9). 
Because over 70% of HCV-infected individuals in the US and Europe have genotype 1, they 
represent the greatest unmet medical need, and therefore will be the priority for generating data 
in renal impairment across cohorts of this study. For Cohort 3, both preclinical and clinical data 
support the inclusion of genotype 4 HCV-infected subjects. Activity of LDV was evaluated in a 
subgenomic genotype 4d HCV replicon. In the replicon system, the EC50 value of LDV against 
genotype 4d HCV was 0.60 nM and 0.39 nM for genotype 4a HCV (compared with EC50 values 
of LDV against genotype 1a and genotype 1b of 0.031 nM and 0.004 nM, respectively).
In the Phase 3 Study GS-US-337-0102 (ION-1), 2 subjects with genotype 4d HCV infection 
were inadvertently randomized in violation of the protocol inclusion/exclusion criteria. Both 
subjects achieved SVR12. Subject 
 was treated for 12 weeks with LDV/SOF and 
Subject
 was treated for 24 weeks with LDV/SOF+RBV.
In Study GS-US-337-1119, a European study investigating the efficacy and safety of LDV/SOF 
in treatment-naive and treatment-experienced subjects with chronic genotype 4 or genotype 
5 HCV infection, a total of 44 subjects with genotype 4 HCV infection, of whom 10 (23%) have 
cirrhosis and 22 (50%) are treatment experienced, have been enrolled to receive LDV/SOF for 
12 weeks. SVR4 data are available from Study GS-US-337-1119 in 25 subjects with genotype 4 
and18 subjects with genotype 5 HCV infection. 
Table 1-2.
SVR4 Rates in Genotype 4 Subjects from Study GS-US-337-1119
Genotype 4
Overall
96% (24/25)
Treatment Naive
100% (12/12)
Treatment Experienced
92% (12/13)
Cirrhosis
100% (7/7)
No Cirrhosis
94% (17/18)
PPD
PPD


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In addition, preliminary data are available from Group E of the NIAID/NIH collaborative 
Study CO-US-337-0117. In this group, 21 subjects with genotype 4 HCV infection, of whom 
13 are treatment naive and 8 are treatment experienced, are receiving 12 weeks of LDV/SOF 
treatment. In total, 6 subjects have cirrhosis. Post-treatment week 12 data is available for 
20 subjects, 19 of 20 subjects have achieved SVR12.
Study GS-US-337-0115 (ION-4) is investigating the efficacy and safety of LDV/SOF in 
genotype 1 and genotype 4 HCV-infected subjects coinfected with HIV. A total of 8 subjects 
with genotype 4 HCV infection have been enrolled. All 8 subjects have achieved SVR4. 
1.7.
Rationale for SOF Dose Selection
Sofosbuvir 400 mg, once daily, when dosed in combination with RBV with or without PEG has 
demonstrated broad genotypic efficacy and a favorable safety profile in over 3300 HCV-infected 
subjects across multiple patient populations in Phase 2 and 3 trials. This dose (400 mg) is the 
proposed to be marketed dose of sofosbuvir for the treatment of HCV-infection.
In study P7977-0915, a single dose PK study in subjects with varying degrees of renal 
impairment, exposure (AUCinf) of sofosbuvir and the renally eliminated metabolite, GS-331007, 
were 2.7- and 5.5-fold higher respectively in subjects with severe renal impairment compared to 
matched controls with normal renal function.  A significant dose reduction (eg, 2- to 4-fold) of 
sofosbuvir would be necessary to provide comparable GS-331007 exposures in subjects with 
severe renal impairment and those with normal renal function. Data from dose-finding and 
Phase 2 studies demonstrated that sofosbuvir, dosed once daily, was necessary to provide the 
active anabolite at the site of action (circulating GS-331007 cannot be phosphorylated to the 
active anabolite); therefore, dose interval modifications may not be appropriate. The efficacy of a 
substantially reduced dose of sofosbuvir in subjects with severe renal impairment has not been 
established.  
Cohorts 1 and 2 of this study will evaluate the safety, efficacy and pharmacokinetics of 2 doses 
of sofosbuvir (200 and 400 mg) in subjects with severe renal impairment. The reduced dose of 
200 mg sofosbuvir provided comparable systemic exposures of sofosbuvir, and approximately 
4-fold higher GS-331007 exposure compared to HCV-infected in subjects with normal renal 
function at the 400 mg dose. As such, GS-331007 and SOF exposures in Cohort 2 (400 mg SOF) 
are expected to increase 2-fold over that observed in Cohort 1. Review of safety, efficacy and 
pharmacokinetic data from Cohort 2 through 12 weeks of treatment will inform the initiation of 
Cohort 3 (90/400 mg LDV/SOF in subjects with severe renal impairment).
1.8.
Rationale for RBV Dose Selection
Ribavirin increases treatment response rates when administered with interferon or PEG. In 
addition, reducing the RBV dose from 1000-1200 mg/day to 600 or 800 mg/day when given in 
combination with SOF reduced SVR rates, as did SOF monotherapy. It is therefore desirable to 
keep RBV as part of the SOF treatment regimen. Since RBV is cleared renally and its main 
toxicity is hemolytic anemia which is poorly tolerated in patients with advanced renal 
insufficiency who are usually anemic at baseline and have little bone marrow reserve, the 


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starting dose of RBV must be substantially lower than 1000-1200 mg/day. For this study, a dose 
of 200 mg/day has been selected based on investigator input in light of the high frequency of 
hemotoxicity of RBV and the general desire to optimize the efficacy of the treatment regimen
{24149}.
To date there has been no safety signal identified that is attributable to SOF when administered 
as part of a combination regimen. Furthermore, SOF does not exacerbate the toxicities associated 
with RBV, most notably hemolytic anemia. Clinical data with SOF in severe renal insufficiency 
and in subjects requiring hemodialysis is limited to a single dose study in non-HCV infected 
subjects. No specific safety signals were identified. The current study is designed to assess the 
safety and efficacy of therapeutic treatment with SOF+RBV in a small number of subjects with 
severe renal insufficiency. 
The potential benefit of successful treatment of HCV in these subjects is substantial. Few 
patients with severe renal insufficiency can tolerate combination therapy with PEG+RBV due to 
profound anemia. SVR rates to interferon monotherapy administered for 48 weeks are less than 
50%. Interferon-free treatment for 24 weeks could provide substantial improvements in safety, 
tolerability and efficacy for individuals with chronic HCV infection.
1.9.
Rationale for Ledipasvir/Sofosbuvir Fixed Dose Combination (FDC) Dose 
Selection
A fixed-dose combination tablet (FDC) of ledipasvir/sofosbuvir 90/400 mg with or without RBV 
has demonstrated favorable safety and efficacy profiles in over 3000 HCV-infected subjects 
across different patient populations in Phase 2 and 3 trials. This FDC represent the marketed 
doses of ledipasvir and sofosbuvir (Harvoni®, LDV/SOF) approved in the US and Europe for the
treatment of chronic HCV infection including treatment naïve and experienced patients with 
GT1.
In support of dosing LDV/SOF to HCV-infected subjects with severe renal impairment, available 
pharmacokinetic data has been evaluated to project mean exposures of GS-331007 and SOF that 
may be achieved in these subjects (Table 1-3). Overall, increased GS-331007 exposures are 
expected in the context of LDV/SOF as compared to SOF administered as single agent 
(SOF USPI and LDV/SOF NDA, Module 2.7.2). Minimal safety data is available at these high 
exposures, irrespective of SOF being administered with LDV or as a single agent. The study 
design allows for consistent progression (~2-3 fold increase) of GS-331007 exposure across
cohorts enabling assessment of exposure vs. safety relationships while potentially providing 
greater efficacy with the two-drug combination. 


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Table 1-3.
Observed and Predicted GS-331007 and SOF Exposure in Subjects 
with Renal Impairment
Mean (%CV, if applicable)
PK Parameter
GS-331007
SOF
AUCtau 
(ng•hr/ml)
Cmax 
(ng/ml)
AUCtau 
(ng•hr/ml)
Cmax
(ng/ml)
Observed Data
GS-US-334-0154 Cohort 1 SOF 200 mg
Week 12 (n = 10)
31,100
(53.9)
1730
(44.9)
1280
(50.3)
904
(66.2)
Predicted Data
Cohort 3:
LDV/SOF 90/400 mg in Severe RIa
111,000
4400
3430
2330
Pharmacokinetic parameters are shown to 3 significant digits
a
Predicted as the LDV/SOF Phase 2/3 population multiplied times the ratio of predicted SOF 400 mg in severe RI to 
SOF Phase 2/3 population.


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2. 
OBJECTIVES 
The prima1y objectives of this study are: 
Final 
Amendment4 
• 
To evaluate the safety of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks and LDV/SOF for 12 weeks as assessed by review of the accumulated safety data 
in each treatment rum 
• 
To evaluate the efficacy of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks and LDV/SOF for 12 weeks measured by the prop01iion of subjects with renal 
insufficiency who have achieved a sustained viral response 12 weeks after treatment 
discontinuation (SVR12) in each treatment ann 
• 
To evaluate the steady state phrum acokinetics ofSOF and its metabolites and LDV upon 
dosing SOF 200 mg or 400 mg or LDV/SOF in subjects with renal insufficiency 
The secondruy objectives of this study ru·e: 
• 
To evaluate the prop01iion of subjects with renal insufficiency who attain SVR at 
4 and 24 weeks after discontinuation of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of plasma HCV RNA during and after treatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV during and after treatment 
discontinuation 
The explorat01y objective of this study is: 
PPO 
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3.
STUDY DESIGN
This is a multicenter, open label study that will evaluate the safety, tolerability and antiviral 
efficacy of SOF with RBV or LDV/ SOF in chronic renal insufficiency and HCV infection
subjects with genotype 1, 3 or genotype 4 HCV infection, including those with compensated 
cirrhosis.
This study will have 3 cohorts.
Approximately 35 subjects with severe renal insufficiency will be enrolled. 

Cohort 1: 10 subjects will receive SOF 200 mg QD + RBV 200 mg QD for 24 weeks.

Cohort 2: Following review of safety, efficacy and PK data through post-treatment Week 4 
of Cohort 1, 10 additional subjects will receive SOF 400 mg QD + RBV 200 mg QD for 
24 weeks.

Cohort 3: Following review of safety and available PK data through Week 12 of Cohort 2, 
15 additional subjects will receive LDV/SOF QD for 12 weeks.
3.1.
Treatment Plan and Regimen
Following screening procedures and Day 1 assessments, eligible subjects will receive 
one of the following treatments:
Cohort 1: SOF 200 mg QD + RBV 200 mg QD for 24 weeks
Cohort 2: SOF 400 mg QD + RBV 200 mg QD for 24 weeks
Cohort 3: LDV/SOF QD for 12 weeks
Additional information about study drug administration can be found in Section 5.
3.2.
Visit Schedule
All subjects will complete screening, on-treatment and post-treatment assessments. Screening 
assessments will be completed within 42 days of the Day 1 visit. All subjects will complete the 
Week 4 Post-Treatment visit. Weeks 12 and 24 Post-Treatment visits will be dependent on 
subject viral load.
The assessments performed at each visit are described in Section 6.


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3.3.
Virologic Response-Based Stopping Criteria
The following stopping criteria will be used for subjects on treatment:

Confirmed HCV RNA ≥LLOQ after 2 consecutive HCV RNA <LLOQ

Confirmed >1 log10 increase from nadir 

Confirmed HCV RNA ≥LLOQ after 8 weeks of treatment
Confirmation should be performed as soon as possible but within 2 weeks after determination of 
initial observation.
Cardiac Function-Based Stopping Criterion
The following stopping criterion will be used for subjects on treatment:

Left ventricular ejection fraction ≤40%
3.4.
Treatment Discontinuation Criteria
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication must be discontinued in the following instances:

Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest.

Pregnancy of female subject, or female partner of male subject.

Efficacy failure as defined in Section 3.3.

Declining cardiac function, defined as left ventricular ejection fraction ≤40%.

Significant protocol violation including non-compliance with study assessments. 

Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy or other reason.

Discontinuation of the study at the request of Gilead, regulatory agency or an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
Subjects who discontinue treatment earlier than the assigned 12 or 24-week treatment duration 
will complete an Early Termination Visit (Section 6.7).


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 35 subjects will be treated in this study.
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) Chronic HCV infection documented by either:
a) a positive anti-HCV antibody test or positive HCV RNA or positive HCV genotyping test 
at least 6 months prior to the Day 1 visit, or
b) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV infection
4) Infection with HCV GT 1, 3 or 4 as determined at Screening, as applicable to cohort
5) Subjects must have the following laboratory parameters at Screening: 
a) HCV RNA ≥104 IU/mL
b) ALT ≤10 the upper limit of normal (ULN)
c) AST ≤10 ULN
d) Hemoglobin ≥9 g/dL 
e) Albumin ≥3.0 g/dL
f)
Direct bilirubin ≤1.5 ULN
g) HbA1c ≤10%


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h) Creatinine clearance (CLcr) 30 mL/min, as calculated by the Cockcroft-Gault equation 
{2202} using ideal body weight (IBW).
Male:
CLcr (mL/min) = [140 −age (years)] IBW (kg)
72 Scr
Female:
CLcr (mL/min) = [140 −age (years)] IBW(kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
Ideal body weight (IBW) is estimated by the following equations: 
Males:
IBW (kg) = 50 kg + 2.3 kg for each inch over 5 feet
Females:
IBW (kg) = 45.5 kg + 2.3 kg for each inch over 5 feet
a.
Subjects with CLcr 30-40 mL/min are eligible if they have a prior CLcr ≤30 mL/min
within 6 months of Screening
6) INR ≤1.5 ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR.
7) A negative serum pregnancy test for female subjects of childbearing potential 
(see Appendix 2 for definition). 
8) Male subjects and female subjects of childbearing potential (see Appendix 2 for definition) 
must agree to use protocol specified method(s) of contraception as described in Appendix 2.
9) Lactating females must agree to discontinue nursing before administration of study drug.
10) Subject must be of generally good health as determined by the Investigator. 
11) Subject must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments.
12) Cirrhosis Determination (For all cohorts)

Cirrhosis is defined as any one of the following:
Liver biopsy showing cirrhosis
Fibroscan (in countries where locally approved) showing cirrhosis or results 
> 12.5 kPa
FibroTest® score of > 0.75 AND an AST: platelet (APRI) ratio of > 2 during 
Screening


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
Absence of cirrhosis is defined as any one of the following:
Liver biopsy within 2 years of Screening showing absence of cirrhosis
Fibroscan (in countries where locally approved) with a result of ≤12.5 kPa within 
≤6 months of Day 1
FibroTest® score of ≤ 0.48 AND APRI of ≤1 during Screening
In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria, 
a liver biopsy is required.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) BMI < 18
2) Prior exposure to an direct-acting antiviral targeting HCV NS5B (all cohorts) or HCV NS5A 
(Cohort 3 only)
3) Prior null response to PEG+RBV therapy (Cohorts 1 and 2) or for patients with cirrhosis, 
prior treatment failure with IFN-based therapy not resulting from treatment intolerance
(Cohort 3)
4) Male with pregnant female partner (Cohorts 1 and 2 only)
5) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency, cholangitis)
6) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)
7) Unstable psychiatric condition 
8) Significant cardiac disease including or resulting in:
a) Cardiomyopathy
b) Left ventricular ejection fraction ≤50%
c) Hospital admission for myocardial infarction, heart failure within 1 year of Screening 
d) Pulmonary hypertension within 1 year of Screening
9) Clinically significant abnormality on ECG at Screening, including a QTcF > 500 msec, or 
> 450 msec in patients who concomitantly use methadone.


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10) History of clinically significant hemoglobinopathy (Cohorts 1 and 2 only)
11) History of porphyria (Cohorts 1 and 2 only)
12) Malignancy within the 5 years prior to screening, with the exception of specific cancers that 
are cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation for 
possible malignancy are not eligible.
13) Chronic use of systemically administered immunosuppressive agents 
(e.g., prednisone equivalent > 10 mg/day)
14) Clinically-relevant drug or alcohol abuse within 12 months of Screening
15) Current or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, 
encephalopathy or variceal hemorrhage)
16) History of clinically-significant illness or any other major medical disorder that may interfere 
with subject treatment, assessment or compliance with the protocol
17) History of a primary gastrointestinal disorder (or post operative condition) that could 
interfere with the absorption of the study drug 
18) Excessive alcohol ingestion, defined as > 3 glasses/day (1 glass is equivalent to: 
beer [284 mL], wine [125 mL], or distilled spirits [25 mL]) for females and > 4 glasses/day 
for males)
19) Inability to collect blood for safety, PK, and efficacy throughout the study
20) Donation or loss of more than 400 mL blood within 2 months prior to Day 1 
21) Use of any prohibited concomitant medications as described in Section 5.8 within 21 days of 
the Day 1 visit
22) Known hypersensitivity to RBV (Cohorts 1 and 2 only), the study investigational medicinal 
product, the metabolites, or formulation excipients
23) Receipt of any investigational product within a time period equal to 10 half-lives of the 
product, if known, or a minimum of 4 weeks prior to study drug administration
24) Subjects with hepatocellular carcinoma (HCC) are excluded from the study. In cirrhotic 
patients, liver imaging (e.g., ultrasound) within 6 months of Day 1 is required to exclude 
hepatocellular carcinoma (HCC)


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Sofosbuvir (SOF)
5.1.1.
Formulation
SOF tablets, 100 mg, are yellow, round, film-coated, plain-faced tablets. 
SOF tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets debossed with “GSI” on 
one side and “7977” on the other side. 
In addition to the active ingredient, SOF tablets contain the following inactive ingredients: 
mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, and yellow iron oxide.
5.1.2.
Packaging and Labeling
SOF tablets, 100 mg, are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 28 tablets and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child-resistant screw cap with an induction-sealed, aluminum-faced liner.
SOF tablets, 400 mg, are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains either 28 or 30 tablets and a silica gel desiccant canister or sachet and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child-resistant screw 
cap with an induction-sealed, aluminum-faced liner.
SOF bottles to be distributed to centers in the US and other countries shall be labeled to meet all 
applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 of 
Good Manufacturing Practices: Manufacture of investigational medicinal products 
(February 2010) and/or other local regulations as applicable.
5.1.3.
Storage and Handling
SOF bottles should be stored at a 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.
Sufficient quantities of SOF 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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5.1.4.
Sofosbuvir (SOF) Dosage and Administration
SOF will be administered as 200 mg or 400 mg po daily. SOF (100 mg or 400 mg) tablets will be 
supplied by Gilead Sciences for all subjects.
5.2.
Ribavirin (RBV)
5.2.1.
Formulation
RBV tablets, 200 mg, are blue, capsule-shaped, film-coated tablets debossed with “3RP” on one 
side and “200” on the other side. In addition to the active ingredient, RBV tablets contain the 
following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose 
sodium, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc,
FD&C blue #2.
5.2.2.
Packaging and Labeling
The RBV tablets are packaged in white, HDPE bottles. Each bottle contains 168 tablets and 
rayon coil packing material and is enclosed with a white, continuous thread, child-resistant screw 
cap with an induction-sealed, aluminum-faced liner.
RBV bottles to be distributed to centers in the US and other countries shall be labeled to meet all 
applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 of Good 
Manufacturing Practices: Manufacture of investigational medicinal products (February 2013) 
and/or other local regulations as applicable.
5.2.3.
Storage and Handling
RBV tablets should be stored at 25 C (77 F); excursions are permitted between 15 and 30 C 
(59 and 86 F).
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling RBV.
5.2.4.
RBV Dosage and Administration
RBV will be administered as 200 mg po daily. RBV should be dosed with food and with SOF to 
maximize adherence. RBV dose may be managed at the discretion of the Investigator in 
communication with the Medical Monitor.
RBV tablets (200 mg) will be supplied by Gilead Sciences for all subjects.


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5.3.
Co-administration of Sofosbuvir (SOF) and Ribavirin (RBV)
Each subject will be given instructions to maintain approximately the same daily dosing interval 
between study drug doses.  
If a subject forgets to take the medication at the correct time, it may be taken later in the day; 
however, no more than 400 mg dose of SOF should be taken on any calendar day. The subject 
should resume the standing dosing schedule on the next day.  Study medications should not be 
cut or split. No food restrictions apply to SOF; however, SOF should be taken with RBV and 
with food for optimal adherence.
On the day of clinic visits, subjects will be instructed to take their study medication on the day 
prior to clinic visits, 20-28 hours before the administration of the study medication at the clinic.
Subjects should bring their medication with them to the clinic and take their study medication
after all pre-dose assessments are completed. 
5.4.
Ledipasvir/ Sofosbuvir (LDV/SOF)
5.4.1.
Formulation
Ledipasvir 90mg/ sofosbuvir 400mg fixed dose combination (FDC) tablets are orange, 
diamond-shaped, film-coated tablets containing 400 mg of SOF and 90 mg of LDV. The tablets 
are debossed with “GSI” on one side and “7985” on the other side. The LDV/SOF
(90mg/400mg) tablets contain the following inactive ingredients: lactose monohydrate, 
copovidone, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, 
FD&C yellow # 6 /sunset yellow FCF aluminium lake.
5.4.2.
Packaging and Labeling
Ledipasvir 90 mg/ sofosbuvir 400 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle will contain 30 tablets, a silica gel desiccant and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant screw cap with 
an induction-sealed, aluminum-faced liner. 
LDV/SOF bottles to be distributed to centers in the US and other countries shall be labeled to 
meet all applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 
of Good Manufacturing Practices: Manufacture of investigational medicinal products 
(February 2010) and/or other local regulations as applicable.
5.4.3.
Storage and Handling
LDV/SOF bottles should be stored at controlled room temperature until required for 
administration. Controlled room temperature is defined as 25 C (77 F); excursions are 
permitted between 15 C and 30 C (59 F to 86 F).


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All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling LDV/SOF tablets.
Sufficient quantities of LDV/SOF tablets to complete the entire study will be shipped to the 
investigator or qualified designee from Gilead Sciences Clinical Supply Management
(or its designee).
5.4.4.
LDV/SOF Dosage and Administration
LDV/SOF will be administered as one 90 mg/400 mg tablet po daily with or without food for 
12 weeks. LDV/SOF tablets will be supplied by Gilead Sciences for all subjects.
5.5.
Study Drug Compliance
On Day 1, subjects will be administered study drugs and the assigned bottles will be dispensed to 
them along with a dosing diary to be used to document at home dosing. Subjects will be 
instructed to return dosing diaries and any unused study drug in the original container at each 
visit following Day 1 for study drug compliance assessment.
Returned medication will be reconciled by the investigator in order to monitor the subject’s 
compliance with the medication regimen.
5.6.
Dispensing and Accountability of Study Drugs
The Investigator (or designee, e.g., study center pharmacist) will acknowledge receipt of the 
study drugs (after reviewing the shipment’s content and condition) from Gilead Sciences 
(or designee). The Investigator will maintain an accurate inventory of all study drugs. Each dose 
of the study drug(s) administered at the study center will be administered by qualified study 
center personnel. All doses of study drug(s) administered to subjects in the clinic under the 
supervision of staff will be accurately recorded on the Investigational Product Inventory Logs 
provided by Gilead Sciences (or on equivalent documentation maintained by the study center), 
which indicates the date and quantity of all doses of study drug(s) dispensed to individual 
subjects. The requirements of all applicable Federal and State drug dispensing laws will apply to 
all doses of study drugs dispensed by the Investigator (or designee). At the end of the study, all 
unused study drugs (both bulk and individual subject returns) will be returned to a location 
designated by Gilead Sciences.


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5.7.
Study Drug Return or Disposal
At the start of the study, the study monitor will evaluate each study center’s study drug disposal 
procedures and provide appropriate instruction for return or destruction of unused study drug 
supplies. If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, 
the site may destroy used and unused study drug supplies performed in accordance with the 
site’s (hospital/pharmacy) SOP. If the site does not have acceptable procedures in place for 
drug destruction, arrangements will be made between the site and Gilead Sciences 
(or Gilead Sciences’ representative) for return of unused study drug supplies. Where possible, 
study drug will be destroyed at the site.  If drug is destroyed on site, the investigator must 
maintain accurate records for all study drug destroyed. All study drug records must be 
maintained at the site and copies must be submitted to Gilead Sciences at the end of the study.
5.8.
Concomitant Medications
Concomitant medications taken within 30 days of Screening, up to and including the date of the 
visit four weeks after discontinuation of study treatment, need to be recorded in the source 
documents and eCRFs.
5.8.1.
Cohorts 1 and 2
The following medications are prohibited from 21 days prior to the Day 1 visit through the end 
of treatment:

Drugs disallowed per prescribing information of RBV (COPEGUS®)

Concomitant use of certain medications or herbal/natural supplements (inducers of 
drug transporters i.e. P-gp) with study drug(s) may result in pharmacokinetic interactions 
resulting in decreases in exposure of study drug(s).  Representative medications which are 
excluded from 21 days prior to Day 1 through the end of treatment are listed below:
Drug
Agents Disallowed
Concomitant use with study drug may 
potentially result in changes of study 
drug concentration as listed below
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Decrease in concentration of study drug
Antimycobacterials
Rifampin, rifabutin, rifapentine
Decrease in concentration of study drug
Herbal/Natural Supplements
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-Tang)
Decrease in concentration of study drug
Other
Modafinil
Decrease in concentration of study drug


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5.8.2.
Cohort 3
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters ie, P-gp) with study drug(s) may result in PK interactions resulting in increases 
or decreases in exposure of study drug(s). 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 from 21 days prior to Baseline/Day 1 through the end of treatment are listed 
below:
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton-Pump Inhibitors, 
H2-Receptor Antagonists, Antacids
Antiarrhythmics b
Quinidine
Anticonvulsantsc
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Antimycobacterialsc
Rifabutin, Rifapentine, Rifampin
Cardiac Medications b
Amiodaronee
Digoxin
Herbal/Natural Supplementsc
St. John’s Wort, Echinaccea, Milk 
thistle (i.e., silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase Inhibitorsd
Rosuvastatin
Pravastatin, Pitavastatin
a
It is recommended to separate antacid and LDV/SOF administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF at a dose that does not exceed doses comparable to 
famotidine 40 mg twice daily.  Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with LDV/SOF. Proton-pump inhibitors should not be taken before LDV/SOF. 
b
May result in an increase in the concentration of study drugs and/or concomitant medications. Coadministration of 
LDV/SOF with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration 
monitoring of digoxin is recommended when coadministered with LDV/SOF. 
c
May result in a decrease in the concentrations of study drugs.
d
Use with study drugs may result in an increase in the concentration of the HMG-CoA Reductase Inhibitors. Monitor for 
signs and symptoms of muscle weakness or myopathy, including rhabdomyolysis.
e
May result in symptomatic bradycardia. Mechanism is not currently known. The use of amiodarone is prohibited from 
60 days prior to Baseline/Day 1 through the end of treatment.


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5.8.3.
All Cohorts
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 
prohibited in the study.
Should it become medically necessary for patients to start treatment with any excluded 
concomitant medication, the sponsor must be consulted prior to initiation of the new medication 
and the subject’s continued participation must be discussed with the Gilead Medical Monitor.
5.8.3.1.
Medications Associated with QT Prolongation
Medications that are known to cause or are associated with QT prolongation and/or a risk of 
causing torsades de pointes should be avoided in patients with risk factors for developing long 
QT intervals or those receiving other QT-prolonging medications. These medications include, 
but may not be limited to those listed below (see table below) and must be approved by the 
Gilead Medical Monitor prior to study enrollment or coadministration during the study.


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Representative List of Medications Known or Associated with QT Prolongation
QT Prolonging Medication Class
Known or Strongly Suspected to cause 
QT Prolongation
Weaker Association with QT Prolongation
Antibiotics/Anti-infectives:
Macrolide Antibiotics
azithromycin, clarithromycin, erythromycin, 
roxithromycin, telithromycin
Quinolone Antibiotics
gatifloxacin, gemifloxacin, levofloxacin, 
moxifloxacin, ofloxacin, sparfloxacin
ciprofloxacin
Certain antimalarials/pneumocystis prophylaxis; others
artenimool+piperaquine, bedaquiline, chloroquine, 
halofantrine, pentamidine
trimethoprim-sulfa, quinine sulfate
Antipsychotics:
Phenothyazine Antipsychotics
chlorpromazine, mesoridazine, thioridazine
Other Antipsychotics
clozapine, haloperidol, iloperidone, olanzepine, 
paliperidone, pimozide, quetiapine, risperidone, 
sertindole, ziprasidone
amisulpride,
Anit-mania Bipolar Disorders:
lithium
Anti-depressants:
Serotonin re-uptake inhibitors
citalopram, escitalopram, venlafaxine
fluoxetine, paroxetine, sertraline
Tricyclic anti-depressants
amitriptyline, clomipramine, desipramine, 
doxepin, imipramine, nortriptyline, 
protriptyline trimipramine,
Tetracyclic anti-depressants
mirtazepine
trazodone


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QT Prolonging Medication Class
Known or Strongly Suspected to cause 
QT Prolongation
Weaker Association with QT Prolongation
Cardiology Medications:
Class I (Na+) and III (K+) anti-arrhythmics
disopyramide, dofetilide, dronedarone, flecainide, 
ibutilide, mexiletine, procainamide, quinidine
Class II (β blockers) and IV (Ca2+) anti-arrythmics
isradipine, sotalol (Class II/III)
Certain anti-anginals/ calcium blocker
bepridil, nicardipine, ranolazine
Anesthetics, Pain Medications and Additional 
Treatment:
levomethadyl, methadone
general anesthetics 
(e.g., enflurane, halothane, isoflurane, 
sevoflurane)
Anti-nausea:
domperidone, droperidol, dolasetron, granisetron, 
ondansentron, promethazine
Azole anti-fungals (systemic use only)
ketoconazole, voriconazole
fluconazole, itraconazole
Others:
alfuzosin, amantadine, astemizole, cisapride, 
famotidine, felbamate, fosphenytoin, galantamine, 
indapamide, moexipril/HCTZ, octreotide, 
oxytocin, pasireotide, perflutren lipid 
microspheres, probucol, sibutramine, terfenadine,   
tizanidine, tolterodine, vardenafil
chloral hydrate, diphenhydramine, 
solifenacin


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Should it become medically necessary for patients to start treatment with any excluded 
concomitant medication, the sponsor must be consulted prior to initiation of the new medication 
and the subject’s continued participation must be discussed with the Gilead Medical Monitor.
5.8.3.2.
Hematopoietic Growth Factors
Erythropoiesis stimulating agents (ESAs) should not be used during Screening solely to elevate 
hematology laboratory parameters to facilitate entry into the study.  Patients taking ESAs for 
anemia related to chronic kidney disease may enter the study. Granulocyte colony-stimulating 
agents and thrombopoietic growth factors should not be used while the subject is receiving study 
treatment.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in
Table 6-1 and Table 6-2 and described in the following text. 
Any deviation from protocol procedures should be noted in the subject’s clinical chart and 
appropriate eCRFs. In addition, the Sponsor should be promptly notified of any protocol 
deviations. 
The study center will not be released to initiate dosing until:

The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) reviewed and 
approved the study and the informed consent document;

All requested regulatory documents have been submitted to and approved by 
Gilead Sciences;

A Master Services Agreement and/or Study Agreement is executed;

The study initiation meeting has been conducted by the Gilead Sciences clinical monitor 
(or designee).
The initiation meeting will include a review of the protocol, the Investigator’s Brochure, and 
Investigator responsibilities.
Documentation of the personally signed and dated informed consent of each subject, using the 
study-specific informed consent form (ICF), is required before initiating the screening process. 
Generic screening consent forms should not be used in lieu of the study-specific ICF.
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment and throughout the study.
Once consent has been obtained, all screening tests and procedures have been assessed, and 
study eligibility has been confirmed, subjects will be enrolled and assigned a unique subject 
identification number.
Subjects will receive the study treatment as described in Section 5.


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Table 6-1.
Schedule of Assessments for Cohorts 1 and 2
Study 
Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Written Informed 
Consent
X
Medical History 
X
HCV RNA 
Genotype
X
IL28B 
Genotyping
X
HbA1c
X
HCV, HBV, 
HIV Serology
X
TSH
X
Physical Exam, 
including 
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram 
X
X
X
Height
X
Weight
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Study 
Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Coagulation 
(PT, PTT, and 
INR)
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA Viral 
Load
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA 
Sequencing 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy 
Teste
X
X
X
X
X
X
X
X
X
X
X
X
Creatinine 
Clearance
X
Optional 
Pharmacogenetic 
Samplek
X
Intensive PK
Xf
Xf
Trough PK 
Sampleg
X
X
X
X
X
X
X
X
X
Archive Plasma 
Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
Administration
X
Weeks 1-24


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Study 
Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Review Dosing 
Diary/Perform 
Accountabilityh
X
X
X
X
X
X
X
X
X
X
AEs/
Concomitant 
Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Screening evaluations must be completed within 42 days prior to Day 1.
b
Day 1 tests and procedures must be completed prior to administration of the first dose of study drugs 
c
Within 72 hours of permanently discontinuing study drug.
d
Full PE at Day 1 and ET visits only; symptom-directed PE at all other timepoints. Vital signs include blood pressure, pulse, respiration rate, and temperature
e
Females of childbearing potential only. To confirm eligibility at Day 1, a urine pregnancy test may be collected for subjects able to pass urine. For subjects unable to pass 
urine, a serum pregnancy test at Day 1 must be performed at a local lab prior to dosing to confirm eligibility along with sample collected and send to central lab. During 
post-treatment of the study, serum or urine pregnancy testing will occur every month during non-clinic post treatment visits. The subject will be contacted by telephone to 
confirm that pregnancy testing has been performed post-treatment during non-clinic visits.
f
Intensive plasma PK evaluations will be assessed at the following timepoints: 0 (predose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose.
g
Trough plasma PK samples will be drawn prior to dosing. 
h
Dosing Diaries will be completed for all non-observed doses and will be reviewed at every visit. Unused study drug will be returned to perform study drug accountability in 
the original container at each visit following Day 1 for study drug compliance assessment.
i
A window of ± 2 days is allowed for the treatment visits on weeks 1, 2, and 12.  A window of ± 4 days is allowed for the treatment visits weeks, 4-10, and 16-24. Subjects 
who cannot complete their study visit per the visit schedule should ensure they do not run out of study drug prior to their next study visit.  Compliance is critical to ensure 
adequate drug exposure.
j
A window of ± 7 days is allowed for the post treatment visits.
k
The sample should be collected on Day 1 prior to dosing, but may be collected at any time during the study or at a separate post-study visit, if necessary.


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Table 6-2.
Schedule of Assessments for Cohort 3
Study Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
4
Week
12
Week
24
Written Informed Consent
X
Medical History 
X
HCV RNA Genotype
X
IL28B Genotyping
X
HbA1c
X
HCV, HBV, HIV Serology
X
TSH
X
Physical Exam, including
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
Echocardiogram 
X
X
Height
X
Weight
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
(PT, PTT, and INR)
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA Viral Load
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA Sequencing 
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy Teste
X
X
X
X
X
X
X
X
X
Creatinine Clearance
X


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Study Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
4
Week
12
Week
24
Optional Pharmacogenetic 
Samplek
X
Intensive PK
Xf
Xf
Trough PK Sampleg
X
X
X
X
X
X
Archive Plasma Sample
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Administration
X
Weeks 1-12
Review Dosing Diary/
Perform Accountabilityh
X
X
X
X
X
X
X
AEs/Concomitant Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Screening evaluations must be completed within 42 days prior to Day 1.
b
Day 1 tests and procedures must be completed prior to administration of the first dose of study drugs 
c
Within 72 hours of permanently discontinuing study drug.
d
Full PE at Day 1 and ET visits only; symptom-directed PE at all other timepoints. Vital signs include blood pressure, pulse, respiration rate, and temperature
e
Females of childbearing potential only. To confirm eligibility at Day 1, a urine pregnancy test may be collected for subjects able to pass urine. For subjects unable to pass 
urine, a serum pregnancy test at Day 1 must be performed at a local lab prior to dosing to confirm eligibility along with sample collected and send to central lab. During post-
treatment of the study, serum or urine pregnancy testing will occur every month during non-clinic post treatment visits. The subject will be contacted by telephone to confirm 
that pregnancy testing has been performed post-treatment during non-clinic visits.
f
Intensive plasma PK evaluations will be assessed at the following timepoints: 0 (predose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose once either on 
Week 2 OR 4, per investigator discretion.
g
Trough plasma PK samples will be drawn prior to dosing. 
h
Dosing Diaries will be completed for all non-observed doses and will be reviewed at every visit. Unused study drug will be returned to perform study drug accountability in 
the original container at each visit following Day 1 for study drug compliance assessment.
i
A window of ± 2 days is allowed for the treatment visits on weeks 1, 2, and 12.  A window of ± 4 days is allowed for the treatment visits weeks, and 4-10. Subjects who 
cannot complete their study visit per the visit schedule should ensure they do not run out of study drug prior to their next study visit.  Compliance is critical to ensure adequate 
drug exposure.
j
A window of ± 7 days is allowed for the post treatment visits. 
k
The sample should be collected on Day 1 prior to dosing, but may be collected at any time during the study or at a separate post-study visit, if necessary.


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6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Prospective subjects should be screened within 42 days prior to first dose on Day 1. If the subject 
does not begin the treatment phase within this 42-day window, all screening evaluation 
procedures must be repeated. No more than one repeat screen visit is allowed for each subject, 
unless prior written approval has been provided by the Sponsor.
Written informed consent must be obtained from each subject before initiation of any screening 
procedure. After a subject has provided informed consent, the investigator and other study 
personnel will determine if the subject is eligible for participation in the study. This assessment 
will include a review of the inclusion/exclusion criteria and completion of all screening 
procedures as outlined in Table 6-1 and Table 6-2.
Once eligibility is confirmed, the study site will complete an eligibility worksheet for each 
screened subject and submit for Sponsor review. The sponsor will assign a unique subject 
number for each eligible subject and provide the subject number information to the site prior to 
Day 1 visit. 
6.2.2.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history will be collected on all subjects during 
screening. Information related to HCV infection will be collected. In addition, a cirrhosis 
determination will be made as follows:
Cirrhosis determination

Cirrhosis is defined as any one of the following:
Liver biopsy showing cirrhosis
Fibroscan (in countries where locally approved) showing cirrhosis or results > 12.5 kPa
within 6 months of Day 1
FibroTest® score of > 0.75 AND an AST:platelet (APRI) ratio of > 2 during Screening

Absence of cirrhosis is defined as any one of the following:
Liver biopsy within 2 years of Screening showing absence of cirrhosis
Fibroscan (in countries where locally approved) with a result of ≤12.5 kPa 
within ≤6 months of Day 1
FibroTest® score of ≤ 0.48 AND APRI of ≤1 during Screening


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In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria, 
a liver biopsy is required.
In addition, a determination of cardiac function will be made as follows:

Echocardiogram demonstrating left ventricular ejection fraction > 50% performed prior to 
Day 1 visit. Enrollment allowed based on local read of study if central read is not available.
6.3.
Day 1 Assessments
Subjects meeting all eligibility criteria following the screening evaluation will return to the study 
site within 42 days for Day 1 assessments as outlined in Table 6-1 and Table 6-2.
6.3.1.
Dosing Diary
Subjects will be provided with self-administration instructions and study drug diaries to record 
the exact date, time and number of tablets of study drug administration. The site staff will record 
the information from the study drug dosing diary into the eCRF. In the event that the dosing 
diary is not available, the site may obtain dosing information via subject interview and record 
this information in the source notes
6.4.
Treatment Assessments
6.4.1.
Cohorts 1 and 2
Study visits will occur at the end of Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24.
Study procedures and assessments are outlined in Table 6-1.
6.4.2.
Cohort 3
Study visits will occur at the end of Weeks 1, 2, 4, 6, 8, 10, and 12
Study procedures and assessments are outlined in Table 6-2.
6.5.
Safety Assessments
Safety will be evaluated throughout the study. Refer to Table 6-1 and Table 6-2 for a schedule of 
assessments.
6.5.1.
Safety ECGs
Subjects should rest quietly in the supine position for a minimum of 10 minutes prior to each 
scheduled ECG acquisition and should remain in that position until the recording is complete. 
There must be no environmental distractions (television, radio, conversation, etc.) while the 
subjects are resting prior to and during the recordings.


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ECGs will be recorded at a sampling frequency of 500+ Hz, at a speed of 25 mm/sec and at a 
standard duration of 10 seconds. All ECGs will be obtained using instruments that analyze data 
using the same algorithms and produce the same data for interpretation. When ECGs are
performed on an ECG machine, site standard operating procedures (SOPs) will be used.
ECG measurements will be collected pre-dose at time-points as per Table 6-1 and Table 6-2.
The Investigator or other qualified individuals at the study center will review ECGs to assess for 
changes in ECG intervals and morphology as compared to pre-dose ECGs. Collection of 
additional ECGs for routine safety monitoring at additional time-points or days is at the 
discretion of the Investigator based on GCP.
6.5.2.
Safety Echocardiograms
Safety echocardiograms will be performed as outlined in Table 6-1 and Table 6-2. A window of 
± 10 days is allowed for the on-treatment visits. These safety echocardiograms will be performed
locally and sent to a central location for standardized reading.
6.5.3.
Physical Examination
Complete physical examinations or a symptom directed physical examination will be conducted 
pre-dose as outlined in Table 6-1 and Table 6-2. A complete physical examination must include 
source documentation of general appearance, and the following body systems: head, neck and 
thyroid; eyes, ears, nose, throat, mouth and tongue; chest (excluding breasts); respiratory; 
cardiovascular; lymph nodes, abdomen; skin, hair, nails; musculoskeletal; neurological. 
6.5.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature and will be conducted pre-dose as outlined in Table 6-1 and Table 6-2.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.


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6.5.5.
BMI
Height and weight will be collected at the times shown in the schedule of assessments 
Table 6-1 and Table 6-2.
BMI is calculated by the following equation.
BMI =
weight (pounds) 703
(height in inches)2
or
weight in kilograms
(height in meters)2
6.5.6.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {2202} using 
ideal body weight (IBW). 
Male:
CLcr (mL/min) = [140 −age (years)] IBW (kg)
72 Scr
Female:
CLcr (mL/min) = [140 −age (years)] IBW (kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
Ideal body weight (IBW) is estimated by the following equations: 
Males: 
IBW (kg) = 50 kg + 2.3 kg for each inch over 5 feet
Females: 
IBW (kg) = 45.5 kg + 2.3 kg for each inch over 5 feet
6.5.7.
Clinical Laboratory Tests/Assessments
In addition to the PK blood samples that will be collected, blood samples will be collected 
pre-dose as outlined in the schedule of assessments, Table 6-1 and Table 6-2 for the following 
laboratory analyses:
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, MCV, and 
Coagulation Panel (PT, PTT, and INR).
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Creatinine, Total Bilirubin (reflex to Direct Bilirubin), Glucose, 
Total Protein, Bicarbonate, BUN, Calcium, Chloride, Phosphorus, Magnesium, Potassium,
Sodium, and FibroTest®.


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Thyroid-stimulating hormone (TSH)
Haemoglobin A1C (HbA1c)
Virological Tests: Serologies for HCV, HBV and HIV. HCV RNA will be measured using 
COBAS® AmpliPrep/COBAS® TaqMan® HCV Test. HCV genotype and subtype will be 
determined using the Siemens VERSANTHCV Genotype INNO-LiPA 2.0 Assay. Gilead 
reserves the right to use alternate assays for HCV RNA and HCV genotype should the above 
assays become unavailable or are not definitive.
Viral RNA Sequencing/Phenotyping plasma samples will be collected to confirm virologic 
breakthrough. Untested samples may be archived.
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: All females of childbearing potential will have serum or urine pregnancy 
testing every 4 weeks during the dosing period and for a minimum of 6 months following the last 
dose of RBV. If required by local regulations, additional pregnancy tests may be collected. In the 
event of a positive urine pregnancy result, subjects will be instructed to stop study drugs 
immediately and return to the clinic as soon as possible for a serum pregnancy test.
Pregnancy tests must be completed for all females of childbearing potential (see Appendix 2
for definition) as specified in Table 6-1 and Table 6-2. When feasible for subjects, a urine 
pregnancy test may also be taken. During post treatment of the study, subject will be contacted 
by telephone monthly to confirm that the serum or urine pregnancy testing has been performed 
post-treatment during non-clinic visits. Alternatively, if required by local regulations or preferred 
by the investigator or subject, the subject may return to the clinic for urine or serum pregnancy 
tests post treatment.
6.5.8.
Adverse Events/Concomitant Medications/Protocol Restrictions
Evaluation for adverse events, review of concomitant medications, and review of protocol 
restrictions will occur at the times shown in the schedule of assessments Table 6-1 and
Table 6-2. See Section 7 for more information regarding adverse events and Section 5 for more 
information about concomitant medications.
6.6.
Pharmacokinetic (PK) Assessments
Subjects will be instructed to take their SOF or LDV/SOF dose on the day prior to clinic visits, 
20-28 hours before the clinic visit. On the day of clinic visits, subjects should bring their 
medication with them to the clinic and take their dose after the trough PK sample is collected, or 
after the predose intensive PK sample is taken.
The exact time of the dose taken prior to collection of the PK sample and the exact time the PK 
sample is drawn will be recorded on the appropriate eCRF.


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Intensive PK Assessments:
Cohorts 1 and 2:
Serial plasma PK samples will be collected on week 2 and 12 at the following timepoints:

0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours post-dose. 
Cohort 3:
Serial blood samples will be collected once either on week 2 OR 4 (per investigator discretion) at 
the following timepoints:

0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours post-dose.
Plasma concentrations of SOF and its metabolites and LDV will be determined and PK 
parameters will be estimated as appropriate. Plasma concentrations of RBV may be determined, 
as applicable.
Trough PK Assessments:
Trough PK plasma samples for analyses of SOF, its metabolites, RBV and LDV concentrations 
will be collected at all other on treatment visits beginning at the Week 1 visit as applicable.
PK Parameters for SOF, its metabolites, LDV and RBV will be estimated as appropriate. 
6.7.
Early Termination (ET)/Unscheduled Visit
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The 
assessments at the unscheduled visits are at the investigator’s discretion. At all unscheduled 
visits initiated for the purpose of confirming virologic failure a Viral RNA 
Sequencing/Phenotyping Sample must be collected. 
The Sponsor (e.g. Medical Monitor and Clinical Program Manager)/CRO must be informed, as 
soon as possible, when a subject prematurely discontinues treatment. The primary reason for 
premature treatment discontinuation must be provided to the Sponsor/CRO.
If a subject discontinues treatment early for any reason then the following assessments for the 
Early Termination (ET) Visit must be performed: 

Perform complete physical examination

Obtain body weight

Obtain vital signs

Assessment of AEs and concomitant medications


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• 
Pregnancy prevention counseling 
• 
Obtain blood samples for: 
-
Hematology & Chemistiy 
-
Coagulation (PT, PTT, and INR) 
-
HCVRNA 
-
Viral Sequencing I Phenotyping Sample 
-
TroughPK 
-
Semm pregnancy test (females of childbearing potential only) 
Final 
Amendment4 
• 
Review study dmg adherence with subject including recording the date and time of the 
subject's last dose of study dmg prior to the PK draw (subject should retum all study dmgs at 
this visit) 
All subjects will attend the 4-Week Post-Treatment Visit. 
6.8. 
Post-Treatment Assessments 
Subjects with HCV RNA < LLOQ at the 4-Week Post-Treatment Visit will attend the 12-Week 
Post-Treatment Visit. 
Subjects with HCV RNA ~ LLOQ do not need to retum for additional visits and they will be 
tenninated early from the study. 
Subjects with HCV RNA < LLOQ at the Post-Treatment Week 12 Visit will retum at the 
post-u·eatment Week 24 Visit. 
6.9. 
Optional Samples for Pharmacogenetic Testing 
PPD 
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6.10.
Archived Plasma Sample
Archive plasma samples will be collected at the study visits, indicated in Table 6-1 and 
Table 6-2. Archive plasma samples are being collected for possible additional analyses, 
including but not limited to, study drug or metabolite measurements, viral load, safety/efficacy 
assessments, HCV gene sequencing, HCV resistance testing and other possible predictors of 
response as determined by Gilead.
In the event of a subject’s death or loss of competence, the subject’s specimens and data will 
continue to be used as part of the future biomarker research.
If a subject wishes to withdraw the testing of his or her specimens for future research, the 
investigator must inform the Gilead Sciences Medical Monitor in writing of the subject’s wishes.
6.11.
Blood Storage
Archived plasma samples will be collected for future testing. These samples will be frozen and 
stored. The stored plasma samples may be used by the Sponsor or its research partner for future 
clinical laboratory testing to provide additional clinical data. At the conclusion of this study, 
these samples may be retained in storage by Gilead Sciences, Inc. at its research partner facility 
for a period up to 10 years.


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


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale 
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs associated 
with laboratory abnormalities, the event should be graded on the basis of the clinical severity in 
the context of the underlying conditions; this may or may not be in agreement with the grading 
of the laboratory abnormality.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication until 30 days after last administration of study IMP, all 
AEs, regardless of cause or relationship, must be reported to the CRF/eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required 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 
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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30-days of the 
last dose of study IMP, regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period, 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:
Gilead DSPH:
Fax:
E-mail:
+1-650-522-5477
safety_fc@gilead.com

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.


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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to expedite 
to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), 
or suspected unexpected serious adverse reactions (SUSARs). In accordance with the 
EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide 
regulatory agencies and the relevant IEC in concerned Member States of applicable SUSARs as 
outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. 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. 
7.5.
Toxicity Management
7.5.1.
Stopping Rules for Toxicity
Subjects who meet any of the following criteria should be instructed to immediately stop all 
study drugs and return for an Early Termination Visit:

Confirmed elevation of ALT and/or AST > 5× Day 1 or nadir, confirmed by immediate 
repeat testing

Confirmed elevation of ALT > 3× Day 1 and total bilirubin > 2 × ULN

Confirmed elevation of ALT >15 x ULN

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event assessed as related to treatment 

Echocardiogram demonstrating left ventricular ejection fraction ≤40%
7.5.2.
Sofosbuvir (SOF) or LDV/SOF 
Administration of SOF or LDV/SOF may be discontinued due to a clinical or laboratory event.  
There is no option for sofosbuvir or LDV/SOF dose reduction. In the event that SOF is stopped, 
RBV should also be discontinued. 


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7.5.3.
Ribavirin (RBV)
Dose reduction or interruption of RBV due to toxicity should be performed based on the clinical 
experience of the Investigator. RBV may be temporarily discontinued due to toxicity without 
stopping SOF. However, if RBV is permanently discontinued due to toxicity, SOF should also be 
discontinued.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.
A pregnancy report is used to report any pregnancy following maternal or paternal exposure to 
the medicinal product.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (ie, signs the informed consent) and throughout the study, including the 
post study drug follow-up period, to the Gilead DSPH using the pregnancy report form within 
24 hours of becoming aware of the pregnancy. Refer to Section 7.3 and the eCRF completion 
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The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.3 and 7.4. 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. 
Clinical staff should also report any relevant pregnancies to the Ribavirin Pregnancy Registry 
at 1-800-593-2214 (see also http://www.ribavirinpregnancyregistry.com).
Refer to Appendix 2 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of medications prohibited by this protocol should not be reported as 
“misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The prima1y objectives of this study are as follows: 
Final 
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• 
To evaluate the safety of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks and LDV/SOF for 12 weeks as assessed by review of the accumulated safety data 
in each treatment mm 
• 
To evaluate the efficacy of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks and LDV/SOF for 12 weeks measured by the prop01iion of subjects with renal 
insufficiency who have achieved a sustained viral response 12 weeks after treatment 
discontinuation (SVR12) in each treatment ann 
• 
To evaluate the steady state phmmacokinetics ofSOF and its metabolites and LDV upon 
dosing SOF 200 mg or 400 mg or LDV/SOF in subjects with renal insufficiency 
The secondmy objectives ofthis study m·e as follows: 
• 
To evaluate the prop01iion of subjects with renal insufficiency who attain SVR at 
4 and 24 weeks after discontinuation of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of plasma HCV RNA during and after treatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV during and after treatment 
discontinuation 
The explorat01y objective of this study is: 
PPO 
8.1.2. 
Primary Endpoint 
The prima1y safety endpoints include incidences of AEs, laborat01y, 12-lead ECG, and vital sign 
abn01malities. 
The prima1y PK endpoints are pm·ameters AUCtau, Cmax, and Ctau for analytes SOF, its 
metabolites, LDV and RBV as applicable. 
The prima1y efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after discontinuation 
of therapy). 
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8.1.3.
Secondary Endpoint
Secondary PK endpoints are parameters AUClast, Clast, Tmax, Tlast, λz, and t1/2 for analytes SOF, its 
metabolites, LDV and RBV as applicable.
Secondary efficacy endpoints include the proportion of subjects with SVR4 and SVR24, the 
proportion of subjects with virologic failure including viral breakthrough and relapse.
8.1.4.
Other Endpoints of Interest
Additional efficacy evaluations may include HCV RNA change from baseline; ALT 
normalization, andviral kinetic parameters.
8.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using SASsoftware (SAS Institute, Cary, North Carolina, USA).
The study drugs in this study include SOF, RBV and LDV/SOF. Last dose of study drug refers to 
the last dose of any of the study drugs in a treatment group and will be used in the definition of 
treatment-emergent AEs and laboratory abnormalities as well as the efficacy endpoints of SVR 
at various post-treatment time points.
All analyses will be presented by treatment cohort. Subjects who receive study drug other than 
that to which they were assigned will be analyzed according to the study drug received.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which includes 
subjects who were enrolled and received at least one dose of study drug. 
8.2.1.2.
Safety
The primary analysis set for safety analyses will be the Safety Analysis Set which includes
subjects who received at least one dose of study drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose of 
study drug through the date of the last dose of study drug plus 30 days.
8.2.1.3.
Pharmacokinetics
The PK analysis set will include all subjects who are enrolled and have received at least one dose 
of study drug and for whom PK concentration data of interested analytes (SOF, its metabolites,
LDV or RBV) are available. The PK analysis set will be used for analyses of general PK.


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8.2.2.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. In general, values for 
missing data will not be imputed. 
For the analysis of post-baseline categorical efficacy endpoints, if a data point is missing and is 
immediately preceded and followed in time by values that are deemed successes, then the 
missing data point will be termed a success; otherwise the data point will be termed a failure.
Any subject with missing data due to premature discontinuation of the study medication will be 
considered a failure at the time points on, or following, the date of discontinuation. If no HCV 
RNA values are obtained after the last dose of study medication, the subject will be considered a 
treatment failure for the SVR endpoints. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject received study medication, the subject will be included in a summary of adverse 
events according to the treatment received; otherwise, if the subject is not dosed then they 
will be excluded from the summary.

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 predose value, then the subject will be excluded from the calculation of summary 
statistics for the predose value and the change from predose values.
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pretreatment laboratory value is 
available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) for the 
summary of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing baseline result will 
be replaced with a screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for 
calculation of summary statistics for the actual HCV RNA values and the change from baseline 
values by study visit. The reported values will be provided in the HCV RNA listing.
For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed to 
the logarithmic (base 10) scale (log10 IU/mL).
PK concentration values below the lower limit of quantitation (BLQ) will be treated as zero for 
determination of summary and order statistics. Individual values that are BLQ will be presented 
as “BLQ” in the concentration data listing. For the presentation of summary and order statistics, 
if at least 1 subject has a concentration value BLQ for the time point, then the minimum value 
will be displayed as “BLQ.” If more than 50% of the subjects have a concentration data value 


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BLQ for the time point, then the minimum and median values will be displayed as “BLQ.” If 
more than 75% of the subjects have a concentration data value of BLQ for a given time point, 
then the minimum. 1st quartile [q1], median, and 3rd quartile [Q3] values will be displayed as 
“BLQ.” If all subjects have concentration data values BLQ for the time point, then all order 
statistics (minimum, first quartile [Q1], median, third quartile [Q3], maximum) will be displayed 
as “BLQ”.
Exposure parameters that are selected for statistical analysis will be natural log-transformed. 
Concentration values that are BLQ will be excluded for any ratio or natural log-transformed 
statistical analysis.
8.2.3.
Interim Analysis
Interim analyses will be performed to support external multidisciplinary data monitoring 
committee meetings (Section 8.9).
8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline characteristics will be summarized using standard descriptive 
methods by treatment cohort.
Demographic data will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include body weight/body mass index, HCV RNA level 
(log10 IU/mL), IL28B genotype, baseline ALT level, creatinine clearance estimated by 
Cockcroft-Gault, and additional endpoints as necessary.
8.4.
Efficacy Analysis
8.4.1.
Primary Analysis
The primary efficacy endpoint is SVR12 in the FAS population. The primary analysis will be 
performed after all enrolled subjects have been followed through 12 weeks post-treatment or 
discontinued from study.
A point estimate with a 2-sided 95% exact confidence interval (CI) using the exact binomial 
distribution (Clopper-Pearson method) will be constructed for the SVR12 rate by treatment 
cohort.
No statistical hypothesis testing will be performed.
8.4.2.
Secondary Analysis
The proportion of subjects with HCV RNA below the LLOQ over time (including SVR12) will 
be presented by treatment cohort in tabular and graphical form. 
Descriptive summaries and listings will be provided for additional efficacy evaluations including 
the proportion of subjects who experience virologic failure, ALT normalization, serum HCV 
RNA actual values and change from baseline. 


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Details on efficacy analyses will be described in the statistical analysis plan (SAP). 
8.5. 
Safety Analysis 
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Safety will be evaluated by assessment of clinical laborat01y tests, physical examinations, vital 
signs measmements, at various time points dming the study, and by the documentation of AEs. 
All safety data collected on or after the first dose of study dmg adminisu·ation up to 30 days after 
the last dose of study dmg will be summarized according to the study dmg received. Safety 
endpoints will be summarized as the number (prop01tion) of subjects with events or 
abnonnalities for categorical data or as an 8-number summaty (n, mean, standard deviation, 
minimum, Ql, median, Q3, maximum) for continuous data. 
8.5.1. 
Extent of Exposure 
A subject's extent of exposme to study dmg will be generated from the study dmg 
adminisu·ation page of the CRF. Exposme data will be summarized by u·eatment coh01t . 
8.5.2. 
Adverse Events 
Clinical and laborat01y AEs will be coded using the Medical Dictionruy for Regulat01y 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Tetm (HLGT), 
High-Level Tetm (HLT), Prefened Tetm (PT), and Lower-Level Tetm (LLT) will be attached to 
the clinical database. 
Events will be summarized on the basis of the date of onset for the event. A u·eatlnent-emergent 
adverse event will be defined as any new or worsening adverse event that begins on or after the 
date of first dose of study dmg up to the date of last dose of study dmg plus 30 days. 
Summaries (number and percentage of subjects) ofu·eatlnent-emergent adverse events 
(by SOC and prefen ed te1m) will be provided by u·eatlnent coh01t: 
• 
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 AEs that caused change in dose or temporary interruption of study drug,

All SAEs (including death), and

All study drug-related SAEs
All AEs collected during the course of the study will be presented in data listings.
8.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, minimum, Q1, median, Q3, 
maximum) by study visit along with corresponding change from baseline.
Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme 
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 baseline at any 
time post-baseline up to the date of last dose of study drug plus 30 days will be summarized by 
treatment cohort. 
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pretreatment laboratory value is 
available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) for the 
summary of graded laboratory abnormalities. Thus, any post-baseline graded abnormality 
(i.e., at least Grade 1) will be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
8.6.
Pharmacokinetic Analysis
Plasma concentrations of the study drug over time will be listed and summarized using 
descriptive statistics. PK parameters (e.g., AUCtau, Cmax, and Ctau) will be listed and summarized 
for study drug (i.e., SOF and its metabolites, LDV and RBV) using descriptive statistics 
(e.g., sample size, arithmetic mean, geometric mean, % coefficient of variation [%CV], SD, 
minimum, Q1, median, Q3, maximum). 
8.7.
Stopping Rules for Individual Groups
There are no predetermined futility criteria which would require enrollment to be halted or 
treatment discontinued.


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8.8.
Sample Size
Due to the exploratory nature of this study, no formal power or sample size calculations were 
performed to determine treatment group size. The total sample size of 35 is largely based on 
feasibility.
8.9.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety, efficacy, and PK data for each cohort of the study 
before proceeding to the next. Specifically, all of the data through post-treatment week 4 from 
the SOF 200 mg group (Cohort 1) will be reviewed before screening, enrollment and dosing for 
the SOF 400 mg group (Cohort 2). A similar review and initiation process will occur between  
SOF 400 mg (Cohort 2) and LDV/SOF dose group (Cohort 3), with review of safety and PK data 
through Week 12 from Cohort 2 prior to initiating Cohort 3. The DMC will provide 
recommendations to Gilead whether the nature, frequency, and severity of adverse effects 
associated with study treatment warrant the early termination of the study in the best interests of 
the participants, whether the study should continue as planned, or the study should continue with 
modifications. The DMC may also provide recommendations as needed regarding the need for 
additional meetings or an alternative meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.


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


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investigator must use the most current IRB- or IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB or IEC or
local requirements. The consent form will inform subjects about pharmacogenomic testing and 
sample retention, and their right to receive clinically relevant pharmacogenomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB or IEC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The 
investigator must keep a screening log showing codes, names, and addresses for all subjects 
screened and for all subjects enrolled in the trial. Subject data will be processed in accordance 
with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully 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 should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);


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
Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. Subsequent to data entry, a study monitor will perform source data verification 
within the EDC system. Original entries as well as any changes to data fields will be stored in the 


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


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead Sciences. All protocol modifications must be submitted to the Competent 
Authorities, IRB or IEC in accordance with local requirements. Approval must be obtained 
before changes can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). 
Gilead will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be
prepared in certain cases. 
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

the results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years

The investigator will submit to Gilead any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).

The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.


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9.3.2.
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.
9.3.3.
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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10.
REFERENCES
2202
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16:31-41.
12557
Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. 
Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 
weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of 
chronic infection with hepatitis C virus. International Hepatitis Interventional 
Therapy Group (IHIT). Lancet 1998;352 (9138):1426-32.
12558
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et 
al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for 
chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 
1998;339 (21):1485-92.
15572
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
Laboratories Inc., Nutley, NJ. Revised: January 2010.
15668
Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
Characteristics. Roche Products Limited, Welwyn Garden City, United Kingdom. 
Revised: March 2010.
23275
Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. 
Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J 
Med 2013;368 (1):34-44.
23338
Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus 
infection in Europe. J Hepatol 2008;48 (1):148-62.
24149
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
Laboratories Inc., Nutley, NJ. Revised: February 2013.
24713
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, 
Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients 
without treatment options. N Engl J Med 2013;368 (20):1867-77.
24715
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et 
al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J 
Med 2013;368 (20):1878-87.
27832
Gilead Sciences Limited. SOVALDI 400 mg film-coated tablets. Summary of 
Product Characteristics.  County Cork Ireland. January 2014.  2014:


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34474
Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. 
US Prescribing Information.  Foster City, CA. Revised March  2015.
34475
Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US 
Prescribing Information.  Foster City, CA. Revised March 2015.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities


Sovaldlll> (Sotosbuvir) 
P'rulucol 08-US-334-0 154 
Final 
Gilead Scieuces, Inc. 
Amendment 4 
Appendix 1. 
lnvestiantor Signatlare Page . 
GILEAD SCIENCES, INC. 
333 LAKESIDE DlUVE 
FOSTER ClTY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2b, Op~:m~Label Study of200 mg or 400 mg Sofosbuvir+RBV for 24 Weeks in 
Genotype 1 or 3 and Ledipasvir/Sofosbuvit (LDY/SOF) Fixed~Dose Combination (FDC) Tablet 
for 12 weeks in Genot:ype 1 or 4 HCV~Infected Subjects with Renal Insufficiency 
GS-U8-334-01~4, Amendment 4, 23 AtJrll 201S 
This protocol has been approved by Gilead Sciences. Inc. The following signature documents 
this approval. 
Theo Sarif, MD {Printed) 
Medical Monitor 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appe.o.dices, 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 lime 
designated. 
I will provide all study personnel under my supetvision copies of the protocol and acce.5s to all 
info.rmation provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are :ft11ly informed about the drugs and the study. 
Principal Investigator Name (.Printed) 
Signature 
Date 
Site Number 
CONPlPENTU\L 
Page76 
23 Apri12015 


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Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Background
For Cohorts 1 and 2
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects have 
been demonstrated in all animal species tested. Pregnancy must be excluded before the start of 
treatment with study drugs and prevented thereafter by reliable contraceptive methods. 
Pregnancy tests will be performed regularly throughout this study. Furthermore, RBV is known 
to accumulate intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, 
extreme care must be taken to avoid pregnancy during RBV therapy and for up to 6 months 
following completion of treatment (7 months for males). Please refer to the latest version of the 
product insert for additional information. 
Non-clinical toxicity studies of SOF demonstrated no adverse effect on fertility or embryo-fetal 
development. However, there are no clinical studies of SOF in pregnant women. Please refer to 
the latest version of the investigator’s brochure for additional information. 
For Cohort 3
Non-clinical toxicity studies of LDV/SOF demonstrated no adverse effect on embryo-fetal 
development. However, there are no clinical studies of LDV/SOF in pregnant women Please 
refer to the latest version of the Investigator’s Brochure for additional information.
2) Definition of Female of Childbearing Potential and Contraceptive Requirements for 
Female Subjects (and their male partners)
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 6 months after last dose of RBV
(Cohorts 1 and 2) or until 30 days after the last dose of study drug in the absence of RBV 
(Cohort 3):


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
Complete abstinence from intercourse. Abstinence is an acceptable method of contraception 
only when it is in line with the subject's preferred and usual lifestyle. Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
Or

Consistent and correct use of 1 of the following methods of birth control listed below, in 
addition to a male partner who correctly uses a condom, from the date of Screening until 
6 months after the last dose of RBV (Cohorts 1 and 2) or 30 days after last dose of study drug 
in the absence of RBV (Cohort 3): 
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent
tubal sterilization
vasectomy in male partner
implants of levonorgestrel
injectable progesterone
oral contraceptives (either combined or progesterone only)
contraceptive vaginal ring 
transdermal contraceptive patch
3) Contraceptive Requirements for Male Subjects (and their female partners)
All male study participants must agree to consistently and correctly use a condom from 
Baseline until 7 months after the last dose of RBV (Cohorts 1 and 2) or until 90 days after 
administration of the last dose of study drug in the absence of RBV (Cohort 3). If their female 
partner is of childbearing potential (as defined above), their female partner must use 1 of the 
methods of birth control listed above from the date of Screening until 7 months after last dose of 
RBV (Cohorts 1 and 2) or until 90 days after administration of the last dose of study drug in the 
absence of RBV (Cohort 3).
Male subjects must agree to refrain from sperm donation for at least 7 months after the last dose 
of RBV (Cohorts 1 and 2) or for at least 90 days after the last dose of study drug in the absence 
of RBV (Cohort 3).


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4) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 6 months (7 months for partners of male subjects) of 
last RBV dose or within 30 days (90 days for partners of male subjects) of last LDV/SOF dose.
Subjects who become pregnant or who suspect that they are pregnant must report the information 
to the investigator and discontinue study drug immediately. Subjects whose partner has become 
pregnant or suspects she is pregnant must report the information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 7.6.2.


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


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 
≥ 7 Months#
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0%
# An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 t o <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL                          
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL              
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL                      
1.51 to < 1.74 mmolL
< 6.1 mg/dL                           
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L


Sovaldi® (Sofosbuvir)
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 


Sovaldi® (Sofosbuvir)
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia               
Adult and Pediatric           
≥ 1 year   
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L


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


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


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


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


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


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


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


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


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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
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social & 
functional activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions


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


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


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


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


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


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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.

Prot_001.pdf: 
Study Title: 
Sponsor: 
IND No.: 
EudraCT No: 
Indication: 
Protocol ID: 
Gilead Sciences Study 
Director 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2b, Open-Label Study of 200 mg or 400 mg 
Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 
HCV-Infected Subjects with Renal Insufficiency 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
106,739 
2013-002897-30 
Hepatitis C Vims Infection 
GS-US-3 34-0154 
Name: 
Telephone: 
Fax: 
E-mail: 
PPD 
PPD 
PPD 
t-'t-'U 
Original: 
11 July 2013 
Amendment 1: 05 September 2013 
CONFIDENTIALITY STATEMENT 
The inf01m ation contained in this document, pmiicularly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Institutional Review Bom·d or Independent Ethics Committee. The inf01m ation is 
only to be used by you in connection with authorized clinical studies of the investigational 
dmg described in the protocol. You will not disclose any of the infonnation to others without 
written authorization from Gilead Sciences, Inc., except to the extent necessm·y to obtain 
inf01m ed consent from those persons to whom the dmg may be administered. 


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Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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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.
Sofosbuvir (formerly GS-7977)......................................................................................................13
1.3.
Ribavirin (RBV)..............................................................................................................................14
1.4.
Rationale for the Current Study ......................................................................................................14
1.5.
Rationale for SOF Dose Selection ..................................................................................................15
1.6.
Rationale for RBV Dose Selection .................................................................................................16
1.7.
Overall Risk/Benefit Assessment....................................................................................................16
2.
OBJECTIVES..............................................................................................................................................17
3.
STUDY DESIGN ........................................................................................................................................18
3.1.
Treatment Plan and Regimen..........................................................................................................18
3.2.
Visit Schedule .................................................................................................................................18
3.3.
Virologic Response-Based Stopping Criteria..................................................................................19
3.3.1.
Cardiac Function-Based Stopping Criterion .................................................................19
3.4.
Treatment Discontinuation Criteria.................................................................................................19
3.5.
Registry Studies ..............................................................................................................................20
3.5.1.
Sequence Registry Study...............................................................................................20
3.5.2.
SVR Registry Study ......................................................................................................20
4.
SUBJECT POPULATION...........................................................................................................................21
4.1.
Number of Subjects and Subject Selection .....................................................................................21
4.2.
Inclusion Criteria ............................................................................................................................21
4.3.
Exclusion Criteria ...........................................................................................................................22
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ....................................................................................25
5.1.
Sofosbuvir (SOF) ............................................................................................................................25
5.1.1.
Formulation...................................................................................................................25
5.1.2.
Packaging and Labeling ................................................................................................25
5.1.3.
Storage and Handling....................................................................................................25
5.1.4.
Sofosbuvir (SOF) Dosage and Administration..............................................................26
5.2.
Ribavirin (RBV)..............................................................................................................................26
5.2.1.
Formulation...................................................................................................................26
5.2.2.
Packaging and Labeling ................................................................................................26
5.2.3.
Storage and Handling....................................................................................................26
5.2.4.
RBV Dosage and Administration..................................................................................27
5.3.
Co-administration of Sofosbuvir (SOF) and Ribavirin (RBV) .......................................................27
5.4.
Study Drug Compliance..................................................................................................................27
5.5.
Dispensing and Accountability of Study Drugs..............................................................................27
5.6.
Study Drug Return or Disposal.......................................................................................................28
5.7.
Concomitant Medications ...............................................................................................................28
5.7.1.
Medications Associated with QT Prolongation.............................................................29
5.7.2.
Hematopoietic Growth Factors .....................................................................................30


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Amendment 1
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6.
STUDY PROCEDURES .............................................................................................................................31
6.1.
Subject Enrollment and Treatment Assignment..............................................................................31
6.2.
Pretreatment Assessments...............................................................................................................35
6.2.1.
Screening Visit..............................................................................................................35
6.2.2.
Medical History.............................................................................................................35
6.3.
Day 1 Assessments..........................................................................................................................36
6.3.1.
Dosing Diary.................................................................................................................36
6.4.
Treatment Assessments...................................................................................................................36
6.5.
Safety Assessments.........................................................................................................................36
6.5.1.
Safety ECGs..................................................................................................................36
6.5.2.
Safety echocardiograms ................................................................................................37
6.5.3.
Physical Examination....................................................................................................37
6.5.4.
Vital Signs.....................................................................................................................37
6.5.5.
BMI...............................................................................................................................37
6.5.6.
Creatinine Clearance .....................................................................................................37
6.5.7.
Clinical Laboratory Tests/Assessments.........................................................................38
6.5.8.
Adverse Events/ Concomitant Medications/ Protocol Restrictions...............................39
6.6.
Pharmacokinetic (PK) Assessments................................................................................................39
6.7.
Early Termination (ET)/Unscheduled Visit ....................................................................................40
6.8.
Post-Treatment Assessments...........................................................................................................41
6.9.
Optional Samples for Pharmacogenetic Testing .............................................................................41
6.10.
Archived Plasma Sample ................................................................................................................41
6.11.
Blood Storage..................................................................................................................................42
7.
ADVERSE EVENTS MANAGEMENT.....................................................................................................43
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events..........................43
7.1.1.
Adverse Events..............................................................................................................43
7.1.2.
Serious Adverse Events.................................................................................................43
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events..............................................................44
7.2.
Assessment of Adverse Events and Serious Adverse Events..........................................................44
7.2.1.
Assessment of Causality for Study Drugs and Procedures............................................44
7.2.2.
Assessment of Severity .................................................................................................45
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead................................................................................................................45
7.4.
Gilead Reporting Requirements......................................................................................................47
7.5.
Toxicity Management .....................................................................................................................47
7.5.1.
Stopping Rules for Toxicity..........................................................................................47
7.5.2.
Sofosbuvir (SOF) ..........................................................................................................47
7.5.3.
Ribavirin (RBV)............................................................................................................48
7.6.
Special Situations Reports ..............................................................................................................48
7.6.1.
Definitions of Special Situations...................................................................................48
7.6.2.
Instructions for Reporting Special Situations................................................................48
8.
STATISTICAL CONSIDERATIONS.........................................................................................................51
8.1.
Analysis Objectives and Endpoints.................................................................................................51
8.1.1.
Analysis Objectives.......................................................................................................51
8.1.2.
Primary Endpoint ..........................................................................................................51
8.1.3.
Secondary Endpoint ......................................................................................................52
8.1.4.
Other Endpoints of Interest ...........................................................................................52
8.2.
Analysis Conventions .....................................................................................................................52
8.2.1.
Analysis Sets.................................................................................................................52
8.2.2.
Data Handling Conventions ..........................................................................................53


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Amendment 1
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8.2.3.
Interim Analysis............................................................................................................54
8.3.
Demographic Data and Baseline Characteristics ............................................................................54
8.4.
Efficacy Analysis............................................................................................................................54
8.4.1.
Primary Analysis...........................................................................................................54
8.4.2.
Secondary Analysis.......................................................................................................55
8.5.
Safety Analysis ...............................................................................................................................55
8.5.1.
Extent of Exposure........................................................................................................55
8.5.2.
Adverse Events..............................................................................................................55
8.5.3.
Laboratory Evaluations .................................................................................................56
8.6.
Pharmacokinetic Analysis...............................................................................................................57
8.7.
Stopping Rules for Individual Groups ............................................................................................57
8.8.
Sample Size.....................................................................................................................................57
9.
RESPONSIBILITIES ..................................................................................................................................58
9.1.
Investigator Responsibilities ...........................................................................................................58
9.1.1.
Good Clinical Practice ..................................................................................................58
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) Approval..............................................................................................................58
9.1.3.
Informed Consent..........................................................................................................58
9.1.4.
Confidentiality ..............................................................................................................59
9.1.5.
Study Files and Retention of Records...........................................................................59
9.1.6.
Case Report Forms........................................................................................................61
9.1.7.
Drug Accountability......................................................................................................61
9.1.8.
Inspections ....................................................................................................................61
9.1.9.
Protocol Compliance.....................................................................................................62
9.2.
Sponsor Responsibilities.................................................................................................................62
9.2.1.
Protocol Modifications..................................................................................................62
9.2.2.
Study Report and Publications ......................................................................................62
9.3.
Joint Investigator/Sponsor Responsibilities ....................................................................................62
9.3.1.
Access to Information for Monitoring...........................................................................62
9.3.2.
Access to Information for Auditing or Inspections .......................................................63
9.3.3.
Study Discontinuation...................................................................................................63
10.
REFERENCES ............................................................................................................................................64
11.
APPENDICES .............................................................................................................................................66
Appendix 1.
Investigator Signature Page...........................................................................................67
Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements ..................................................................68
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities .............................................................................................70
LIST OF IN-TEXT TABLES
Table 6-1.
Schedule of Assessments ..............................................................................................32


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2b, Open-Label Study of 200 mg or 400 mg 
Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 HCV-Infected 
Subjects with Renal Insufficiency
IND Number:
Eudra CT Number:
106,739
2013-002897-30
Study Centers 
Planned:
Multiple sites in New Zealand, Europe, North America and South 
America
Number of Subjects 
Planned:
Approximately 40 subjects
Target Population:
Adults with chronic renal insufficiency and HCV infection
Treatment Duration:
24 weeks
Objectives:
The primary objectives of this study are:

To evaluate the safety of sofosbuvir (SOF) 200 mg or 400 mg
+ ribavirin (RBV) for 24 weeks as assessed by review of the 
accumulated safety data in each treatment arm

To evaluate the efficacy of sofosbuvir (SOF) 200 mg or 
400 mg + ribavirin (RBV) for 24 weeks measured by the 
proportion of subjects with renal insufficiency who have 
achieved a sustained viral response 12 weeks after treatment 
discontinuation (SVR12) in each treatment arm

To evaluate the steady state pharmacokinetics of SOF and its 
metabolites upon dosing SOF 200 mg or 400 mg in subjects
with renal insufficiency 
The secondary objectives of this study are:

To evaluate the proportion of subjects with renal insufficiency 
who attain SVR at 4 and 24 weeks after discontinuation of 
treatment (SVR4 and SVR24)

To evaluate the kinetics of plasma HCV RNA during and after 
treatment discontinuation

To evaluate the emergence of viral resistance to SOF during 
and after treatment discontinuation


Sofosbuvir 
Protocol GS-US-334-0154 
Gilead Sciences, Inc. 
Study Design: 
Registry Studies: 
CONFIDENTIAL 
The explorat01y objective of this study is: 
This study will have 2 pmis. 
Final 
Amendment 1 
Pmi 1 will enroll approximately 20 subjects with severe renal 
insufficiency. 
• 
10 subjects will receive SOF 200 mg QD + RBV 200 mg QD 
for 24 weeks. 
• 
Following review of safety, efficacy and PK data through 
post-tr·eatrnent Week 4 of the Pmi 1 SOF 200 mg group, 
10 additional subjects will receive SOF 400 mg QD + RBV 
200 mg QD for 24 weeks. 
Pmi 2 will enroll approximately 20 subjects on dialysis following 
review of safety, efficacy and PK data through post-tr·eatrnent 
Week 4 of Pmi 1 SOF 400 mg group. 
• 
10 subjects will receive SOF 200 mg QD + RBV 200 mg QD 
for 24 weeks. 
• 
Following review of safety, efficacy and PK data through 
post-tr·eatrnent Week 4 of the Pmi 2 SOF 200 mg group, 
10 additional subjects will receive SOF 400 mg QD + RBV 
200 mg QD for 24 weeks. 
Sequence Registry Study 
Subjects who do not achieve SVR will be eligible for enrollment in 
the Sequence Registry Study where available and approved. The 
pmpose of the Sequence Registry Study will be to monitor the 
persistence of resistant mutations for up to 3 yem·s. The Sequence 
Registry Study is described in a sepm·ate protocol 
(GS-US-248-0123). 
SVR Registry Study 
All subjects who achieve SVR will be eligible for enrollment in the 
SVR Registry Study where available and approved. The pmpose of 
the SVR Registry Study will be to evaluate dmability of SVR for 
up to 3 yem·s post-tr·eat:Inent. The SVR Regisby Study is described 
in a sepm·ate protocol (GS-US-248-0122). 
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Diagnosis and Main 
Eligibility Criteria:
Adults (≥ 18 years) with chronic genotype 1 or genotype 3 HCV 
infection. Reference Sections 4.2 and 4.3 for detailed Inclusion and 
Exclusion criteria.
Study Procedures/
Frequency:
Screening assessments will be completed within 42 days of the 
Day 1 visit. 
Study visits will occur at Screening, Day 1, and at the end of 
Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20 and 24 and at Post-Treatment 
Weeks 4, 12, and 24. Screening assessments will include physical 
examination, height, weight, vital signs, 12-lead ECG, 
echocardiogram, concomitant medications, safety laboratory tests, 
HCV RNA, serology (HIV, HCV, HBV), hemoglobin A1c 
(HbA1c), serum β-hCG (females of child bearing potential only), 
IL28B genotyping 
On-treatment assessments will include adverse events (AEs), 
concomitant medications, study medication pill count, physical 
examination, vital signs, 12-lead ECGs, echocardiogram, safety 
laboratory tests, HCV RNA, pharmacokinetic samples, and serum 
pregnancy tests (females of child bearing potential only). 
Post-treatment assessments will include AEs, concomitant 
medications, vital signs, safety laboratory tests, HCV RNA, and 
serum pregnancy tests (females of child bearing potential only).
Samples for viral RNA sequencing will be collected at Day 1 and 
every visit thereafter. Samples will be collected during treatment 
visits for PK analysis of study drug(s).
PK assessments
Intensive PK Assessments
Serial blood samples will be collected on week 2 and 12 at the 
following timepoints:
0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours 
post-dose.
Plasma concentrations of SOF and its metabolites will be 
determined and PK parameters will be estimated as appropriate. 
Plasma concentrations of RBV may be determined, if necessary.
Trough PK Assessments:
Trough PK plasma samples for analyses of SOF, its metabolites 
and RBV concentrations will be collected at all other on treatment 
visits beginning at the Week 1 visit.
PK Parameters for SOF, its metabolites, and RBV will be 
estimated as appropriate. 


Sofosbuvir 
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Test Product, Dose, 
and Mode of 
Administration: 
Optional Genetic Sample Collection 
PPD 
Archived Plasma Sample 
Final 
Amendment 1 
Archive plasma samples are being collected for possible additional 
analyses, including but not limited to, study dmg or metabolite 
measurements, viral load, safety/efficacy assessments, HCV gene 
sequencing, HCV resistance testing and other possible predictors 
of response as detennined by Gilead. 
Sofosbuvir is manufactured as 100 mg and 400 mg tablets for oral 
administration. Subjects randomized to the 200 mg dose will take 
2 x 100 mg tablets for a total dose of 200 mg orally QD in the 
moming with RBV and with food. Subjects randomized to the 
400 mg dose will take 1x400 mg tablet for a total dose of 400 mg 
orally QD in the moming with RBV and with food. 
RBV will be supplied as a 200 mg tablet for oral administration by 
Gilead Sciences. Subjects will take 1 x 200 mg tablet in the 
moming with SOF and with food. 
Reference Therapy: 
None 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
PK: 
CONFIDENTIAL 
AEs will be collected through 4 weeks post-treatment. Safety labs 
and SAEs will be collected throughout the study. Safety will be 
evaluated by assessment of clinical laborat01y tests, ECG, 
echocardiogram, periodic physical examinations including vital 
signs at various time points during the study, and by the 
documentation of adverse events. 
Efficacy will be evaluated using scheduled assessments of HCV 
RNA perf01m ed using CO BAS® AmpliPrep/COBAS® TaqMan® 
HCV Test. 
Plasma PK parameters will be calculated for sofosbuvir and its 
metabolites GS-566500 and GS-331007 and RBV, as applicable. 
Examples are AUCiast, AUCtau, Cmax, Clast, Ctau, and t112. 
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Statistical Methods:
Safety data will be listed by subject and summarized by treatment 
in each renal function subgroup (study part) using frequency of 
event/abnormality or descriptive statistics (e.g., sample size, 
arithmetic mean, geometric mean, % coefficient of variation [CV], 
standard deviation [SD], minimum, Q1, median, Q3, and 
maximum).
The steady state PK plasma concentrations and parameters will be 
listed by subject and summarized by treatment and study part using 
descriptive statistics for each analyte (SOF, GS-566500, 
GS-331007, and RBV, as appropriate). 
In the efficacy analysis, no statistical hypothesis testing will be 
performed and no formal inference will be made on primary 
efficacy endpoint SVR12. A point-estimate with two-sided 95% 
exact confidence interval (CI) using the binomial distribution 
(Clopper-Pearson method) will be constructed for the SVR12 rate 
by treatment and study part. Similar analysis will be also 
performed for secondary endpoints SVR4 and SVR24.
To evaluate the kinetics of circulating HCV RNA during and after 
treatment discontinuation, viral load data will be listed by subject 
and summarized by treatment and visit in each study part using 
descriptive statistics.
Due to the exploratory nature of this study, no formal power or 
sample size calculations were performed to determine treatment 
group size. The total sample size of 40 (i.e., 10 enrolled to obtain 
8 evaluable for each dose level group in each study part) is largely 
based on feasibility.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
β-hCG
β-human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase  (also SGOT)
AUC
area under the curve
AUCtau
area under the plasma concentration versus time curve over the dosing 
interval (tau)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BW
body weight
CLcr
Creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear 
(PBMC) concentration of drug
Ctau
observed drug concentration at the end of the dosing interval (tau)
CRF
case report form(s)
CRO
Contract (or clinical) research organization 
dL
Deciliter
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
ESRD
End Stage Renal Disease
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
HBV
Hepatitis B virus
HCV
Hepatitis C virus


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
HDPE
high-density polyethylene
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
IBW
High-Level Term
Ideal Body Weight
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL28B
IL28B gene
IND
Investigational New Drug (Application)
IRB
institutional review board
IUD
intrauterine device
IV
Intravenous
kg
Kilogram
L
Liter
LDH
Lactase dehydrogenase
LLN
lower limit of the normal range
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MH
Mantel-Haenszel
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PBMC
peripheral blood mononuclear cell(s)
PEG
Pegylated interferon
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
QD
once daily (use only in tables)
QTcF
QT interval corrected using Fridericia’ formula
RBC
Red blood cell count 
RBV
Ribavirin
RNA
ribonucleic acid
RVR
rapid virologic response 
SADR
Serious adverse drug reaction
SAE
serious adverse event


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
SD
Standard deviation
SOC
Standard of Care
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TND
Target not detected
TSH
Thyroid stimulating hormone
t½
An estimate of the terinal elimination half-life of the drug in 
serum/plasma/PBMC, calculated by dividing the natural log of 2 by the 
terminal elimination rate contstant (λz)
ULN
upper limit of the normal range
US
United States
WBC
white blood cell count


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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) is responsible for a large proportion of chronic liver disease 
worldwide and accounts for 70% of cases of chronic hepatitis in industrialized countries. The 
global prevalence of chronic hepatitis C is estimated to average 3% {19705}. The most 
common genotype worldwide is genotype 1 followed by genotypes 2 and 3 {19705}. 
Although there is evidence that the incidence of viral infection may be decreasing, the 
prevalence of liver disease caused by HCV is on the rise, primarily due to the lag between the 
onset of infection and the clinical manifestation of liver disease {19705}. The prevalence of 
chronic HCV is significantly higher among patients with chronic renal failure, and HCV 
itself is associated with impaired renal function. Treatment of these individuals is therefore 
recommended but is often complicated by the substantial increase in hematologic toxicities 
associated with the use of ribavirin in the setting of low creatinine clearance {23275}.
Standard of care for genotype 1 HCV infection involves 24-48 weeks of an HCV protease 
inhibitor in combination with pegylated interferon-alfa (PEG)+ribavirin (RBV). The 
recommended first-line treatment for subjects with genotype 2 or genotype 3 chronic 
hepatitis C is PEG+ RBV for 24 weeks {13693}, {17940}. There are minimal data regarding 
the optimal regimen for patients with severe renal disease (e.g., Cr clearance<30 mL/min) or 
end stage renal disease on maintenance hemodialysis. Interferon monotherapy for 48 weeks 
which provides an SVR rate of approximately 40% in clinical trials is often deemed the 
treatment of choice. Due to the side effects and lengthy duration of current treatment, there is 
substantial need for a short, simple, interferon-free regimen, particularly in patients who are 
more susceptible to drug toxicities, such as those with renal insufficiency. 
Sofosbuvir (SOF) is a potent nucleotide analogue that inhibits HCV RNA replication in vitro 
and has demonstrated high rates of sustained viral response (SVR) when given with RBV to 
subjects with chronic genotype 1, 2 or 3 HCV infection {23275}, {24713}, {24715}. The 
degree of RBV-associated hemolytic anemia is reduced in the absence of interferon. 
Therefore, the combination of SOF+RBV may represent a promising therapeutic option for 
HCV-infected patients with severe renal insufficiency.
1.2.
Sofosbuvir (formerly GS-7977)
Sofosbuvir (SOF), formerly GS-7977, is a nucleotide analog that is a potent and selective 
inhibitor of NS5B-directed HCV replication.
Please refer to the Investigator’s Brochure (IB) for additional information on SOF including:

In Vitro Anti-HCV Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience


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1.3.
Ribavirin (RBV)
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of 
RNA and DNA viruses {15572}, {15668}. Ribavirin monotherapy has little or no effect on the 
replication of HCV but can result in short term normalization of serum ALT activity. When 
combined with interferon or PEG therapy, RBV decreases substantially the relapse rate seen 
after cessation of interferon therapy {12557}, {12558}.
Ribavirin is a known teratogen (FDA category X). Furthermore, RBV is known to 
accumulate intracellularly where it is cleared slowly, and is also excreted in semen. 
Therefore, extreme care must be taken to avoid pregnancy during RBV therapy and for up to 
6 months following completion of treatment. A comprehensive review of RBV is contained 
in the package insert/SmPC.
1.4.
Rationale for the Current Study
This study will evaluate the safety, efficacy and pharmacokinetics of treatment with 
SOF+RBV for 24 weeks in subjects with chronic genotype 1 or 3 HCV infection and severe 
renal impairment.
Liver disease caused by HCV causes significant morbidity and mortality among patients with 
end-stage renal disease, particularly those treated with dialysis. Although treatment for 
chronic HCV has evolved over the last decade resulting in response rates of approximately 
70%, treatment with PEG and RBV is not recommended in ESRD patients {24913}. 
Interferon monotherapy, however, is associated with poor tolerability, a 48 week treatment 
duration, and efficacy of approximately 40%. Furthermore, once patients have failed this 
course of treatment, they have no further treatment options and are at risk for progression of 
liver disease, cirrhosis, and hepatocellular carcinoma.
To date, SOF+RBV has demonstrated safety and efficacy in a broad range of subjects with 
chronic HCV infection in Phase 2 and Phase 3 clinical trials. However, subjects with Cr 
clearance <60 mL/min have been excluded from these studies due to the recommendation 
that RBV not be administered to patients with Cr clearance <50 mL/min. In addition, study 
P7977-0915 has shown the major circulating metabolite of SOF, GS-331007, is renally 
cleared and a single dose study conducted in subjects with severe renal impairment or 
end-stage renal disease on hemodialysis demonstrated exposures approximately 1.6-fold and 
14 to 22-fold higher, respectively, than those observed in matched controls with normal renal 
function. Whilst dose reduction of SOF would reduce these exposures, viral efficacy is 
dependent on SOF exposures such that lower SOF doses or intermittent administration could 
be associated with reduced efficacy. Thus, this exploratory study of safety and efficacy of 
standard (400 mg) and reduced (200 mg) doses of SOF in combination with low-dose RBV 
in a small number of subjects will provide important data regarding dosing recommendations 
for use of SOF in this patient population with a high unmet medical need.
Phase 3 studies of SOF+RBV for 12 or 16 weeks in treatment-naïve and 
treatment-experienced genotype 3 HCV-infected subjects demonstrated SVR12 rates of 56% 


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and 62%, respectively. Increasing treatment duration to 24 weeks may further improve 
response rates. In Phase 2 studies of SOF+RBV for 12 or 24 weeks in treatment-naïve 
genotype 1 HCV-infected subjects, SVR rates have varied from 47% to 84% depending on 
the study and patient population. In both genotypes 1 and 3, lower doses of RBV have been 
associated with reduced efficacy of the regimen. Given the safety need for a reduced RBV 
dose in the current study (Section 1.6), treatment with SOF+RBV will be administered for 
24 weeks to maximize efficacy. Subjects with genotypes 1 or 3 HCV infection have been 
selected for this study since they represent the largest group of HCV-infected individuals in 
the regions where this study will be conducted and because the 24 week treatment regimen is 
appropriate. In contrast, genotype 2 HCV-infected subjects have been shown to have high 
response rates following 12 weeks of SOF+RBV therapy. If SOF+RBV is well tolerated for 
24 weeks in patients with severe renal insufficiency, safety for 12 weeks in this smaller HCV 
population may be inferred.
1.5.
Rationale for SOF Dose Selection 
Sofosbuvir 400 mg, once daily, when dosed in combination with RBV with or without PEG 
has demonstrated broad genotypic efficacy and a favorable safety profile in over 
3300 HCV-infected subjects across multiple patient populations in Phase 2 and 3 trials.  This 
dose (400 mg) is the proposed to be marketed dose of sofosbuvir for the treatment of 
HCV-infection.  
In study P7977-0915, a single dose PK study in subjects with varying degrees of renal 
impairment, exposure (AUCinf) of sofosbuvir and the renally eliminated metabolite, 
GS-331007, were 2.7- and 5.5-fold higher respectively in subjects with severe renal 
impairment compared to matched controls with normal renal function.  A significant dose 
reduction (eg, 2- to 4-fold) of sofosbuvir would be necessary to provide comparable 
GS-331007 exposures in subjects with severe renal impairment and those with normal renal 
function. Data from dose-finding and Phase 2 studies demonstrated that sofosbuvir, dosed 
once daily, was necessary to provide the active anabolite at the site of action (circulating 
GS-331007 cannot be phosphorylated to the active anabolite); therefore, dose interval 
modifications may not be appropriate. The efficacy of a substantially reduced dose of 
sofosbuvir in subjects with severe renal impairment has not been established.  
Part 1 of this study will evaluate the safety, efficacy and pharmacokinetics of 2 doses of 
sofosbuvir in subjects with severe renal impairment; the reduced dose of 200 mg sofosbuvir 
is expected to provide sofosbuvir systemic exposures that are comparable to the 400 mg dose 
in subjects with normal renal function function and GS-331007 exposures that are 
approximately 2.2-fold above those observed in subjects with normal renal function at the 
400 mg dose. Safety, efficacy and pharmacokinetic data from the 200 mg and then the 
400 mg dose of sofosbuvir in Part 1 will inform the initiation of Part 2.  In Part 2, the safety, 
efficacy and pharmacokinetics of SOF at a dose of 200 mg and then 400 mg will be 
evaluated in subjects with End Stage Renal Disease (ESRD) on dialysis.  In study 
P7977-0915, exposure (AUCinf) of sofosbuvir and GS-331007, were 1.6 fold and 14 to 22-
fold higher respectively in subjects with ESRD compared to matched controls with normal 


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renal function.  Dose reduction of sofosbuvir to mitigate increased GS-331007 exposure in 
subjects with ESRD may result in suboptimal sofosbuvir exposure.  As such, in this patient 
population with a high unmet medical need, to balance both safety and efficacy, the 200 mg 
and 400 mg dose will be evaluated in Part 2 in subjects with ESRD.
1.6.
Rationale for RBV Dose Selection
Ribavirin increases treatment response rates when administered with interferon or PEG. In 
addition, reducing the RBV dose from 1000-1200 mg/day to 600 or 800 mg/day when given 
in combination with SOF reduced SVR rates, as did SOF monotherapy. It is therefore 
desirable to keep RBV as part of the SOF treatment regimen. Since RBV is cleared renally 
and its main toxicity is hemolytic anemia which is poorly tolerated in patients with advanced 
renal insufficiency who are usually anemic at baseline and have little bone marrow reserve, 
the starting dose of RBV must be substantially lower than 1000-1200 mg/day. For this study, 
a dose of 200 mg/day has been selected based on investigator input in light of the high 
frequency of hemotoxicity of RBV and the general desire to optimize the efficacy of the 
treatment regimen {24149}.
1.7.
Overall Risk/Benefit Assessment
To date there has been no safety signal identified that is attributable to SOF when 
administered as part of a combination regimen. Furthermore, SOF does not exacerbate the 
toxicities associated with RBV, most notably hemolytic anemia. Clinical data with SOF in 
severe renal insufficiency and in subjects requiring hemodialysis is limited to a single dose 
study in non-HCV infected subjects. No specific safety signals were identified. The current 
study is designed to assess the safety and efficacy of therapeutic treatment with SOF+RBV in 
a small number of subjects with severe renal insufficiency. The 2-part stepwise design will 
allow a full review of the risk/benefit of both doses and treatment arms in patients with Cr 
clearance <30 mL/min before proceeding to the cohort of patients on dialysis who are 
predicted to have higher SOF and GS-331007 exposures. 
The potential benefit of successful treatment of HCV in these subjects is substantial. Few 
patients with severe renal insufficiency can tolerate combination therapy with PEG+RBV 
due to profound anemia. SVR rates to interferon monotherapy administered for 48 weeks are 
less than 50%. Interferon-free treatment for 24 weeks could provide substantial 
improvements in safety, tolerability and efficacy for individuals with chronic HCV infection 
and end stage renal disease.


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2. 
OBJECTIVES 
The prima1y objectives of this study are: 
Final 
Amendment 1 
• 
To evaluate the safety of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks as assessed by review of the accumulated safety data in each treatment ann 
• 
To evaluate the efficacy of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks measured by the proportion of subjects with renal insufficiency who have 
achieved a sustained viral response 12 weeks after treatment discontinuation (SVR12) in 
each treatment rum 
• 
To evaluate the steady state phrumacokinetics ofSOF and its metabolites upon dosing 
SOF 200 mg or 400 mg in subjects with renal insufficiency 
The secondruy objectives of this study ru·e: 
• 
To evaluate the prop01iion of subjects with renal insufficiency who attain SVR at 4 and 
24 weeks after discontinuation of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of plasma HCV RNA during and after treatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF during and after treatment 
discontinuation 
The explorat01y objective of this study is: 
IT 
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3.
STUDY DESIGN
This is a multicenter, open label study that will evaluate the safety, tolerability and antiviral 
efficacy of SOF with RBV in chronic renal insufficiency and HCV infection subjects with 
genotype 1 or genotype 3 HCV infection, including those with compensated cirrhosis.
This study will have 2 parts. 
Part 1 will enroll approximately 20 subjects with severe renal insufficiency. 

10 subjects will receive SOF 200 mg QD + RBV 200 mg QD for 24 weeks.

Following review of safety, efficacy and PK data through post-treatment Week 4 of the 
Part 1 SOF 200 mg group, 10 additional subjects will receive SOF 400 mg QD + RBV 
200 mg QD for 24 weeks.
Part 2 will enroll approximately 20 subjects on dialysis following review of safety, efficacy 
and PK data through post-treatment Week 4 of Part 1 SOF 400 mg group.  

10 subjects will receive SOF 200 mg QD + RBV 200 mg QD for 24 weeks.

Following review of safety, efficacy and PK data through post-treatment Week 4 of the 
Part 2 SOF 200 mg group, 10 additional subjects will receive SOF 400 mg QD + RBV 
200 mg QD for 24 weeks.
3.1.
Treatment Plan and Regimen
In Part 1, following screening procedures and Day 1 assessments, eligible subjects will 
receive either SOF 200 mg or 400 mg QD + RBV 200 mg QD for 24 weeks.
In Part 2, following screening procedures and Day 1 assessments, eligible subjects receive 
either SOF 200 mg or 400 mg QD + RBV 200 mg QD for 24 weeks. 
Additional information about study drug administration can be found in Section 5.
3.2.
Visit Schedule
All subjects will complete screening, on-treatment and post-treatment assessments. Screening 
assessments will be completed within 42 days of the Day 1 visit. All subjects will complete 
the Week 4 Post-Treatment visit. Weeks 12 and 24 Post-Treatment visits will be dependent 
on subject viral load.
The assessments performed at each visit are described in Section 6.


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3.3.
Virologic Response-Based Stopping Criteria
The following stopping criteria will be used for subjects on treatment:

Confirmed HCV RNA ≥LLOQ after 2 consecutive HCV RNA <LLOQ

Confirmed >1 log10  increase from nadir 

Confirmed HCV RNA ≥LLOQ after 8 weeks of treatment
Confirmation should be performed as soon as possible but within 2 weeks after determination 
of initial observation.
3.3.1.
Cardiac Function-Based Stopping Criterion
The following stopping criterion will be used for subjects on treatment:

Left ventricular ejection fraction ≤40%
3.4.
Treatment Discontinuation Criteria
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication must be discontinued in the following instances:

Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises 
the ability to continue study-specific procedures or is considered to not be in the subject’s 
best interest.

Pregnancy of female subject, or female partner of male subject.

Efficacy failure as defined in Section 3.4.

Declining cardiac function, defined as left ventricular ejection fraction ≤40%.

Significant protocol violation including non-compliance with study assessments. 

Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy or other reason.

Discontinuation of the study at the request of Gilead, regulatory agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC).
Subjects who discontinue treatment earlier than the assigned 24-week treatment duration will 
complete an Early Termination Visit (Section 6.7).


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3.5.
Registry Studies
3.5.1.
Sequence Registry Study
Subjects who do not achieve SVR will be eligible for enrollment in the Sequence Registry 
Study where available and approved. The purpose of the Sequence Registry Study will be to 
monitor the persistence of resistant mutations for up to 3 years. The Sequence Registry Study 
is described in a separate protocol (GS-US-248-0123).
3.5.2.
SVR Registry Study
All subjects who achieve SVR will be eligible for enrollment in the SVR Registry Study
where available and approved. The purpose of the SVR Registry Study will be to evaluate 
durability of SVR for up to 3 years post-treatment. The SVR Registry Study is described in a 
separate protocol (GS-US-248-0122).


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 40 subjects will be treated in this study.
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) Chronic HCV infection documented by either:
a) a positive anti-HCV antibody test or positive HCV RNA or positive HCV genotyping 
test at least 6 months prior to the Day 1 visit, or
b) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV 
infection
4) Infection with HCV GT 1 or 3 as determined at Screening
5) Subjects must have the following laboratory parameters at Screening: 
a) HCV RNA 104 IU/mL
b) ALT 10 the upper limit of normal  (ULN)
c) AST 10 ULN
d) Hemoglobin  9 g/dL 
e) Albumin 3.0 g/dL
f)
Direct bilirubin 1.5 x ULN
g) HbA1c 10%


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h) Creatinine clearance (CLcr) 30 mL/min, as calculated by the Cockcroft-Gault 
equation {2202} using ideal body weight (IBW). For Part 1 subjects, CLcr  ≤ 30 
mL/min and not on dialysis, and for Part 2 subjects,on dialysis 
Male:
CLcr (mL/min) = [140 - age (years)] IBW(kg)
72 Scr
Female:
CLcr (mL/min) = [140 - age (years)] IBW(kg) 0.85
72 S
Scr = serum creatinine (mg/dL)
Ideal body weight (IBW) is estimated by the following equations: 
      Males:                   
IBW (kg) = 50 kg + 2.3 kg for each inch over 5 feet
Females: 
            IBW (kg) = 45.5 kg + 2.3 kg for each inch over 5 feet
a.
Subjects with CLcr 30-40 mL/min are eligible if they have a prior 
CLcr 30 mL/min within 6 months of Screening
6) INR 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR.
7) A negative serum pregnancy test for female subjects of childbearing potential (see
Appendix 2 for definition). 
8) Male subjects and female subjects of childbearing potential (see Appendix 2 for 
definition) must agree to use protocol specified method(s) of contraception as described 
in Appendix 2.
9) Lactating females must agree to discontinue nursing before administration of study drug.
10) Subject must be of generally good health as determined by the Investigator. 
11) Subject must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) BMI < 18
2) Prior exposure to an direct-acting antiviral targeting the HCV NS5B polymerase


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3) Prior null response to PEG+RBV therapy 
4) Male with pregnant female partner
5) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency, cholangitis)
6) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)
7) Unstable psychiatric condition 
8) Significant cardiac disease including:
a) Cardiomyopathy
b) Left ventricular ejection fraction ≤50%
c) Hospital admission for myocardial infarction or heart failure within 1 year of 
Screening 
9) Clinically significant abnormality on ECG at Screening, including a QT prolongation 
>500 msec, or >450 msec in patients who concomitantly use methadone.
10) History of clinically significant hemoglobinopathy
11) History of porphyria
12) Malignancy within the 5 years prior to screening, with the exception of specific cancers 
that are cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation 
for possible malignancy are not eligible.
13) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone 
equivalent > 10 mg/day)
14) Clinically-relevant drug or alcohol abuse within 12 months of Screening
15) Current or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, 
encephalopathy or variceal hemorrhage)
16) History of clinically-significant illness or any other major medical disorder that may 
interfere with subject treatment, assessment or compliance with the protocol
17) History of a primary gastrointestinal disorder (or post operative condition) that could 
interfere with the absorption of the study drug 


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18) Excessive alcohol ingestion, defined as 3 glasses/day (1 glass is equivalent to: beer 
[284 mL], wine [125 mL], or distilled spirits [25 mL]) for females and 4 glasses/day for 
males)
19) Inability to collect blood for safety, PK, and efficacy throughout the study
20) Donation or loss of more than 400 mL blood within 2 months prior to Day 1 
21) Use of any prohibited concomitant medications as described in Section 5.7 within 
21 days of the Day 1 visit
22) Known hypersensitivity to RBV, the study investigational medicinal product, the 
metabolites, or formulation excipients
23) Receipt of any investigational product within a time period equal to 10 half-lives of the 
product, if known, or a minimum of 4 weeks prior to study drug administration
24) Subjects with hepatocellular carcinoma (HCC) are excluded from the study. In cirrhotic 
patients, liver imaging (e.g., ultrasound) within 6 months of Day 1 is required to exclude 
hepatocellular carcinoma (HCC)


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Sofosbuvir (SOF)
5.1.1.
Formulation
SOF tablets, 100 mg, are yellow, round, film-coated, plain-faced tablets. 
SOF tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets debossed with “GSI” on 
one side and “7977” on the other side. 
In addition to the active ingredient, SOF tablets contain the following inactive ingredients: 
mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, and yellow iron 
oxide.
5.1.2.
Packaging and Labeling
SOF tablets, 100 mg, are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 28 tablets and polyester packing material. Each bottle is enclosed with a 
white, continuous thread, child-resistant screw cap with an induction-sealed, aluminum-faced 
liner.
SOF tablets, 400 mg, are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 30 tablets and a silica gel desiccant canister or sachet and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant screw cap 
with an induction-sealed, aluminum-faced liner.
SOF bottles to be distributed to centers in the US and other countries shall be labeled to meet 
all applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 of 
Good Manufacturing Practices: Manufacture of investigational medicinal products 
(February 2010) and/or other local regulations as applicable.
5.1.3.
Storage and Handling
SOF bottles should be stored at a controlled room temperature until required for 
administration. Controlled room temperature is defined as 25 C (77 F); excursions are 
permitted between 15 C and 30 C (59 F to 86 F).
All drug products should be stored in a securely locked area, accessible only to authorized 
site personnel. To ensure the stability of the study drug and to ensure proper product 
identification, the drug product should not be stored in a container other than the container in 
which they are supplied. Consideration should be given to handling, preparation, and 
disposal through measures that minimize drug contact with the body. Appropriate 
precautions should be followed to avoid direct eye contact or exposure through inhalation 
when handling SOF.


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Sufficient quantities of SOF tablets to complete the entire study will be shipped to the 
investigator or qualified designee from Gilead Sciences Materials & Logistics (or its 
designee).
5.1.4.
Sofosbuvir (SOF) Dosage and Administration 
SOF will be administered as 200 mg or 400 mg po daily. SOF (100 mg or 400 mg) tablets
will be supplied by Gilead Sciences for all subjects.
5.2.
Ribavirin (RBV)
5.2.1.
Formulation
RBV tablets, 200 mg, are blue, capsule-shaped, film-coated tablets debossed with “3RP” on 
one side and “200” on the other side. In addition to the active ingredient, RBV tablets contain 
the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, 
croscarmellose sodium, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, 
macrogol, talc, FD&C blue #2.
5.2.2.
Packaging and Labeling
The RBV tablets are packaged in white, HDPE bottles. Each bottle contains 168 tablets and 
rayon coil packing material and is enclosed with a white, continuous thread, child-resistant 
screw cap with an induction-sealed, aluminum-faced liner.  
RBV bottles to be distributed to centers in the US and other countries shall be labeled to meet 
all applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 of 
Good Manufacturing Practices: Manufacture of investigational medicinal products 
(February 2010) and/or other local regulations as applicable.
5.2.3.
Storage and Handling
RBV tablets should be stored at 25 C (77 F); excursions are permitted between 15 and 
30 C (59 and 86 F).
All drug products should be stored in a securely locked area, accessible only to authorized 
site personnel. To ensure the stability of the study drug and to ensure proper product 
identification, the drug product should not be stored in a container other than the container in 
which they are supplied. Consideration should be given to handling, preparation, and 
disposal through measures that minimize drug contact with the body. Appropriate 
precautions should be followed to avoid direct eye contact or exposure through inhalation 
when handling RBV.


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5.2.4.
RBV Dosage and Administration 
RBV will be administered as 200 mg po daily. RBV should be dosed with food and with SOF 
to maximize adherence.
RBV tablets (200 mg) will be supplied by Gilead Sciences for all subjects.
5.3.
Co-administration of Sofosbuvir (SOF) and Ribavirin (RBV)
Each subject will be given instructions to maintain approximately the same daily dosing 
interval between study drug doses.  
If a subject forgets to take the medication at the correct time, it may be taken later in the day; 
however, no more than 400 mg dose of SOF should be taken on any calendar day. The 
subject should resume the standing dosing schedule on the next day.  Study medications 
should not be cut or split.  No food restrictions apply to SOF; however, SOF should be taken 
with RBV and with food for optimal adherence.
On the day of clinic visits, subjects will be instructed to take their study medication on the 
day prior to clinic visits, 20-28 hours before the administration of the study medication at the 
clinic. Subjects should bring their medication with them to the clinic and take their study 
medication after all pre-dose assessments are completed. 
5.4.
Study Drug Compliance
On Day 1, subjects will be administered study drugs and the assigned bottles will be 
dispensed to them along with a dosing diary to be used to document at home dosing. Subjects
will be instructed to return dosing diaries and any unused study drug in the original container 
at each visit following Day 1 for study drug compliance assessment.
Returned medication will be reconciled by the investigator in order to monitor the subject’s 
compliance with the medication regimen.
5.5.
Dispensing and Accountability of Study Drugs
The Investigator (or designee, e.g., study center pharmacist) will acknowledge receipt of the 
study drugs (after reviewing the shipment’s content and condition) from Gilead Sciences (or 
designee). The Investigator will maintain an accurate inventory of all study drugs. Each dose 
of the study drug(s) administered at the study center will be administered by qualified study 
center personnel. All doses of study drug(s) administered to subjects in the clinic under the 
supervision of staff will be accurately recorded on the Investigational Product Inventory Logs 
provided by Gilead Sciences (or on equivalent documentation maintained by the study 
center), which indicates the date and quantity of all doses of study drug(s) dispensed to 
individual subjects. The requirements of all applicable Federal and State drug dispensing 
laws will apply to all doses of study drugs dispensed by the Investigator (or designee). At the 


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end of the study, all unused study drugs (both bulk and individual subject returns) will be 
returned to a location designated by Gilead Sciences.
5.6.
Study Drug Return or Disposal
At the start of the study, the study monitor will evaluate each study center’s study drug 
disposal procedures and provide appropriate instruction for return or destruction of unused 
study drug supplies. If the site has an appropriate Standard Operating Procedure (SOP) for 
drug destruction, the site may destroy used and unused study drug supplies performed in 
accordance with the site’s (hospital/pharmacy) SOP. If the site does not have acceptable 
procedures in place for drug destruction, arrangements will be made between the site and 
Gilead Sciences (or Gilead Sciences’ representative) for return of unused study drug 
supplies. Where possible, study drug will be destroyed at the site.  If drug is destroyed on 
site, the investigator must maintain accurate records for all study drug destroyed. All study 
drug records must be maintained at the site and copies must be submitted to Gilead Sciences 
at the end of the study.
5.7.
Concomitant Medications
Concomitant medications taken within 30 days of Screening, up to and including the date of 
the visit four weeks after discontinuation of study treatment, need to be recorded in the 
source documents and eCRFs.
The following medications are prohibited from 21 days prior to the Day 1 visit through the 
end of treatment:

Drugs disallowed per prescribing information of RBV (COPEGUS®)

Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters i.e. P-gp) with study drug(s) may result in pharmacokinetic interactions 
resulting in decreases in exposure of study drug(s).  Representative medications which 
are excluded from 21 days prior to Day 1 through the end of treatment are listed below:
Drug
Agents Disallowed
Concomitant use with study drug may 
potentially result in changes of study 
drug concentration as listed below
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Decrease in concentration of study drug
Antimycobacterials
Rifampin, rifabutin, rifapentine
Decrease in concentration of study drug
Herbal/Natural 
Supplements
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-
to (or Xiao-Shai-Hu-Tang)
Decrease in concentration of study drug
Other
Modafinil
Decrease in concentration of study drug


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Medications for disease conditions excluded from the protocol (e.g., HIV-1 infection, active 
cancer, transplantationare not listed under this Concomitant Medication section and are 
prohibited in the study.
5.7.1.
Medications Associated with QT Prolongation
Medications that are known to cause or are associated with QT prolongation and/or a risk of 
causing torsades de pointes should be avoided in patients with risk factors for developing 
long QT intervals or those receiving other QT-prolonging medications.  These medications 
include, but may not be limited to those listed below (see table below) and must be approved 
by the Gilead Medical Monitor prior to study enrollment or coadministration during the 
study.  
Representative List of Medications Known or Associated with QT Prolongation
QT Prolonging Medication Class
Known or Strongly Suspected to cause 
QT Prolongation
Weaker Association with 
QT Prolongation
Antibiotics/Anti-infectives:
Macrolide Antibiotics
azithromycin, clarithromycin, 
erythromycin, roxithromycin, 
telithromycin
Quinolone Antibiotics
gatifloxacin, gemifloxacin, levofloxacin, 
moxifloxacin, ofloxacin, sparfloxacin
ciprofloxacin
Certain 
antimalarials/pneumocystis 
prophylaxis; others
artenimool+piperaquine, bedaquiline, 
chloroquine, halofantrine, pentamidine
trimethoprim-sulfa, quinine 
sulfate
Antipsychotics:
Phenothyazine 
Antipsychotics
chlorpromazine, mesoridazine, 
thioridazine
Other Antipsychotics
clozapine, haloperidol, iloperidone, 
olanzepine, paliperidone, pimozide, 
quetiapine, risperidone, sertindole, 
ziprasidone
amisulpride,
Anit-mania Bipolar Disorders:
lithium
Anti-depressants:
Serotonin re-uptake 
inhibitors
citalopram, escitalopram, venlafaxine
fluoxetine, paroxetine, 
sertraline
Tricyclic anti-depressants
amitriptyline, 
clomipramine, 
desipramine, doxepin, 
imipramine, nortriptyline, 
protriptyline trimipramine,
Tetracyclic anti-
depressants
mirtazepine
trazodone


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QT Prolonging Medication Class
Known or Strongly Suspected to cause 
QT Prolongation
Weaker Association with 
QT Prolongation
Cardiology Medications:
Class I (Na+) and III (K+) 
anti-arrhythmics
amiodarone, disopyramide, dofetilide, 
dronedarone, flecainide, ibutilide, 
mexiletine, procainamide, quinidine
Class II (β blockers) and 
IV (Ca2+) anti-arrythmics
isradipine, sotalol (Class II/III)
Certain anti-anginals/ 
calcium blocker
bepridil, nicardipine, ranolazine
Anesthetics, Pain Medications 
and Additional Treatment:
levomethadyl, methadone
general anesthetics (e.g., 
enflurane, halothane, 
isoflurane, sevoflurane)
Anti-nausea:
domperidone, droperidol, dolasetron, 
granisetron, ondansentron, promethazine
Azole anti-fungals (systemic use 
only)
ketoconazole, voriconazole
fluconazole, itraconazole
Others:
alfuzosin, amantadine, astemizole, 
cisapride, famotidine, felbamate, 
fosphenytoin, galantamine, indapamide, 
moexipril/HCTZ, octreotide, oxytocin, 
pasireotide, perflutren lipid microspheres, 
probucol, sibutramine, terfenadine,   
tizanidine, tolterodine, vardenafil
chloral hydrate, 
diphenhydramine, 
solifenacin
a
Should it become medically necessary for patients to start treatment with any excluded concomitant medication, the 
sponsor must be consulted prior to initiation of the new medication and the subject’s continued participation must be 
discussed with the Gilead Medical Monitor.
5.7.2.
Hematopoietic Growth Factors
Erythropoiesis stimulating agents (ESAs) should not be used during Screening solely to 
elevate hematology laboratory parameters to facilitate entry into the study.  Patients taking 
ESAs for anemia related to chronic kidney disease may enter the study. Granulocyte colony-
stimulating agents and thrombopoietic growth factors should not be used while the subject is 
receiving study treatment. 


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in
Table 6-1 and described in the following text. 
Any deviation from protocol procedures should be noted in the subject’s clinical chart and 
appropriate eCRFs. In addition, the Sponsor should be promptly notified of any protocol 
deviations. 
The study center will not be released to initiate dosing until:

The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) reviewed 
and approved the study and the informed consent document;

All requested regulatory documents have been submitted to and approved by 
Gilead Sciences;

A Master Services Agreement and/or Study Agreement is executed;

The study initiation meeting has been conducted by the Gilead Sciences clinical monitor 
(or designee).
The initiation meeting will include a review of the protocol, the Investigator’s Brochure, and 
Investigator responsibilities.
Documentation of the personally signed and dated informed consent of each subject, using 
the study-specific informed consent form (ICF), is required before initiating the screening 
process. Generic screening consent forms should not be used in lieu of the study-specific 
ICF.
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that subjects are eligible to participate in 
the study prior to enrollment and throughout the study.
Once consent has been obtained, all screening tests and procedures have been assessed, and 
study eligibility has been confirmed, subjects will be enrolled and assigned a unique subject 
identification number.
Subjects will receive the study treatment as described in Section 5.


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Table 6-1.
Schedule of Assessments
Study Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment 
Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Written Informed 
Consent
X
Medical History 
X
HCV RNA 
Genotype
X
IL28B Genotyping
X
HbA1c  
X
HCV, HBV, HIV 
Serology
X
TSH
X
Physical Exam, 
including Vital 
Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram 
X
X
X
Height
X
Weight
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Study Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment 
Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Coagulation (PT, 
PTT, and INR)
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA Viral 
Load
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA 
Sequencing 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy 
Teste
X
X
X
X
X
X
X
X
X
X
X
X
Creatinine 
Clearance
X
Optional 
Pharmacogenetic 
Sample
X
Intensive PK
Xf
Xf
Trough PK Sampleg
X
X
X
X
X
X
X
X
X
Archive Plasma 
Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
Administration
X
Weeks 1 -24


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Study Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment 
Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Review Dosing 
Diary/Perform 
Accountabilityh
X
X
X
X
X
X
X
X
X
X
AEs/
Concomitant Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Screening evaluations must be completed within 42 days prior to Day 1.
b
Day 1 tests and procedures must be completed prior to administration of the first dose of study drugs 
c
Within 72 hours of permanently discontinuing study drug.
d
Full PE at Day 1 and ET visits only; symptom-directed PE at all other timepoints. Vital signs include blood pressure, pulse, respiration rate, and temperature
e
Females of childbearing potential only. To confirm eligibility at Day 1, a urine pregnancy test may be collected for subjects able to pass urine. For subjects unable to pass 
urine, a serum pregnancy test at Day 1 must be performed at a local lab prior to dosing to confirm eligibility along with sample collected and send to central lab. During post-
treatment of the study, serum or urine pregnancy testing will occur every month during non-clinic post treatment visits. The subject will be contacted by telephone to confirm 
that pregnancy testing has been performed post-treatment during non-clinic visits.
f
Intensive plasma PK evaluations will be assessed at the following timepoints: 0 (predose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose. In Part 2 (ESRD 
subjects on dialysis), the Week 2 and 12 visits (intensive PK assessments) must be conducted the same number of days after the previous dialysis session.
g
Trough plasma PK samples will be drawn prior to dosing. 
h
Dosing Diaries will be completed for all non-observed doses and will be reviewed at every visit. Unused study drug will be returned to perform study drug accountability in 
the original container at each visit following Day 1 for study drug compliance assessment.
i
A window of ± 2 days is allowed for the treatment visits on weeks 1, 2, and 12.  A window of ± 4 days is allowed for the treatment visits weeks, 4-10, and 16-24. Subjects 
who cannot complete their study visit per the visit schedule should ensure they do not run out of study drug prior to their next study visit.  Compliance is critical to ensure 
adequate drug exposure.
j
A window of ± 7 days is allowed for the post treatment visits.


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6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Prospective subjects should be screened within 42 days prior to first dose on Day 1. If the 
subject does not begin the treatment phase within this 42-day window, all screening 
evaluation procedures must be repeated. No more than one repeat screen visit is allowed for 
each subject, unless prior written approval has been provided by the Sponsor.
Written informed consent must be obtained from each subject before initiation of any
screening procedure. After a subject has provided informed consent, the investigator and 
other study personnel will determine if the subject is eligible for participation in the study.  
This assessment will include a review of the inclusion/exclusion criteria and completion of 
all screening procedures as outlined in Table 6-1.
Once eligibility is confirmed, the study site will complete an eligibility worksheet for each 
screened subject and submit for Sponsor review. The sponsor will assign a unique subject 
number for each eligible subject and provide the subject number information to the site prior 
to Day 1 visit. 
6.2.2.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and 
whether condition(s) is currently ongoing, and medication history will be collected on all 
subjects during screening. Information related to HCV infection will be collected. In 
addition, a cirrhosis determination will be made as follows:
Cirrhosis determination

Cirrhosis is defined as any one of the following:
— Liver biopsy showing cirrhosis
— Fibroscan (in countries where locally approved) showing cirrhosis or results 
> 12.5 kPa
— FibroTest® score of > 0.75 AND an AST:platelet (APRI) ratio of > 2 during 
Screening

Absence of cirrhosis is defined as any one of the following:
— Liver biopsy within 2 years of Screening showing absence of cirrhosis
— Fibroscan (in countries where locally approved) with a result of ≤12.5 kPa within 
≤6 months of Day 1
— FibroTest® score of ≤ 0.48 AND APRI of ≤1 during Screening


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In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above 
criteria, a liver biopsy is required.
In addition, a determination of cardiac function will be made as follows:

Echocardiogram demonstrating left ventricular ejection fraction > 50% performed prior 
to Day 1 visit.  Enrollment allowed based on local read of study if central read is not 
available.   
6.3.
Day 1 Assessments
Subjects meeting all eligibility criteria following the screening evaluation will return to the 
study site within 42 days for Day 1 assessments as outlined in Table 6-1.
6.3.1.
Dosing Diary
Subjects will be provided with self-administration instructions and study drug diaries to 
record the exact date, time and number of tablets of study drug administration.  The site staff 
will record the information from the study drug dosing diary into the eCRF.  In the event that 
the dosing diary is not available, the site may obtain dosing information via subject interview 
and record this information in the source notes
6.4.
Treatment Assessments
Study visits will occur at the end of Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24.
Study procedures and assessments are outlined in Table 6-1. 
6.5.
Safety Assessments
Safety will be evaluated throughout the study. Refer to Table 6-1 for a schedule of 
assessments.
6.5.1.
Safety ECGs
Subjects should rest quietly in the supine position for a minimum of 10 minutes prior to each 
scheduled ECG acquisition and should remain in that position until the recording is complete. 
There must be no environmental distractions (television, radio, conversation, etc.) while the 
subjects are resting prior to and during the recordings.
ECGs will be recorded at a sampling frequency of 500+ Hz, at a speed of 25 mm/sec and at a 
standard duration of 10 seconds. All ECGs will be obtained using instruments that analyze 
data using the same algorithms and produce the same data for interpretation. When ECGs are 
performed on an ECG machine, site standard operating procedures (SOPs) will be used.
ECG measurements will be collected pre-dose at time-points as per Table 6-1.
The Investigator or other qualified individuals at the study center will review ECGs to assess 
for changes in ECG intervals and morphology as compared to pre-dose ECGs. Collection of 


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additional ECGs for routine safety monitoring at additional time-points or days is at the 
discretion of the Investigator based on GCP.
6.5.2.
Safety echocardiograms
Safety echocardiograms will be performed as outlined in Table 6-1.  A window of ± 10 days 
is allowed for the on-treatment visits. These safety echocardiograms will be performed
locally and sent to a central location for standardized reading.  
6.5.3.
Physical Examination
Complete physical examinations or a symptom directed physical examination will be
conducted pre-dose as outlined in Table 6-1. A complete physical examination must include 
source documentation of general appearance, and the following body systems: head, neck 
and thyroid; eyes, ears, nose, throat, mouth and tongue; chest (excluding breasts); respiratory; 
cardiovascular; lymph nodes, abdomen; skin, hair, nails; musculoskeletal; neurological. 
6.5.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, 
respiratory rate, and temperature and will be conducted pre-dose as outlined in Table 6-1.
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.
6.5.5.
BMI
Height and weight will be collected at the times shown in the schedule of assessments 
Table 6-1.
BMI is calculated by the following equation.
BMI = weight (pounds) 703           or            weight in kilograms
   (height in inches)2                                (height in meters)2
6.5.6.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {2202} using ideal body 
weight (IBW). 


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Male:
CLcr (mL/min) = [140 - age (years)] IBW(kg)
72 Scr
Female:
CLcr (mL/min) = [140 - age (years)] IBW(kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
Ideal body weight (IBW) is estimated by the following equations: 
      Males:                   
IBW (kg) = 50 kg + 2.3 kg for each inch over 5 feet
Females: 
            IBW (kg) = 45.5 kg + 2.3 kg for each inch over 5 feet
6.5.7.
Clinical Laboratory Tests/Assessments
In addition to the PK blood samples that will be collected, blood samples will be collected 
pre-dose as outlined in the schedule of assessments, Table 6-1 for the following laboratory 
analyses:
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, MCV, 
and Coagulation Panel (PT, PTT, and INR).
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase 
(AST/SGOT), Albumin, Alkaline phosphatase, Creatinine, Total Bilirubin (reflex to Direct 
Bilirubin), Glucose, Total Protein, Bicarbonate, BUN, Calcium, Chloride, Phosphorus, 
Magnesium, Potassium, Sodium, and FibroTest®.
Thyroid-stimulating hormone (TSH)
Haemoglobin A1C (HbA1c)
Virological Tests: Serologies for HCV, HBV and HIV. HCV RNA will be measured using 
COBAS® AmpliPrep/COBAS® TaqMan® HCV Test. HCV genotype and subtype will be 
determined using the Siemens VERSANTHCV Genotype INNO-LiPA 2.0 Assay. Gilead 
reserves the right to use alternate assays for HCV RNA and HCV genotype should the above 
assays become unavailable or are not definitive.
Viral RNA Sequencing / Phenotyping plasma samples will be collected to confirm virologic 
breakthrough. Untested samples may be archived.


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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: All females of childbearing potential will have serum or urine pregnancy 
testing every 4 weeks during the dosing period and for a minimum of 6 months following the 
last dose of RBV. If required by local regulations, additional pregnancy tests may be 
collected. In the event of a positive urine pregnancy result, subjects will be instructed to stop 
study drugs immediately and return to the clinic as soon as possible for a serum pregnancy 
test.
Pregnancy tests must be completed for all females of childbearing potential (see Appendix 2
for definition) as specified in Table 6-1. When feasible for subjects, a urine pregnancy test 
may also be taken. During post treatment of the study, subject will be contacted by telephone 
monthly to confirm that the serum or urine pregnancy testing has been performed 
post-treatment during non-clinic visits.. Alternatively, if required by local regulations or 
preferred by the investigator or subject, the subject may return to the clinic for urine or serum 
pregnancy tests post treatment.
6.5.8.
Adverse Events/ Concomitant Medications/ Protocol Restrictions
Evaluation for adverse events, review of concomitant medications, and review of protocol 
restrictions will occur at the times shown in the schedule of assessments Table 6-1. See 
Section 7 for more information regarding adverse events and Section 5 for more information 
about concomitant medications.
6.6.
Pharmacokinetic (PK) Assessments
Subjects will be instructed to take their SOF dose on the day prior to clinic visits, 
20-28 hours before the clinic visit. On the day of clinic visits, subjects should bring their 
medication with them to the clinic and take their dose after the trough PK sample is 
collected, or after the predose intensive PK sample is taken.
In Part 2 (ESRD subjects on dialysis), the Week 2 and 12 visits (intensive PK assessments) 
must be conducted the same number of days after the previous dialysis session.
The exact time of the dose taken prior to collection of the PK sample and the exact time the 
PK sample is drawn will be recorded on the appropriate eCRF.
Intensive PK Assessments:
Intensive plasma PK samples will be collected on week 2 and 12 at the following timepoints: 
0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours post-dose.


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Plasma concentrations of SOF and its metabolites will be determined and PK parameters will 
be estimated as appropriate. Plasma concentrations of RBV may be determined, if necessary.
Trough PK Assessments:
Trough PK plasma samples for analyses of SOF, its metabolites and RBV concentrations will 
be collected at all other on treatment visits beginning at the Week 1 visit.
PK Parameters for SOF, its metabolites, and RBV will be estimated as appropriate. 
6.7.
Early Termination (ET)/Unscheduled Visit 
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. 
The assessments at the unscheduled visits are at the investigator’s discretion. At all 
unscheduled visits initiated for the purpose of confirming virologic failure a Viral RNA 
Sequencing / Phenotyping Sample must be collected. 
The Sponsor (e.g. Medical Monitor and Clinical Program Manager)/CRO must be informed, 
as soon as possible, when a subject prematurely discontinues treatment.  The primary reason 
for premature treatment discontinuation must be provided to the Sponsor/CRO.  
If a subject discontinues treatment early for any reason then the following assessments for the 
Early Termination (ET) Visit must be performed: 

Perform complete physical examination

Obtain body weight

Obtain vital signs

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Obtain blood samples for:
— Hematology & Chemistry
— Coagulation (PT, PTT, and INR)
— HCV RNA
— Viral Sequencing / Phenotyping Sample 
— Trough PK
— Serum pregnancy test (females of childbearing potential only)


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Review study dmg adherence with subject including recording the date and time of the 
subject's last dose of study dmg prior to the PK draw (subject should retum all study 
dtugs at this visit) 
All subjects will attend the 4-Week Post-Treatment Visit. 
6.8. 
Post-Treatment Assessments 
Subjects with HCV RNA < LLOQ at the 4-Week Post-Treatment Visit will attend the 
12-Week Post-Treatment Visit. 
Subjects with HCV RNA ~ LLOQ do not need to retum for additional visits and they will be 
tenninated early from the study. 
Subjects with HCV RNA < LLOQ at the Post-Treatment Week 12 Visit will retum at the 
post-treatment Week 24 Visit. 
6.9. 
Optional Samples for Pharmacogenetic Testing 
PPD 
6.10. 
Archived Plasma Sample 
Archive plasma samples will be collected at the study visits, indicated in Table 6-1. Archive 
plasma samples are being collected for possible additional analyses, including but not limited 
to, study dtug or metabolite measurements, viral load, safety/efficacy assessments, HCV 
gene sequencing, HCV resistance testing and other possible predictors of response as 
determined by Gilead. 
In the event of a subject's death or loss of competence, the subject's specimens and data will 
continue to be used as pmi of the future biomm·ker research. 
If a subject wishes to withdraw the testing of his or her specimens for future resem·ch, the 
investigator must inf01m the Gilead Sciences Medical Monitor in writing of the subject's 
wishes. 
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6.11.
Blood Storage
Archived plasma samples will be collected for future testing. These samples will be frozen 
and stored. The stored plasma samples may be used by the Sponsor or its research partner for 
future clinical laboratory testing to provide additional clinical data. At the conclusion of this 
study, these samples may be retained in storage by Gilead Sciences, Inc. at its research 
partner facility for a period up to 10 years.


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


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
In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; and development of drug 
dependency or drug abuse. For the avoidance of doubt, infections resulting from 
contaminated medicinal product will be considered a medically important event and 
subject to expedited reporting requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event 
information and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to 
IMP therapy using clinical judgment and the following considerations:


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
No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, 
an alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally 
related in the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or 
biopsy) should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study 
procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading 
Scale for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs 
associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in 
agreement with the grading of the laboratory abnormality.
7.3.
Investigator Requirements and Instructions for Reporting Adverse 
Events and Serious Adverse Events to Gilead.
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to 
the eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This 
also includes any SAEs resulting from protocol-associated procedures performed from 
screening onwards.
All AEs, regardless of cause or relationship, that occur from initiation of study medication 
until 4 weeks after last administration of study IMP must be reported to the eCRF database as 
instructed. 
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of 
the last dose of study IMP, regardless of causality, should also be reported.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the post-treatment 
follow-up period.
Investigators are not obligated to actively seek SAEs after the post treatment follow-up 
period. However, if the investigator learns of any SAEs that occur after study participation 
has concluded and the event is deemed relevant to the use of IMP, he/she should promptly 
document and report the event to Gilead DSPH.


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All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in 
the eCRF completion guideline. 
• 
At the time of study start, SAEs will be reported using a paper serious adverse event 
rep01ting fo1m. During the study conduct, sites may transition to an electronic SAE 
( eSAE) system. Gilead will notify sites in writing and provide training and account 
inf01mation prior to implementing an eSAE system. 
Serious Adverse Event Paper Rep01ting Process 
• 
All SAEs will be recorded on the serious adverse event rep01i fonn and submitted by 
faxing the report f01m within 24 hours of the investigator's knowledge of the event to the 
attention of Gilead DSPH. 
Electronic Serious Adverse Event (eSAE) Rep01ting Process 
• 
Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
inf01mation to Gilead DSPH within 24 hours 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 inf01mation electr·onically, ie, the 
eCRF database is not ftmctioning, record the SAE on the paper serious adverse event 
rep01ting f01m and submit within 24 hours as described above. 
• 
As soon as it is possible to do so, any SAE rep01ted via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been rep01ted via a paper fonn because the eCRF database has been 
locked, no ftnther action is necessruy. 
Gilead DSPH: 
Gilead Sciences 
Medical Monitor: 
Fax: 
E-mail: 
Nrune: 
Phone: 
Fax: 
E-mail: 
+ 1-650-522-5477 
safety_ fc@gilead.com 
Luisa Stamm, MD, PhD 
PPD 
PPD 
PPD 
• 
For fatal or life-threatening events, copies of hospital case rep01ts, autopsy rep01ts, and 
other documents ru·e also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the tr·aceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensure the timely completion of accurate 
safety rep01ts. 
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Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to 
expedite to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions 
(SADRs), or suspected unexpected serious adverse reactions (SUSARs). In accordance with 
the EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify 
worldwide regulatory agencies and the relevant IEC in concerned Member States of 
applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. 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. 
7.5.
Toxicity Management 
7.5.1.
Stopping Rules for Toxicity
Subjects who meet any of the following criteria should be instructed to immediately stop all 
study drugs and return for an Early Termination Visit:

Confirmed elevation of ALT and/or AST > 5x Day 1 or nadir, confirmed by immediate 
repeat testing

Confirmed elevation of ALT >3x Day 1 and total bilirubin >2 x ULN

Confirmed elevation of ALT >15 x ULN

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event assessed as related to treatment 

Echocardiogram demonstrating left ventricular ejection fraction ≤40%
7.5.2.
Sofosbuvir (SOF)
Administration of SOF may be discontinued due to a clinical or laboratory event.  In the 
event that SOF is stopped, RBV should also be discontinued. 


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7.5.3.
Ribavirin (RBV)
Dose reduction or interruption of RBV due to toxicity should be performed based on the 
clinical experience of the Investigator. RBV may be permanently discontinued due to toxicity 
without stopping SOF. 
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, and 
pregnancy reports regardless of an associated AE.  Also includes reports of adverse reactions 
in infants following exposure from breastfeeding, and reports of adverse reactions associated 
with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following maternal or paternal exposure 
to the medicinal product.
Medication error is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by 
a subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not 
in accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a 
medicinal product given per administration or cumulatively which is above the maximum 
recommended dose as per protocol or in the product labelling (as it applies to the daily dose 
of the subject in question). In cases of a discrepancy in drug accountability, overdose will be 
established only when it is clear that the subject has taken the excess dose(s). Overdose 
cannot be established when the subject cannot account for the discrepancy except in cases in 
which the investigator has reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the 
manufacture, packaging, or distribution of the medicinal product.  
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first 
consents to participate in the study (ie, signs the informed consent) and throughout the study, 
including the post study drug follow-up period, to the Gilead DSPH using the pregnancy 
report form within 24 hours of becoming aware of the pregnancy. Refer to Section 7.3 and 


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the eCRF completion guidelines for full instructions on the mechanism of pregnancy 
reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate 
a pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as 
an SAE. The underlying medical reason for this procedure should be recorded as the AE 
term.
A spontaneous abortion is always considered to be an SAE and will be reported as described 
in Sections 7.1.1 and 7.1.2 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. 
Clinical staff should also report any pregnancies to the Ribavirin Pregnancy Registry at 
1-800-593-2214 (see also http://www.ribavirinpregnancyregistry.com).
Refer to Appendix 2 for Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the 
situation. These reports must consist of situations that involve study IMP, but do not apply to 
concomitant medications. Except for situations that result in AEs, special situations involving 
concomitant medications will not be reported. Any inappropriate use of medications 
prohibited by this protocol should not be reported as “misuse,” but may be more 
appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.


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All clinical sequelae in relation to these special situation reports will be reported as AEs or 
SAEs at the same time using the AE eCRF and/or the SAE report form. Details of the 
symptoms and signs, clinical management, and outcome will be reported, when available.


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The prima1y objectives of this study are as follows: 
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• 
To evaluate the safety of SOF 200 mg or 400 mg + RBV for 24 weeks as assessed by 
review of the accumulated safety data in each treatment rum 
• 
To evaluate the efficacy of SOF 200 mg or 400 mg + RBV for 24 weeks measured by the 
prop01iion of subjects with renal insufficiency who have achieved a SVR12 after 
treatment discontinuation in each treatment ann 
• 
To evaluate the steady state PK ofSOF and its metabolites upon dosing SOF 200 mg or 
400 mg in subjects with renal insufficiency 
The secondruy objectives of this study ru·e as follows: 
• 
To evaluate the prop01iion of subjects with renal insufficiency who attain SVR4 and 
SVR24 weeks after discontinuation of treatment 
• 
To evaluate the kinetics of plasma HCV RNA during and after treatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF during and after treatment 
discontinuation 
The explorat01y objective ofthis study is: 
PPO 
8.1.2. 
Primary Endpoint 
The primary safety endpoints include incidences of AEs, laborat01y, 12-lead ECG, and vital 
sign abn01malities. 
The prima1y PK endpoints ru·e pru·ameters AUCtau, Cmax, and Ctau for analytes SOF, its 
metabolites, and RBV as applicable. 
The prima1y efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after discontinuation 
of therapy). 
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8.1.3.
Secondary Endpoint
Secondary PK endpoints are parameters AUClast, Clast, Tmax, Tlast, λz, and t1/2 for analytes SOF,
its metabolites, and RBV as applicable.
Secondary efficacy endpoints include the proportion of subjects with SVR4 and SVR24, the 
proportion of subjects with virologic failure including viral breakthrough and relapse.
8.1.4.
Other Endpoints of Interest
Additional efficacy evaluations may include HCV RNA change from baseline; ALT 
normalization; viral kinetic parameters, and the health related quality of life endpoints.
8.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses 
will be performed using SASsoftware (SAS Institute, Cary, North Carolina, USA).
The study drugs in this study include SOF and RBV. Last dose of study drug refers to the last 
dose of any of the study drugs in a treatment group and will be used in the definition of 
treatment-emergent AEs and laboratory abnormalities as well as the efficacy endpoints of 
SVR at various post-treatment time points.
All analyses will be presented by treatment in each renal function subgroup (study part). 
Subjects who receive study drug other than that to which they were assigned will be analyzed 
according to the study drug received.
8.2.1.
Analysis Sets
8.2.1.1
Efficacy
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which 
includes subjects who were enrolled and received at least one dose of study drug. 
8.2.1.2
Safety
The primary analysis set for safety analyses will be the Safety Analysis Set which includes
subjects who received at least one dose of study drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose of 
study drug through the date of the last dose of study drug plus 30 days.
8.2.1.3
Pharmacokinetics
The PK analysis set will include all subjects who are enrolled and have received at least 
one dose of study drug and for whom PK concentration data of interested analytes (SOF, its 
metabolites, or RBV) are available. The PK analysis set will be used for analyses of general 
PK.


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8.2.2.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. In general, values 
for missing data will not be imputed. 
For the analysis of post-baseline categorical efficacy endpoints, if a data point is missing and 
is immediately preceded and followed in time by values that are deemed successes, then the 
missing data point will be termed a success; otherwise the data point will be termed a failure.
Any subject with missing data due to premature discontinuation of the study medication will 
be considered a failure at the time points on, or following, the date of discontinuation. If no 
HCV RNA values are obtained after the last dose of study medication, the subject will be 
considered a treatment failure for the SVR endpoints. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject received study medication, the subject will be included in a summary of 
adverse events according to the treatment received; otherwise, if the subject is not dosed 
then they will be excluded from the summary.

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 predose value, then the subject will be excluded from the 
calculation of summary statistics for the predose value and the change from predose 
values.
Values for missing safety laboratory data will not be imputed; however, a missing baseline 
result will be replaced with a screening result, if available. If no pretreatment laboratory 
value is available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) 
for the summary of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for 
calculation of summary statistics for the actual HCV RNA values and the change from 
baseline values by study visit. The reported values will be provided in the HCV RNA listing.
For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed 
to the logarithmic (base 10) scale (log10 IU/mL).
PK concentration values below the lower limit of quantitation (BLQ) will be treated as zero
for determination of summary and order statistics. Individual values that are BLQ will be 
presented as “BLQ” in the concentration data listing. For the presentation of summary and 
order statistics, if at least 1 subject has a concentration value BLQ for the time point, then the 


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minimum value will be displayed as “BLQ.” If more than 50% of the subjects have a 
concentration data value BLQ for the time point, then the minimum and median values will 
be displayed as “BLQ.” If more than 75% of the subjects have a concentration data value of 
BLQ for a given time point, then the minimum. 1st quartile [q1], median, and 3rd quartile 
[Q3] values will be displayed as “BLQ.” If all subjects have concentration data values BLQ 
for the time point, then all order statistics (minimum, first quartile [Q1], median, third 
quartile [Q3], maximum) will be displayed as “BLQ”.
Exposure parameters that are selected for statistical analysis will be natural log-transformed. 
Concentration values that are BLQ will be excluded for any ratio or natural log-transformed 
statistical analysis.
8.2.3.
Interim Analysis
No formal interim analyses are planned for this study. For the purpose of making the decision 
to initiate Part 1 SOF 400 mg. Part 2 SOF 200 mg and Part 2 SOF 400 mg, an informal data 
review of available safety, efficacy, and PK data will be conducted by the Sponsor..
8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline characteristics will be summarized using standard descriptive 
methods by treatment in each study part.
Demographic data will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include body weight/body mass index, HCV RNA level 
(log10 IU/mL), IL28B genotype, baseline ALT level, creatinine clearance estimated by 
Cockcroft-Gault, and additional endpoints as necessary.
8.4.
Efficacy Analysis
8.4.1.
Primary Analysis
The primary efficacy endpoint is SVR12 in the FAS population. The primary analysis will be 
performed after all enrolled subjects have been followed through 12 weeks post-treatment or 
discontinued from study.
A point estimate with a 2-sided 95% exact confidence interval (CI) using the exact binomial 
distribution (Clopper-Pearson method) will be constructed for the SVR12 rate by treatment 
and study part.
No statistical hypothesis testing will be performed.


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Secondary Analysis 
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The prop01tion of subjects with HCV RNA below the LLOQ over time (including SVR12) 
will be presented by treatment and study pmt in tabulm· and graphical f01m . 
Descriptive summm·ies and listings will be provided for additional efficacy evaluations 
including the prop01tion of subjects who experience virologic fail me, AL T n01m alization, 
sennn HCV RNA actual values and change from baseline, other endpoints of interest 
including AL T nonnalization and health related quality of life endpoints. 
PPD 
Details on efficacy analyses will be described in the statistical analysis plan (SAP). 
8.5. 
Safety Analysis 
Safety will be evaluated by assessment of clinical laborat01y tests, physical examinations, 
vital signs measmements, at vm·ious time points dming the study, and by the doclnnentation 
of AEs. 
All safety data collected on or after the first dose of study dmg adminisu·ation up to 30 days 
after the last dose of study dmg will be summm·ized according to the study dmg received. 
Safety endpoints will be sUIIllnm·ized as the number (proportion) of subjects with events or 
abn01m alities for categorical data or as an 8-number summmy (n, mean, standai·d deviation, 
minimum, Ql , median, Q3, maximum) for continuous data .. 
8.5.1. 
Extent of Exposure 
A subject's extent of exposme to study dmg will be generated from the study dmg 
adminisu·ation page of the CRF. Exposme data will be summm·ized by u·eatment and study 
pmt. 
8.5.2. 
Adverse Events 
Clinical and laborat01y AEs will be coded using the Medical Dictionmy for Regulat01y 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Te1m (HLGT), 
High-Level Te1m (HLT), Prefened Te1m (PT), and Lower-Level Te1m (LLT) will be 
attached to the clinical database. 
Events will be sUIIllnarized on the basis of the date of onset for the event. A 
u·eatment-emergent adverse event will be defined as any new or worsening adverse event that 
begins on or after the date of first dose of study dmg up to the date of last dose of study dmg 
plus 30 days. 
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Summaries (number and percentage of subjects) of treatment-emergent adverse events (by 
SOC and preferred term) will be provided by treatment and study part:

All AEs,

All study drug-related AEs,

Combined Grade 2, 3 and 4 AEs,

Combined Grade 3 and 4 AEs,

Combined Grade 2, 3 and 4 study drug-related AEs,

Combined Grade 3 and 4 study drug-related AEs,

All AEs that caused permanent discontinuation from study drug,

All AEs that caused change in dose or temporary interruption of study drug,

All SAEs (including death), and

All study drug-related SAEs
All AEs collected during the course of the study will be presented in data listings.
8.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, minimum, Q1, median, Q3, 
maximum) by study visit along with corresponding change from baseline.
Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme 
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 baseline at 
any time post-baseline up to the date of last dose of study drug plus 30 days will be 
summarized by treatment and study part. 
Values for missing safety laboratory data will not be imputed; however, a missing baseline 
result will be replaced with a screening result, if available. If no pretreatment laboratory 
value is available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) 
for the summary of graded laboratory abnormalities. Thus, any post-baseline graded 
abnormality (i.e., at least Grade 1) will be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.


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8.6.
Pharmacokinetic Analysis
Plasma concentrations of the study drug over time will be listed and summarized using 
descriptive statistics. PK parameters (e.g., AUCtau, Cmax, and Ctau) will be listed and 
summarized for study drug (i.e., SOF and its metabolites, and RBV) using descriptive 
statistics (e.g., sample size, arithmetic mean, geometric mean, % coefficient of variation
[%CV], SD, minimum, Q1, median, Q3, maximum). 
8.7.
Stopping Rules for Individual Groups
There are no predetermined futility criteria which would require enrollment to be halted or 
treatment discontinued.
8.8.
Sample Size
Due to the exploratory nature of this study, no formal power or sample size calculations were 
performed to determine treatment group size. The total sample size of 40 ( i.e., 10 enrolled to 
obtain 8 evaluable for each dose level group in each study part) is largely based on 
feasibility.


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


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potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB- or IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be 
appropriately signed and dated by the subject or the subject’s legally authorized 
representative and the person conducting the consent discussion, and also by an impartial 
witness if required by IRB or IEC or local requirements. The consent form will inform 
subjects about pharmacogenomic testing and sample retention, and their right to receive 
clinically relevant pharmacogenomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties. Only subject initials, date of birth, 
another unique identifier (as allowed by local law) and an identification code will be 
recorded on any form or biological sample submitted to the Sponsor, IRB or IEC, or 
laboratory. Laboratory specimens must be labeled in such as way as to protect subject 
identity while allowing the results to be recorded to the proper subject. Refer to specific 
laboratory instructions. NOTE: The investigator must keep a screening log showing codes, 
names, and addresses for all subjects screened and for all subjects enrolled in the trial. 
Subject data will be processed in accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to 
the investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study 
information, remain the sole and exclusive property of Gilead during the conduct of the study 
and thereafter. This information is not to be disclosed to any third party (except employees or 
agents directly involved in the conduct of the study or as required by law) without prior 
written consent from Gilead. The investigator further agrees to take all reasonable 
precautions to prevent the disclosure by any employee or agent of the study site to any third 
party or otherwise into the public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully 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 should include sequential notes containing at least the following 
information for each subject:


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
Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and 
return;

Record of all adverse events and other safety parameters (start and end date, and 
including causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing 
application in an ICH region (ie, United States, Europe, or Japan) and until there are no 
pending or planned marketing applications in an ICH region; or, if no application is filed or if 
the application is not approved for such indication, until 2 years after the investigation is 
discontinued and regulatory authorities have been notified. Investigators may be required to 
retain documents longer if specified by regulatory requirements, by local regulations, or by 
an agreement with Gilead. The investigator must notify Gilead before destroying any clinical 
study records.
Should the investigator wish to assign the study records to another party or move them to 
another location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all 
of the documents, special arrangements must be made between the investigator and Gilead to 
store these records securely away from the site so that they can be returned sealed to the 
investigator in case of an inspection. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage away from the site.


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9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should 
be completed on the day of the subject visit to enable the sponsor to perform central 
monitoring of safety data.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system. Original entries as well as any changes to data 
fields will be stored in the audit trail of the system.  Prior to database lock (or any interim 
time points as described in the clinical data management plan), the investigator will use 
his/her log in credentials to confirm that the forms have been reviewed, and that the entries 
accurately reflect the information in the source documents. The eCRF capture the data 
required per the protocol schedule of events and procedures. System-generated or manual 
queries will be issued to the investigative site staff as data discrepancies are identified by the 
monitor or internal Gilead staff, who routinely review the data for completeness, correctness, 
and consistency. The site coordinator is responsible for responding to the queries in a timely 
manner, within the system, either by confirming the data as correct or updating the original 
entry, and providing the reason for the update (e.g. data entry error). At the conclusion of the 
trial, Gilead will provide the site with a read-only archive copy of the data entered by that 
site. This archive must be stored in accordance with the records retention requirements 
outlined in Section 9.1.5.
9.1.7.
Drug Accountability
Gilead recommends that used and unused IMP supplies be returned to the shipping facility 
from which it came for eventual destruction. The study monitor will provide instructions for 
return. If return is not possible, the study monitor will evaluate each study center’s IMP 
disposal procedures and provide appropriate instruction for destruction of unused IMP 
supplies. If the site has an appropriate standard operating procedure (SOP) for drug 
destruction as determined by Gilead QA, the site may destroy used (empty or partially 
empty) and unused IMP supplies in accordance with that site’s approved SOP. A copy of the 
site’s approved SOP will be obtained for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the IMP. Upon study completion, 
copies of the IMP accountability records must be filed at the site. Another copy will be 
returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs or IECs or to regulatory authority or health 
authority inspectors.


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9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, 
may be made only by Gilead Sciences. All protocol modifications must be submitted to the 
Competent Authorities, IRB or IEC in accordance with local requirements. Approval must be 
obtained before changes can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). 
Gilead will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report 
may be prepared in certain cases. 
Investigators in this study may communicate, orally present, or publish in scientific journals 
or other scholarly media only after the following conditions have been met:

the results of the study in their entirety have been publicly disclosed by or with the 
consent of Gilead in an abstract, manuscript, or presentation form or the study has been 
completed at all study sites for at least 2 years

The investigator will submit to Gilead any proposed publication or presentation along 
with the respective scientific journal or presentation forum at least 30 days before 
submission of the publication or presentation. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).

The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to 
withhold publication or presentation for an additional 60 days in order to obtain patent 
protection if deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to 
the investigator’s source documentation in order to verify the accuracy of the data recorded 
in the CRF/eCRF.


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The monitor is responsible for routine review of the CRF/eCRF at regular intervals 
throughout the study to verify adherence to the protocol and the completeness, consistency, 
and accuracy of the data being entered on them. The monitor should have access to any 
subject records needed to verify the entries on the CRF/eCRF. The investigator agrees to 
cooperate with the monitor to ensure that any problems detected through any type of 
monitoring (central, on site) are resolved.
9.3.2.
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.
9.3.3.
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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10.
REFERENCES
2202
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16:31-41.
12557
Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. 
Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks 
versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic 
infection with hepatitis C virus. International Hepatitis Interventional Therapy 
Group (IHIT). Lancet 1998;352 (9138):1426-32.
12558
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et 
al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for 
chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 
1998;339 (21):1485-92.
13693
Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and 
treatment of hepatitis C: an update. Hepatology 2009;49 (4):1335-74.
15572
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
Laboratories Inc., Nutley, NJ. Revised: January 2010.
15668
Copegus 200 mg and 400 mg Film-coated Tablets. Summary of Product 
Characteristics. Roche Products Limited, Welwyn Garden City, United Kingdom. 
Revised: March 2010.
17940
Craxi A. EASL clinical practice guidelines: management of hepatitis C virus 
infection, European association for the study of the liver. J Hepatol 2011;55:245-
64.
19705
Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus 
infection in Europe. J Hepatol 2008;48 (1):148-62.
23275
Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. 
Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J 
Med 2013;368 (1):34-44.
24149
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
Laboratories Inc., Nutley, NJ. Revised: February 2013.
24713
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, 
Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without 
treatment options. N Engl J Med 2013;368 (20):1867-77.


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24715
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et 
al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 
2013;368 (20):1878-87.
24913
Abboud O, Becker G, Bellorin-Font E, Field M, Johnson R, Li PK, et al. KDIGO 
clinical practice guidelines on hepatitis C in chronic kidney disease acknowledged 
by ISN. Nature clinical practice 2008;4 (12):648-9.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2b Randomized, Open-Label Study of200 mg or 400 mg Sofosbuvit+RBV for 
24 Weeks in Genotype lor 3 HCV-Infected Subjects with Renal Insufficiency 
GS-US-334-0154, Amendment 1, 05 Septembet· 2013 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Luisa Stamm, MD, PhD (Printed) 
Medical Monitor 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and l agree that it contains all necessary 
details for me and my staff to conduct this study as described. l will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to 
all information provided by Gilead Sciences, Inc. I will discuss this material with them to 
ensure that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 67 
05 September 2013 


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Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
11.1.1.
Background
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects 
have been demonstrated in all animal species tested. Pregnancy must be excluded before the 
start of treatment with study drugs and prevented thereafter by reliable contraceptive 
methods. Pregnancy tests will be performed regularly throughout this study. Furthermore, 
RBV is known to accumulate intracellularly where it is cleared slowly, and is also excreted in 
semen. Therefore, extreme care must be taken to avoid pregnancy during RBV therapy and 
for up to 6 months following completion of treatment (7 months for males). Please refer to 
the latest version of the product insert for additional information. 
Non-clinical toxicity studies of SOF demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of SOF in pregnant 
women. Please refer to the latest version of the investigator’s brochure for additional 
information. 
11.1.2.
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 randomization. They must also 
agree to one of the following from 3 weeks prior to Day 1 until 6 months after last dose of 
RBV:

Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) is not permitted.
Or

Consistent and correct use of 1 of the following methods of birth control listed below, in 
addition to a male partner who correctly uses a condom, from the date of Screening until 
6 months after the last dose of RBV: 
— intrauterine device (IUD) with a failure rate of < 1% per year
— female barrier method: cervical cap or diaphragm with spermicidal agent


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— tubal sterilization
— vasectomy in male partner
— implants of levonorgestrel
— injectable progesterone
— oral contraceptives (either combined or progesterone only)
— contraceptive vaginal ring 
— transdermal contraceptive patch
11.1.3.
Contraceptive Requirements for Male Subjects (and their female 
partners)
All male study participants must agree to consistently and correctly use a condom from 
Baseline until 7 months after the last dose of RBV. If their female partner is of childbearing 
potential (as defined above), their female partner must use 1 of the methods of birth control 
listed above from the date of Screening until 7 months after last dose of RBV.
Male subjects must agree to refrain from sperm donation for at least 7 months after the last 
dose of RBV.
11.1.4.
Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any 
time during the study, or if they become pregnant within 6 months (7 months for 
partners of male subjects) of last RBV dose. Subjects who become pregnant or who 
suspect that they are pregnant must report the information to the investigator and 
discontinue study drug immediately. Subjects whose partner has become pregnant 
or suspects she is pregnant must report the information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined 
in Section 7.6.2. 


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


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


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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
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


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated


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


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


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


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


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


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


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


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


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


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

Prot_000.pdf: 
Study Title: 
Sponsor: 
IND No.: 
EudraCT No: 
Indication: 
Protocol ID: 
Gilead Sciences Study 
Director 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2b Randomized, Open-Label Study of200 mg or 
400 mg Sofosbuvii+RBV for 24 Weeks in Genotype 1 or 3 
HCV-Infected Subjects with Renal Insufficiency 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
106,739 
2013-002897-30 
Hepatitis C Vims Infection 
GS-US-3 34-0154 
Name: 
Telephone: 
Mobile: 
Fax: 
E-mail: 
Original: 
PPD 
t-'t-'U 
PPD 
PPD 
PPD 
11 July 2013 
I 
CONFIDENTIALITY STATEMENT 
I 
The inf01mation contained in this document, pmiicularly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Institutional Review Bom·d or Independent Ethics Committee. The inf01mation is 
only to be used by you in connection with authorized clinical studies of the investigational 
dmg described in the protocol. You will not disclose any of the infonnation to others without 
written authorization from Gilead Sciences, Inc., except to the extent necessmy to obtain 
inf01med consent from those persons to whom the dmg may be administered. 


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Protocol GS-US-334-0154
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TABLE OF CONTENTS
TABLE OF CONTENTS .......................................................................................................................................2
LIST OF IN-TEXT TABLES.................................................................................................................................4
LIST OF IN-TEXT FIGURES ...............................................................................................................................4
PROTOCOL SYNOPSIS .......................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................10
1.
INTRODUCTION .......................................................................................................................................13
1.1.
Background.....................................................................................................................................13
1.2.
Sofosbuvir (formerly GS-7977)......................................................................................................13
1.3.
Ribavirin (RBV)..............................................................................................................................14
1.4.
Rationale for the Current Study ......................................................................................................14
1.5.
Rationale for SOF Dose Selection ..................................................................................................15
1.6.
Rationale for RBV Dose Selection .................................................................................................16
1.7.
Overall Risk/Benefit Assessment....................................................................................................16
2.
OBJECTIVES..............................................................................................................................................17
3.
STUDY DESIGN ........................................................................................................................................18
3.1.
Treatment Plan and Regimen..........................................................................................................18
3.2.
Visit Schedule .................................................................................................................................18
3.3.
Virologic Response-Based Stopping Criteria..................................................................................19
3.4.
Treatment Discontinuation Criteria.................................................................................................20
3.5.
Registry Studies ..............................................................................................................................20
3.5.1.
Sequence Registry Study...............................................................................................20
3.5.2.
SVR Registry Study ......................................................................................................20
4.
SUBJECT POPULATION...........................................................................................................................21
4.1.
Number of Subjects and Subject Selection .....................................................................................21
4.2.
Inclusion Criteria ............................................................................................................................21
4.3.
Exclusion Criteria ...........................................................................................................................22
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ....................................................................................25
5.1.
Sofosbuvir (SOF) ............................................................................................................................25
5.1.1.
Formulation...................................................................................................................25
5.1.2.
Packaging and Labeling ................................................................................................25
5.1.3.
Storage and Handling....................................................................................................25
5.1.4.
Sofosbuvir (SOF) Dosage and Administration..............................................................26
5.2.
Ribavirin (RBV)..............................................................................................................................26
5.2.1.
Formulation...................................................................................................................26
5.2.2.
Packaging and Labeling ................................................................................................26
5.2.3.
Storage and Handling....................................................................................................26
5.2.4.
RBV Dosage and Administration..................................................................................26
5.3.
Co-administration of Sofosbuvir (SOF) and Ribavirin (RBV) .......................................................27
5.4.
Study Drug Compliance..................................................................................................................27
5.5.
Dispensing and Accountability of Study Drugs..............................................................................27
5.6.
Study Drug Return or Disposal.......................................................................................................28
5.7.
Concomitant Medications ...............................................................................................................28
5.7.1.
Medications Associated with QT Prolongation.............................................................29


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6.
STUDY PROCEDURES .............................................................................................................................31
6.1.
Subject Enrollment and Treatment Assignment..............................................................................31
6.2.
Pretreatment Assessments...............................................................................................................35
6.2.1.
Screening Visit..............................................................................................................35
6.2.2.
Medical History.............................................................................................................35
6.3.
Day 1 Assessments..........................................................................................................................36
6.3.1.
Dosing Diary.................................................................................................................36
6.4.
Treatment Assessments...................................................................................................................36
6.5.
Safety Assessments.........................................................................................................................36
6.5.1.
Safety ECGs..................................................................................................................36
6.5.2.
Physical Examination....................................................................................................36
6.5.3.
Vital Signs.....................................................................................................................37
6.5.4.
BMI...............................................................................................................................37
6.5.5.
Creatinine Clearance .....................................................................................................37
6.5.6.
Clinical Laboratory Tests/Assessments.........................................................................37
6.5.7.
Adverse Events/ Concomitant Medications/ Protocol Restrictions...............................38
6.6.
Pharmacokinetic (PK) Assessments................................................................................................39
6.7.
Early Termination (ET)/Unscheduled Visit ....................................................................................39
6.8.
Post-Treatment Assessments...........................................................................................................40
6.9.
Optional Samples for Pharmacogenetic Testing .............................................................................40
6.10.
Archived Plasma Sample ................................................................................................................40
6.11.
Blood Storage..................................................................................................................................41
7.
ADVERSE EVENTS MANAGEMENT.....................................................................................................42
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events..........................42
7.1.1.
Adverse Events..............................................................................................................42
7.1.2.
Serious Adverse Events.................................................................................................42
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events..............................................................43
7.2.
Assessment of Adverse Events and Serious Adverse Events..........................................................43
7.2.1.
Assessment of Causality for Study Drugs and Procedures............................................43
7.2.2.
Assessment of Severity .................................................................................................44
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead................................................................................................................44
7.4.
Gilead Reporting Requirements......................................................................................................46
7.5.
Toxicity Management .....................................................................................................................46
7.5.1.
Stopping Rules for Toxicity..........................................................................................46
7.5.2.
Sofosbuvir (SOF) ..........................................................................................................46
7.5.3.
Ribavirin (RBV)............................................................................................................46
7.6.
Special Situations Reports ..............................................................................................................47
7.6.1.
Definitions of Special Situations...................................................................................47
7.6.2.
Instructions for Reporting Special Situations................................................................47
8.
STATISTICAL CONSIDERATIONS.........................................................................................................49
8.1.
Analysis Objectives and Endpoints.................................................................................................49
8.1.1.
Analysis Objectives.......................................................................................................49
8.1.2.
Primary Endpoint ..........................................................................................................49
8.1.3.
Secondary Endpoint ......................................................................................................50
8.1.4.
Other Endpoints of Interest ...........................................................................................50
8.2.
Analysis Conventions .....................................................................................................................50
8.2.1.
Analysis Sets.................................................................................................................50
8.2.2.
Data Handling Conventions ..........................................................................................51
8.2.3.
Interim Analysis............................................................................................................52


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8.3.
Demographic Data and Baseline Characteristics ............................................................................52
8.4.
Efficacy Analysis............................................................................................................................52
8.4.1.
Primary Analysis...........................................................................................................52
8.4.2.
Secondary Analysis.......................................................................................................53
8.5.
Safety Analysis ...............................................................................................................................53
8.5.1.
Extent of Exposure........................................................................................................53
8.5.2.
Adverse Events..............................................................................................................53
8.5.3.
Laboratory Evaluations .................................................................................................54
8.6.
Pharmacokinetic Analysis...............................................................................................................55
8.7.
Stopping Rules for Individual Groups ............................................................................................55
8.8.
Sample Size.....................................................................................................................................55
9.
RESPONSIBILITIES ..................................................................................................................................56
9.1.
Investigator Responsibilities ...........................................................................................................56
9.1.1.
Good Clinical Practice ..................................................................................................56
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) Approval..............................................................................................................56
9.1.3.
Informed Consent..........................................................................................................56
9.1.4.
Confidentiality ..............................................................................................................57
9.1.5.
Study Files and Retention of Records...........................................................................57
9.1.6.
Case Report Forms........................................................................................................58
9.1.7.
Drug Accountability......................................................................................................59
9.1.8.
Inspections ....................................................................................................................59
9.1.9.
Protocol Compliance.....................................................................................................59
9.2.
Sponsor Responsibilities.................................................................................................................60
9.2.1.
Protocol Modifications..................................................................................................60
9.2.2.
Study Report and Publications ......................................................................................60
9.3.
Joint Investigator/Sponsor Responsibilities ....................................................................................60
9.3.1.
Access to Information for Monitoring...........................................................................60
9.3.2.
Access to Information for Auditing or Inspections .......................................................61
9.3.3.
Study Discontinuation...................................................................................................61
10.
REFERENCES ............................................................................................................................................62
11.
APPENDICES .............................................................................................................................................64
Appendix 1.
Investigator Signature Page...........................................................................................65
Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements ..................................................................66
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities .............................................................................................68
LIST OF IN-TEXT TABLES
Table 6-1.
Schedule of Assessments ..............................................................................................32
LIST OF IN-TEXT FIGURES
Figure 3-1.
Part 1 and Part 2 Study Schema ....................................................................................19


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2b Randomized, Open-Label Study of 200 mg or 400 mg 
Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 HCV-Infected 
Subjects with Renal Insufficiency
IND Number:
Eudra CT Number:
106,739
2013-002897-30
Study Centers 
Planned:
Multiple sites in New Zealand, Europe, North America and South 
America
Number of Subjects 
Planned:
Approximately 40 subjects
Target Population:
Adults with chronic renal insufficiency and HCV infection
Treatment Duration:
24 weeks
Objectives:
The primary objectives of this study are:

To evaluate the safety of sofosbuvir (SOF) 200mg or 400mg + 
ribavirin (RBV) for 24 weeks as assessed by review of the 
accumulated safety data in each treatment arm

To evaluate the efficacy of sofosbuvir (SOF) 200mg or 400 mg
+ ribavirin (RBV) for 24 weeks measured by the proportion of 
subjects with renal insufficiency who have achieved a
sustained viral response 12 weeks after treatment 
discontinuation (SVR12) in each treatment arm

To evaluate the steady state pharmacokinetics of SOF and its 
metabolites upon dosing SOF 200mg or 400mg in subjects 
with renal insufficiency 
The secondary objectives of this study are:

To evaluate the proportion of subjects with renal insufficiency 
who attain SVR at 4 and 24 weeks after discontinuation of 
treatment (SVR4 and SVR24)

To evaluate the kinetics of plasma HCV RNA during and after 
treatment discontinuation

To evaluate the emergence of viral resistance to SOF during 
and after treatment discontinuation


Sofosbuvir 
Protocol GS-US-334-0154 
Gilead Sciences, Inc. 
Study Design: 
Registry Studies: 
The explorat01y objective of this study is: 
Final 
Original 
This study will have 2 pruis. Prui 1 will randomize approximately 
20 subjects with severe renal insufficiency to tr·eatment with either 
SOF 200mg or 400mg QD + RBV 200mg QD for 24 weeks. Based 
on the review of preliminruy safety, efficacy and PK data through 
Week 4 from at least 4 subjects at each dose level in Prui 1, Part 2 
will begin with End Stage Renal Disease (on hemodialysis) to 
initiate tr·eatment with SOF at a single dose level from 200 mg to 
up to 400mg QD + RBV 200mg QD for 24 weeks. 
Sequence Registry Study 
Subjects who do not achieve SVR will be eligible for enrollment in 
the Sequence Registry Study where available and approved. The 
pmpose of the Sequence Registry Study will be to monitor the 
persistence of resistant mutations for up to 3 yeru·s. The Sequence 
Registry Study is described in a sepru·ate protocol 
(GS-US-248-0123). 
SVR Registry Study 
All subjects who achieve SVR will be eligible for enrollment in the 
SVR Registry Study where available and approved. The pmpose of 
the SVR Registry Study will be to evaluate dmability of SVR for 
up to 3 yeru·s post-tr·eatment. The SVR Regisby Study is described 
in a sepru·ate protocol (GS-US-248-0122). 
Diagnosis and Main 
Adults(~ 18 years) with chronic genotype 1 or genotype 3 HCV 
Eligibility Criteria: 
infection. Reference Sections 4.2 and 4.3 for detailed Inclusion and 
Exclusion criteria. 
Study Procedures/ 
Frequency: 
CONFIDENTIAL 
Screening assessments will be completed within 35 days of the 
Day 1 visit. 
Study visits will occm at Screening, Day 1, and at the end of 
Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20 and 24 and at Post-Treatment 
Weeks 4, 12, and 24. Screening assessments will include physical 
exrunination, height, weight, vital signs, 12-lead ECG, concomitant 
medications, safety laborat01y tests, HCV RNA, serology (HIV, 
HCV, HBV), hemoglobin Ale (HbAl c), sennn ~-hCG (females of 
child beru·ing potential only), IL28B genotyping 
Page6 
11 July 2013 


Sofosbuvir 
Protocol GS-US-334-0154 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Final 
Original 
On-treatment assessments will include adverse events (AEs ), 
concomitant medications, study medication pill count, physical 
examination, vital signs, 12-lead ECGs, safety laborat01y tests, 
HCV RNA, phannacokinetic samples, and semm pregnancy tests 
(females of child bearing potential only). 
Post-u·eatment assessments will include AEs, concomitant 
medications, vital signs, safety laborat01y tests, HCV RNA, and 
senun pregnancy tests (females of child bearing potential only). 
Samples for viral RNA sequencing will be collected at Day 1 and 
eve1y visit thereafter. Samples will be collected during u·eatment 
visits for PK analysis of study dmg(s). 
PK assessments 
Serial blood samples will be collected on week 2 and 12 at the 
following timepoints: 
0 (pre-dose +/-5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours 
post-dose. 
Trough PK samples will be collected at all other on u·eatment 
visits. 
Plasma concenu·ations of SOF and its metabolites will be 
detennined and PK parameters will be estimated as appropriate. 
Plasma concenu·ations of RBV may be detennined, if necessary. 
Optional Genetic Sample Collection 
PPD 
Archived Plasma Sample 
Archive plasma samples are being collected for possible additional 
analyses, including but not limited to, study dmg or metabolite 
measurements, viral load, safety/efficacy assessments, HCV gene 
sequencing, HCV resistance testing and other possible predictors 
of response as detennined by Gilead. 
Page 7 
11 July 2013 


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Protocol GS-US-334-0154
Final
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Test Product, Dose, 
and Mode of 
Administration:
Sofosbuvir is manufactured as 100mg and 400 mg tablets for oral 
administration. Subjects randomized to the 200mg dose will take 
2x100mg tablets for a total dose of 200 mg orally QD in the 
morning with RBV and with food. Subjects randomized to the 
400mg dose will take 1x400mg tablet for a total dose of 400 mg 
orally QD in the morning with RBV and with food.
RBV will be supplied as a 200 mg tablet for oral administration by 
Gilead Sciences. Subjects will take 1x200mg tablet in the morning 
with SOF and with food. 
Reference Therapy:
None
Criteria for 
Evaluation:
Safety:
AEs will be collected through 4 weeks post-treatment. Safety labs 
and SAEs will be collected throughout the study. Safety will be 
evaluated by assessment of clinical laboratory tests, ECG, periodic 
physical examinations including vital signs at various time points 
during the study, and by the documentation of adverse events.
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV 
RNA performed using COBAS® TaqMan® HCV Test, v2.0 for 
use with the High Pure System.
PK:
The following plasma PK parameters will be calculated for 
sofosbuvir and its metabolites GS-566500 and GS-331007 as 
applicable: AUClast, AUCtau, Cmax, Clast, Ctau, Tmax, Tlast, λz, and t1/2.
Statistical Methods:
Safety data will be listed by subject and summarized by treatment 
in each renal function subgroup (study part) using frequency of 
event/abnormality or descriptive statistics (e.g., sample size, 
arithmetic mean, geometric mean, % coefficient of variation [CV], 
standard deviation [SD], minimum, Q1, median, Q3, and 
maximum).
The steady state PK plasma concentrations and parameters will be 
listed by subject and summarized by treatment and study part using 
descriptive statistics for each analyte (SOF, GS-566500, 
GS-331007, and RBV, as appropriate). 
In the efficacy analysis, no statistical hypothesis testing will be 
performed and no formal inference will be made on primary 
efficacy endpoint SVR12. A point-estimate with two-sided 95% 
exact confidence interval using the binomial distribution 
(Clopper-Pearson method) will be constructed for the SVR12 rate 
by treatment and study part. Similar analysis will be also 
performed for secondary endpoints SVR4 and SVR24.


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Protocol GS-US-334-0154
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To evaluate the kinetics of circulating HCV RNA during and after 
treatment discontinuation, viral load data will be listed by subject 
and summarized by treatment and visit in each study part using 
descriptive statistics.
Due to the exploratory nature of this study, no formal power or 
sample size calculations were used to determine treatment group 
size. The total sample size of 40 (i.e., 10 enrolled to obtain 8 
evaluable for each treatment in each study part) is largely based on 
feasibility.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


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Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Original
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
β-hCG
β-human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase  (also SGOT)
AUC
area under the curve
AUCtau
area under the plasma concentration versus time curve over the dosing 
interval (tau)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BW
body weight
CLcr
Creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear 
(PBMC) concentration of drug
Ctau
observed drug concentration at the end of the dosing interval (tau)
CRF
case report form(s)
CRO
Contract (or clinical) research organization 
dL
Deciliter
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDPE
high-density polyethylene


Sofosbuvir
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
High-Level Term
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL28B
IL28B gene
IND
Investigational New Drug (Application)
IRB
institutional review board
IUD
intrauterine device
IV
Intravenous
kg
Kilogram
L
Liter
LDH
Lactase dehydrogenase
LLN
lower limit of the normal range
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MH
Mantel-Haenszel
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PBMC
peripheral blood mononuclear cell(s)
PEG
Pegylated interferon
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
QD
once daily (use only in tables)
QTcF
QT interval corrected using Fridericia’ formula
RBC
Red blood cell count 
RBV
Ribavirin
RNA
ribonucleic acid
RVR
rapid virologic response 
SADR
Serious adverse drug reaction
SAE
serious adverse event
SD
Standard deviation


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
SOC
Standard of Care
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TND
Target not detected
TSH
Thyroid stimulating hormone
t½
An estimate of the terinal elimination half-life of the drug in 
serum/plasma/PBMC, calculated by dividing the natural log of 2 by the 
terminal elimination rate contstant (λz)
ULN
upper limit of the normal range
US
United States
WBC
white blood cell count


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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) is responsible for a large proportion of chronic liver disease 
worldwide and accounts for 70% of cases of chronic hepatitis in industrialized countries. The 
global prevalence of chronic hepatitis C is estimated to average 3% {19705}. The most 
common genotype worldwide is genotype 1 followed by genotypes 2 and 3 {19705}. 
Although there is evidence that the incidence of viral infection may be decreasing, the 
prevalence of liver disease caused by HCV is on the rise, primarily due to the lag between the 
onset of infection and the clinical manifestation of liver disease {19705}. The prevalence of 
chronic HCV is significantly higher among patients with chronic renal failure, and HCV 
itself is associated with impaired renal function. Treatment of these individuals is therefore 
recommended but is often complicated by the substantial increase in hematologic toxicities 
associated with the use of ribavirin in the setting of low creatinine clearance {23275}.
Standard of care for genotype 1 HCV infection involves 24-48 weeks of an HCV protease 
inhibitor in combination with pegylated interferon-alfa (PEG)+ribavirin (RBV). The 
recommended first-line treatment for subjects with genotype 2 or genotype 3 chronic 
hepatitis C is PEG+ RBV for 24 weeks {13693}, {17940}. There are minimal data regarding 
the optimal regimen for patients with severe renal disease (e.g., Cr clearance<30 mL/min) or 
end stage renal disease on maintenance hemodialysis. Interferon monotherapy for 48 weeks 
which provides an SVR rate of approximately 40% in clinical trials is often deemed the 
treatment of choice. Due to the side effects and lengthy duration of current treatment, there is 
substantial need for a short, simple, interferon-free regimen, particularly in patients who are 
more susceptible to drug toxicities, such as those with renal insufficiency. 
Sofosbuvir (SOF) is a potent nucleotide analogue that inhibits HCV RNA replication in vitro 
and has demonstrated high rates of sustained viral response (SVR) when given with RBV to 
subjects with chronic genotype 1, 2 or 3 HCV infection {23275}, {24713}, {24715}. The 
degree of RBV-associated hemolytic anemia is reduced in the absence of interferon. 
Therefore, the combination of SOF+RBV may represent a promising therapeutic option for 
HCV-infected patients with severe renal insufficiency.
1.2.
Sofosbuvir (formerly GS-7977)
Sofosbuvir (SOF), formerly GS-7977, is a nucleotide analog that is a potent and selective 
inhibitor of NS5B-directed HCV replication.
Please refer to the Investigator’s Brochure (IB) for additional information on SOF including:

In Vitro Anti-HCV Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience


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1.3.
Ribavirin (RBV)
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of 
RNA and DNA viruses {15572}, {15668}. Ribavirin monotherapy has little or no effect on the 
replication of HCV but can result in short term normalization of serum ALT activity. When 
combined with interferon or PEG therapy, RBV decreases substantially the relapse rate seen 
after cessation of interferon therapy {12557}, {12558}.
Ribavirin is a known teratogen (FDA category X). Furthermore, RBV is known to 
accumulate intracellularly where it is cleared slowly, and is also excreted in semen. 
Therefore, extreme care must be taken to avoid pregnancy during RBV therapy and for up to 
6 months following completion of treatment. A comprehensive review of RBV is contained 
in the package insert/SmPC.
1.4.
Rationale for the Current Study
This study will evaluate the safety, efficacy and pharmacokinetics of treatment with 
SOF+RBV for 24 weeks in subjects with chronic genotype 1 or 3 HCV infection and severe 
renal impairment.
Liver disease caused by HCV causes significant morbidity and mortality among patients with 
end-stage renal disease, particularly those treated with dialysis. Although treatment for 
chronic HCV has evolved over the last decade resulting in response rates of approximately 
70%, treatment with PEG and RBV is not recommended in ESRD patients {24913}. 
Interferon monotherapy, however, is associated with poor tolerability, a 48 week treatment 
duration, and efficacy of approximately 40%. Furthermore, once patients have failed this 
course of treatment, they have no further treatment options and are at risk for progression of 
liver disease, cirrhosis, and hepatocellular carcinoma.
To date, SOF+RBV has demonstrated safety and efficacy in a broad range of subjects with 
chronic HCV infection in Phase 2 and Phase 3 clinical trials. However, subjects with Cr 
clearance <60 mL/min have been excluded from these studies due to the recommendation 
that RBV not be administered to patients with Cr clearance <50 mL/min. In addition, study 
P7977-0915 has shown the major circulating metabolite of SOF, GS-331007, is renally 
cleared and a single dose study conducted in subjects with severe renal impairment or end-
stage renal disease on hemodialysis demonstrated exposures approximately 1.6-fold and 14 
to 22-fold higher, respectively, than those observed in matched controls with normal renal 
function. Whilst dose reduction of SOF would reduce these exposures, viral efficacy is 
dependent on SOF exposures such that lower SOF doses or intermittent administration could 
be associated with reduced efficacy. Thus, this exploratory study of safety and efficacy of 
standard (400mg) and reduced (200mg) doses of SOF in combination with low-dose RBV in 
a small number of subjects will provide important data regarding dosing recommendations 
for use of SOF in this patient population with a high unmet medical need.
Phase 3 studies of SOF+RBV for 12 or 16 weeks in treatment-naïve and 
treatment-experienced genotype 3 HCV-infected subjects demonstrated SVR12 rates of 56% 


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and 62%, respectively. Increasing treatment duration to 24 weeks may further improve 
response rates. In Phase 2 studies of SOF+RBV for 12 or 24 weeks in treatment-naïve 
genotype 1 HCV-infected subjects, SVR rates have varied from 47% to 84% depending on 
the study and patient population. In both genotypes 1 and 3, lower doses of RBV have been 
associated with reduced efficacy of the regimen. Given the safety need for a reduced RBV 
dose in the current study (Section 1.6), treatment with SOF+RBV will be administered for 
24 weeks to maximize efficacy. Subjects with genotypes 1 or 3 HCV infection have been 
selected for this study since they represent the largest group of HCV-infected individuals in 
the regions where this study will be conducted and because the 24 week treatment regimen is 
appropriate. In contrast, genotype 2 HCV-infected subjects have been shown to have high 
response rates following 12 weeks of SOF+RBV therapy. If SOF+RBV is well tolerated for 
24 weeks in patients with severe renal insufficiency, safety for 12 weeks in this smaller HCV 
population may be inferred.
1.5.
Rationale for SOF Dose Selection 
Sofosbuvir 400 mg, once daily, when dosed in combination with RBV with or without PEG 
has demonstrated broad genotypic efficacy and a favorable safety profile in over 
3300 HCV-infected subjects across multiple patient populations in Phase 2 and 3 trials.  This 
dose (400 mg) is the proposed to be marketed dose of sofosbuvir for the treatment of 
HCV-infection.  
In study P7977-0915, a single dose PK study in subjects with varying degrees of renal 
impairment, exposure (AUCinf) of sofosbuvir and the renally eliminated metabolite, 
GS-331007, were 2.7- and 5.5-fold higher respectively in subjects with severe renal 
impairment compared to matched controls with normal renal function.  A significant dose 
reduction (eg, 2- to 4-fold) of sofosbuvir would be necessary to provide comparable 
GS-331007 exposures in subjects with severe renal impairment and those with normal renal 
function. Data from dose-finding and Phase 2 studies demonstrated that sofosbuvir, dosed 
once daily, was necessary to provide the active anabolite at the site of action (circulating 
GS-331007 can not be phosphorylated to the active anabolite); therefore, dose interval 
modifications may not be appropriate. The efficacy of a substantially reduced dose of 
sofosbuvir in subjects with severe renal impairment has not been established.  


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Part 1 of this study will evaluate the safety, efficacy and pharmacokinetics of 2 doses of 
sofosbuvir in subjects with severe renal impairment; the proposed to be marketed dose of 
400 mg SOF, as well as a reduced dose of 200 mg sofosbuvir which is expected to provide 
sofosbuvir exposure that are comparable to the 400 mg dose in subjects with normal renal 
function.  Safety, efficacy and pharmacokinetic data from the 200 mg and 400 mg dose of 
sofosbuvir in Part 1 will inform the initiation of Part 2.  In Part 2, the safety, efficacy and 
pharmacokinetic of SOF at a dose up to 400 mg and 200 mg will be evaluated in subjects 
with End Stage Renal Disease (ESRD).  In study P7977-0915, exposure (AUCinf) of 
sofosbuvir and GS-331007, were 1.6 fold and 14 to 22-fold higher respectively in subjects 
with ESRD compared to matched controls with normal renal function.  Dose reduction of 
sofosbuvir to mitigate increased GS-331007 exposure in subjects with ESRD may result in 
suboptimal sofosbuvir exposure.  As such, in this patient population with a high unmet 
medical need, to balance both safety and efficacy, the 200 mg and up to 400 mg dose will be 
evaluated in Part 2 in subjects with ESRD.
1.6.
Rationale for RBV Dose Selection
Ribavirin increases treatment response rates when administered with interferon or PEG. In 
addition, reducing the RBV dose from 1000-1200 mg/day to 600 or 800 mg/day when given 
in combination with SOF reduced SVR rates, as did SOF monotherapy. It is therefore 
desirable to keep RBV as part of the SOF treatment regimen. Since RBV is cleared renally 
and its main toxicity is hemolytic anemia which is poorly tolerated in patients with advanced 
renal insufficiency who are usually anemic at baseline and have little bone marrow reserve, 
the starting dose of RBV must be substantially lower than 1000-1200 mg/day. For this study, 
a dose of 200 mg/day has been selected based on investigator input in light of the high 
frequency of hemotoxicity of RBV and the general desire to optimize the efficacy of the 
treatment regimen {24149}.
1.7.
Overall Risk/Benefit Assessment
To date there has been no safety signal identified that is attributable to SOF when 
administered as part of a combination regimen. Furthermore, SOF does not exacerbate the 
toxicities associated with RBV, most notably hemolytic anemia. Clinical data with SOF in 
severe renal insufficiency and in subjects requiring hemodialysis is limited to a single dose 
study in non-HCV infected subjects. No specific safety signals were identified. The current 
study is designed to assess the safety and efficacy of therapeutic treatment with SOF+RBV in 
a small number of subjects with severe renal insufficiency. The 2-part design will allow a full 
review of the risk/benefit of both treatment arms in patients with Cr clearance <30 mL/min 
before proceeding to the cohort of patients on hemodialysis who are predicted to have higher 
SOF and GS-331007 exposures. 
The potential benefit of successful treatment of HCV in these subjects is substantial. Few 
patients with severe renal insufficiency can tolerate combination therapy with PEG+RBV 
due to profound anemia. SVR rates to interferon monotherapy administered for 48 weeks are 
less than 50%. Interferon-free treatment for 24 weeks could provide substantial 
improvements in safety, tolerability and efficacy for individuals with chronic HCV infection 
and end stage renal disease.


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2. 
OBJECTIVES 
The prima1y objectives of this study are: 
Final 
Original 
• 
To evaluate the safety ofsofosbuvir (SOF) 200mg or 400mg + ribavirin (RBV) for 
24 weeks as assessed by review of the accumulated safety data in each treatment ann 
• 
To evaluate the efficacy of sofosbuvir (SOF) 200mg or 400mg + ribavirin (RBV) for 
24 weeks measured by the proportion of subjects with renal insufficiency who have 
achieved a sustained viral response 12 weeks after treatment discontinuation (SVR12) in 
each treatment rum 
• 
To evaluate the steady state phrumacokinetics ofSOF and its metabolites upon dosing 
SOF 200mg or 400mg in subjects with renal insufficiency 
The secondruy objectives of this study ru·e: 
• 
To evaluate the prop01iion of subjects with renal insufficiency who attain SVR at 4 and 
24 weeks after discontinuation of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of plasma HCV RNA during and after treatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF during and after treatment 
discontinuation 
The explorat01y objective of this study is: 
IT 
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3.
STUDY DESIGN
This is a multicenter, randomized, open label study that will evaluate the safety, tolerability 
and antiviral efficacy of SOF with RBV in chronic renal insufficiency and HCV infection
subjects with genotype 1 or genotype 3 HCV infection, including those with compensated 
cirrhosis.
This study will have 2 parts. Part 1 will randomize approximately 20 subjects with severe 
renal insufficiency to treatment with either SOF 200mg or 400mg QD + RBV 200 mg QD 
for 24 weeks. Based on the review of preliminary safety, efficacy and PK data through Week 
4 from at least 4 subjects at each dose level in Part 1, Part 2 will begin with End Stage Renal 
Disease (on hemodialysis) to initiate treatment with SOF at a single dose level from 200 mg 
to up to 400mg QD + RBV 200mg QD for 24 weeks.
3.1.
Treatment Plan and Regimen
In Part 1, following screening procedures and Day 1 assessments, eligible subjects will be 
randomized to receive either SOF 200mg or 400mg QD + RBV 200mg QD for 24 weeks.
In Part 2, following screening procedures and Day 1 assessments, eligible subjects will be 
randomized to receive either SOF 200mg or up to 400mg QD + RBV 200mg QD for 
24 weeks. 
Additional information about study drug administration can be found in Section 5.
3.2.
Visit Schedule
All subjects will complete screening, on-treatment and post-treatment assessments. Screening 
assessments will be completed within 35 days of the Day 1 visit. All subjects will complete 
Post-Treatment visits at Weeks 4, 12, and 24.
The assessments performed at each visit are described in Section 6.
The study schema is presented in Figure 3-1.


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Figure 3-1.
Part 1 and Part 2 Study Schema
Day -35       Day 1       1         2             4            6     
8        10       12         16         20      24       
4                12                  24
Screening



Study Drug Administration
Initiate Intensive PK 
Sample Draw
On-Treatment Visits 
(Week)
Off-Treatment Visits 
(Week)
3.3.
Virologic Response-Based Stopping Criteria
The following stopping criteria will be used for subjects on treatment:

Confirmed HCV RNA ≥LLOQ after 2 consecutive HCV RNA <LLOQ

Confirmed >1 log10  increase from nadir 

Confirmed HCV RNA ≥LLOQ after 8 weeks of treatment
Confirmation should be performed as soon as possible but within 2 weeks after determination 
of initial observation.


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3.4.
Treatment Discontinuation Criteria
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication must be discontinued in the following instances:

Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises 
the ability to continue study-specific procedures or is considered to not be in the subject’s 
best interest.

Pregnancy of female subject, or female partner of male subject.

Efficacy failure as defined in Section 3.3. 

Significant protocol violation including non-compliance with study assessments. 

Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy or other reason.

Discontinuation of the study at the request of Gilead, regulatory agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC)
Subjects who discontinue treatment earlier than the assigned 24-week treatment duration will 
complete an Early Termination Visit (Section 6.7).
3.5.
Registry Studies
3.5.1.
Sequence Registry Study
Subjects who do not achieve SVR will be eligible for enrollment in the Sequence Registry 
Study where available and approved. The purpose of the Sequence Registry Study will be to 
monitor the persistence of resistant mutations for up to 3 years. The Sequence Registry Study 
is described in a separate protocol (GS-US-248-0123).
3.5.2.
SVR Registry Study
All subjects who achieve SVR will be eligible for enrollment in the SVR Registry Study
where available and approved. The purpose of the SVR Registry Study will be to evaluate 
durability of SVR for up to 3 years post-treatment. The SVR Registry Study is described in a 
separate protocol (GS-US-248-0122).


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 40 subjects will be treated in this study.
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) Chronic HCV infection documented by either:
a) a positive anti-HCV antibody test or positive HCV RNA or positive HCV genotyping 
test at least 6 months prior to the Day 1 visit, or
b) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV 
infection
4) Infection with HCV GT 1 or 3 as determined at Screening
5) Subjects must have the following laboratory parameters at Screening: 
a) HCV RNA 104 IU/mL
b) ALT 10 the upper limit of normal  (ULN)
c) AST 10 ULN
d) Hemoglobin  9 g/dL 
e) Albumin 3.0 g/dL
f)
Direct bilirubin 1.5 x ULN
g) HbA1c 10%


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h) h)
For Part 1 subjects, estimated GFR between 15 ml/ min and ≤30 mL/min, and 
for Part 2 subjects, estimated GFR < 15 ml/min, as calculated by the Cockcroft Gault 
equation{2202}
Male:
(140 – age in years) (wt in kg) CLCr (mL/min)
72 (serum creatinine in mg/dL)
Female:
(140 – age in years) (wt in kg) 0.85 CLCr (mL/min)
72 (serum creatinine in mg/dL)
a.
Subjects with eGFR 30-40 mL/min are eligible if they have a prior 
eGFR 30 mL/min within 6 months of Screening
6) INR 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR.
7) A negative serum pregnancy test for female subjects of childbearing potential (see 
Appendix 2 for definition). 
8) Male subjects and female subjects of childbearing potential (see Appendix 2 for 
definition) must agree to use protocol specified method(s) of contraception as described 
in Appendix 2.
9) Lactating females must agree to discontinue nursing before administration of study drug.
10) Subject must be of generally good health as determined by the Investigator. 
11) Subject must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) BMI < 18
2) Prior exposure to an direct-acting antiviral targeting the HCV NS5B polymerase
3) Prior null response to PEG+RBV therapy 
4) Male with pregnant female partner
5) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency, cholangitis)
6) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)


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7) Unstable psychiatric condition 
8) Significant cardiac disease including cardiomyopathy or myocardial infarction within 
1 year of Screening
9) Clinically significant abnormality on ECG at Screening, including a QT prolongation 
>500 msec, or >450 msec in patients who concomitantly use methadone.
10) History of clinically significant hemoglobinopathy
11) History of porphyria
12) Malignancy within the 5 years prior to screening, with the exception of specific cancers 
that are cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation 
for possible malignancy are not eligible.
13) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone 
equivalent > 10 mg/day)
14) Clinically-relevant drug or alcohol abuse within 12 months of Screening. 
15) Current or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, 
encephalopathy or variceal hemorrhage)
16) History of clinically-significant illness or any other major medical disorder that may 
interfere with subject treatment, assessment or compliance with the protocol
17) History of a primary gastrointestinal disorder (or post operative condition) that could 
interfere with the absorption of the study drug 
18) Excessive alcohol ingestion, defined as 3 glasses/day (1 glass is equivalent to: beer 
[284 mL], wine [125 mL], or distilled spirits [25 mL]) for females and 4 glasses/day for 
males)
19) Inability to collect blood for safety, PK, and efficacy throughout the study
20) Donation or loss of more than 400 mL blood within 2 months prior to Day 1 
21) Use of any prohibited concomitant medications as described in Section 5.7 within 
21 days of the Day 1 visit
22) Known hypersensitivity to RBV, the study investigational medicinal product, the 
metabolites, or formulation excipients
23) Receipt of any investigational product within a time period equal to 10 half-lives of the 
product, if known, or a minimum of 4 weeks prior to study drug administration


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24) Subject must be of generally good health as determined by the Investigator
25) Subject must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments.
26) Subjects with hepatocellular carcinoma (HCC) are excluded from the study. In cirrhotic 
patients, liver imaging (e.g., ultrasound) within 6 months of Day 1 is required to exclude 
hepatocellular carcinoma (HCC)


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Sofosbuvir (SOF)
5.1.1.
Formulation
SOF tablets, 100 mg, are yellow, round, film-coated, plain-faced tablets. 
SOF tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets debossed with “GSI” on 
one side and “7977” on the other side.
In addition to the active ingredient, SOF tablets contain the following inactive ingredients: 
mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, and yellow iron 
oxide.
5.1.2.
Packaging and Labeling
SOF tablets, 100mg, 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 tablets, 400mg, are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 30 tablets and a silica gel desiccant canister or sachet and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant screw cap 
with an induction-sealed, aluminum-faced liner.
SOF bottles to be distributed to centers in the US and other countries shall be labeled to meet 
all applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 of 
Good Manufacturing Practices: Manufacture of investigational medicinal products 
(February 2010) and/or other local regulations as applicable.
5.1.3.
Storage and Handling
SOF bottles should be stored at a 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.
Sufficient quantities of SOF tablets to complete the entire study will be shipped to the 
investigator or qualified designee from Gilead Sciences Materials & Logistics (or its 
designee).


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5.1.4.
Sofosbuvir (SOF) Dosage and Administration 
SOF will be administered as 200 mg or 400 mg po daily. SOF (100 mg or 400 mg) tablets
will be supplied by Gilead Sciences for all subjects.
5.2.
Ribavirin (RBV)
5.2.1.
Formulation
RBV tablets, 200 mg, are blue, capsule-shaped, film-coated tablets debossed with “3RP” on 
one side and “200” on the other side. In addition to the active ingredient, RBV tablets contain 
the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, 
croscarmellose sodium, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, 
macrogol, talc, FD&C blue #2.
5.2.2.
Packaging and Labeling
The RBV tablets are packaged in white, HDPE bottles. Each bottle contains 168 tablets and 
rayon coil packing material and is enclosed with a white, continuous thread, child-resistant 
screw cap with an induction-sealed, aluminum-faced liner.  
RBV bottles to be distributed to centers in the US and other countries shall be labeled to meet 
all applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 of 
Good Manufacturing Practices: Manufacture of investigational medicinal products 
(February 2010) and/or other local regulations as applicable.
5.2.3.
Storage and Handling
RBV tablets should be stored at 25 C (77 F); excursions are permitted between 15 and 
30 C (59 and 86 F).
All drug products should be stored in a securely locked area, accessible only to authorized 
site personnel. To ensure the stability of the study drug and to ensure proper product 
identification, the drug product should not be stored in a container other than the container in 
which they are supplied. Consideration should be given to handling, preparation, and 
disposal through measures that minimize drug contact with the body. Appropriate 
precautions should be followed to avoid direct eye contact or exposure through inhalation 
when handling RBV.
5.2.4.
RBV Dosage and Administration 
RBV will be administered as 200 mg po daily. RBV should be dosed with food and with SOF 
to maximize adherence.
RBV tablets (200 mg) will be supplied by Gilead Sciences for all subjects.


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5.3.
Co-administration of Sofosbuvir (SOF) and Ribavirin (RBV)
Each subject will be given instructions to maintain approximately the same daily dosing 
interval between study drug doses.  
If a subject forgets to take the medication at the correct time, it may be taken later in the day; 
however, no more than 400 mg dose of SOF should be taken on any calendar day. The 
subject should resume the standing dosing schedule on the next day.  Study medications 
should not be cut or split.  No food restrictions apply to SOF; however, SOF should be taken 
with RBV and with food for optimal adherence.
On the day of clinic visits, subjects will be instructed to take their study medication on the 
day prior to clinic visits, 20-28 hours before the administration of the study medication at the 
clinic. Subjects should bring their medication with them to the clinic and take their study 
medication after all pre-dose assessments are completed. 
5.4.
Study Drug Compliance
On Day 1, subjects will be administered study drugs and the assigned bottles will be 
dispensed to them along with a dosing diary to be used to document at home dosing. Subjects 
will be instructed to return dosing diaries and any unused study drug in the original container 
at each visit following Day 1 for study drug compliance assessment.
Returned medication will be reconciled by the investigator in order to monitor the subject’s 
compliance with the medication regimen.
5.5.
Dispensing and Accountability of Study Drugs
The Investigator (or designee, e.g., study center pharmacist) will acknowledge receipt of the 
study drugs (after reviewing the shipment’s content and condition) from Gilead Sciences (or 
designee). The Investigator will maintain an accurate inventory of all study drugs. Each dose 
of the study drug(s) administered at the study center will be administered by qualified study 
center personnel. All doses of study drug(s) administered to subjects in the clinic under the 
supervision of staff will be accurately recorded on the Investigational Product Inventory Logs 
provided by Gilead Sciences (or on equivalent documentation maintained by the study 
center), which indicates the date and quantity of all doses of study drug(s) dispensed to 
individual subjects. The requirements of all applicable Federal and State drug dispensing 
laws will apply to all doses of study drugs dispensed by the Investigator (or designee). At the 
end of the study, all unused study drugs (both bulk and individual subject returns) will be 
returned to a location designated by Gilead Sciences.


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5.6.
Study Drug Return or Disposal
At the start of the study, the study monitor will evaluate each study center’s study drug 
disposal procedures and provide appropriate instruction for return or destruction of unused 
study drug supplies. If the site has an appropriate Standard Operating Procedure (SOP) for 
drug destruction, the site may destroy used and unused study drug supplies performed in 
accordance with the site’s (hospital/pharmacy) SOP. If the site does not have acceptable 
procedures in place for drug destruction, arrangements will be made between the site and 
Gilead Sciences (or Gilead Sciences’ representative) for return of unused study drug 
supplies. Where possible, study drug will be destroyed at the site.  If drug is destroyed on 
site, the investigator must maintain accurate records for all study drug destroyed. All study 
drug records must be maintained at the site and copies must be submitted to Gilead Sciences 
at the end of the study.
5.7.
Concomitant Medications
Concomitant medications taken within 30 days of Screening, up to and including the date of 
the visit four weeks after discontinuation of study treatment, need to be recorded in the 
source documents and eCRFs.
The following medications are prohibited from 21 days prior to the Day 1 visit through the 
end of treatment:

Drugs disallowed per prescribing information of RBV (COPEGUS®)

Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters i.e. P-gp) with study drug(s) may result in pharmacokinetic interactions 
resulting in decreases in exposure of study drug(s).  Representative medications which 
are excluded from 21 days prior to Day 1 through the end of treatment are listed below:
Drug
Agents Disallowed
Concomitant use with study drug may 
potentially result in changes of study 
drug concentration as listed below
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Decrease in concentration of study drug
Antimycobacterials
Rifampin, rifabutine, rifapentine
Decrease in concentration of study drug
Herbal/Natural 
Supplements
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-
to (or Xiao-Shai-Hu-Tang)
Decrease in concentration of study drug
Other
Modafinil
Decrease in concentration of study drug
Medications for disease conditions excluded from the protocol (e.g., HIV-1 infection, active 
cancer, transplantation) are not listed under this Concomitant Medication section and are 
prohibited in the study.


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5.7.1.
Medications Associated with QT Prolongation
Medications that are known to cause or are associated with QT prolongation and/or a risk of 
causing torsades de pointes should be avoided in patients with risk factors for developing 
long QT intervals or those receiving other QT-prolonging medications.  These medications 
include, but may not be limited to those listed below (see table below) and must be approved 
by the Gilead Medical Monitor prior to study enrollment or coadministration during the 
study.  
Representative List of Medications Known or Associated with QT Prolongation
QT Prolonging Medication Class
Known or Strongly Suspected to cause 
QT Prolongation
Weaker Association with 
QT Prolongation
Antibiotics/Anti-infectives:
Macrolide Antibiotics
azithromycin, clarithromycin, 
erythromycin, roxithromycin, 
telithromycin
Quinolone Antibiotics
gatifloxacin, gemifloxacin, levofloxacin, 
moxifloxacin, ofloxacin, sparfloxacin
ciprofloxacin
Certain 
antimalarials/pneumocystis 
prophylaxis; others
artenimool+piperaquine, bedaquiline, 
chloroquine, halofantrine, pentamidine
trimethoprim-sulfa, quinine 
sulfate
Antipsychotics:
Phenothyazine 
Antipsychotics
chlorpromazine, mesoridazine, 
thioridazine
Other Antipsychotics
clozapine, haloperidol, iloperidone, 
olanzepine, paliperidone, pimozide, 
quetiapine, risperidone, sertindole, 
ziprasidone
amisulpride,
Anit-mania Bipolar Disorders:
lithium
Anti-depressants:
Serotonin re-uptake 
inhibitors
citalopram, escitalopram, venlafaxine
fluoxetine, paroxetine, 
sertraline
Tricyclic anti-depressants
amitriptyline, 
clomipramine, 
desipramine, doxepin, 
imipramine, nortriptyline, 
protriptyline trimipramine,
Tetracyclic anti-
depressants
mirtazepine
trazodone


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QT Prolonging Medication Class
Known or Strongly Suspected to cause 
QT Prolongation
Weaker Association with 
QT Prolongation
Cardiology Medications:
Class I (Na+) and III (K+) 
anti-arrhythmics
amiodarone, disopyramide, dofetilide, 
dronedarone, flecainide, ibutilide, 
mexiletine, procainamide, quinidine
Class II (β blockers) and 
IV (Ca2+) anti-arrythmics
isradipine, sotalol (Class II/III)
Certain anti-anginals/ 
calcium blocker
bepridil, nicardipine, ranolazine
Anesthetics, Pain Medications 
and Additional Treatment:
levomethadyl, methadone
general anesthetics (e.g., 
enflurane, halothane, 
isoflurane, sevoflurane)
Anti-nausea:
domperidone, droperidol, dolasetron, 
granisetron, ondansentron, promethazine
Azole anti-fungals (systemic use 
only)
ketoconazole, voriconazole
fluconazole, itraconazole
Others:
alfuzosin, amantadine, astemizole, 
cisapride, famotidine, felbamate, 
fosphenytoin, galantamine, indapamide, 
moexipril/HCTZ, octreotide, oxytocin, 
pasireotide, perflutren lipid microspheres, 
probucol, sibutramine, terfenadine,   
tizanidine, tolterodine, vardenafil
chloral hydrate, 
diphenhydramine, 
solifenacin
a
Should it become medically necessary for patients to start treatment with any excluded concomitant medication, the 
sponsor must be consulted prior to initiation of the new medication and the subject’s continued participation must be 
discussed with the Gilead Medical Monitor.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in
Table 6-1 and described in the following text. 
Any deviation from protocol procedures should be noted in the subject’s clinical chart and 
appropriate eCRFs. In addition, the Sponsor should be promptly notified of any protocol 
deviations. 
The study center will not be released to initiate dosing until:

The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) reviewed 
and approved the study and the informed consent document;

All requested regulatory documents have been submitted to and approved by 
Gilead Sciences;

A Master Services Agreement and/or Study Agreement is executed;

The study initiation meeting has been conducted by the Gilead Sciences clinical monitor 
(or designee).
The initiation meeting will include a review of the protocol, the Investigator’s Brochure, and
Investigator responsibilities.
Documentation of the personally signed and dated informed consent of each subject, using 
the study-specific informed consent form (ICF), is required before initiating the screening 
process. Generic screening consent forms should not be used in lieu of the study-specific 
ICF.
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that subjects are eligible to participate in 
the study prior to enrollment and throughout the study.
Once consent has been obtained, all screening tests and procedures have been assessed, and 
study eligibility has been confirmed, subjects will be enrolled and assigned a unique subject 
identification number.
Subjects will receive the study treatment as described in Section 5.


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Table 6-1.
Schedule of Assessments
Study Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment 
Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Written Informed 
Consent
X
Medical History 
X
HCV RNA Genotype
X
IL28B Genotyping
X
HbA1c  
X
HCV, HBV, HIV 
Serology
X
TSH
X
Physical Exam, 
including Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation (PT, PTT, 
and INR)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Study Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment 
Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
HCV RNA Viral Load
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA
Sequencing 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy 
Teste
X
X
X
X
X
X
X
X
X
X
X
X
Estimated GFR
X
Optional 
Pharmacogenetic 
Sample
X
Intensive PK
Xf
Xf
Trough PK Sampleg
X
X
X
X
X
X
X
X
X
Archive Plasma 
Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
Administration
X
Weeks 1 -24
Review Dosing 
Diary/Perform 
Accountabilityh
X
X
X
X
X
X
X
X
X
X
AEs/
Concomitant Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Screening evaluations must be completed within 35 days prior to Day 1.
b
Day 1 tests and procedures must be completed prior to administration of the first dose of study drugs 
c
Within 72 hours of permanently discontinuing study drug.


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d
Full PE at Day 1 and ET visits only; symptom-directed PE at all other timepoints. Vital signs include blood pressure, pulse, respiration rate, and temperature
e
Females of childbearing potential only. To confirm eligibility at Day 1, a urine pregnancy test may be collected for subjects able to pass urine. For subjects unable to pass 
urine, a serum pregnancy test at Day 1 must be performed at a local lab prior to dosing to confirm eligibility along with sample collected and send to central lab. During post-
treatment of the study, serum or urine pregnancy testing will occur every month during non-clinic post treatment visits. The subject will be contacted by telephone to confirm 
that pregnancy testing has been performed post-treatment during non-clinic visits.
f
Intensive PK evaluations will be assessed at the following timepoints: 0 (predose +/-5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose. In Part 2 (ESRD subjects on 
dialysis), the Week 2 and 12 visits (intensive PK assessments) must be conducted the same number of days after the previous dialysis session.
g
Trough PK samples will be drawn prior to dosing. 
h
Dosing Diaries will be completed for all non-observed doses and will be reviewed at every visit. Unused study drug will be returned to perform study drug accountability in 
the original container at each visit following Day 1 for study drug compliance assessment.
i
A window of ± 2 days is allowed for the treatment visits on weeks 1, 2, and 12.  A window of ± 4 days is allowed for the treatment visits weeks, 4-10, and 16-24. Subjects 
who cannot complete their study visit per the visit schedule should ensure they do not run out of study drug prior to their next study visit.  Compliance is critical to ensure 
adequate drug exposure.
j
A window of ± 7 days is allowed for the post treatment visits on week 4.


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6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Prospective subjects should be screened within 35 days prior to first dose on Day 1. If the 
subject does not begin the treatment phase within this 35-day window, all screening 
evaluation procedures must be repeated. No more than one repeat screen visit is allowed for 
each subject, unless prior written approval has been provided by the Sponsor.
Written informed consent must be obtained from each subject before initiation of any
screening procedure. After a subject has provided informed consent, the investigator and 
other study personnel will determine if the subject is eligible for participation in the study.  
This assessment will include a review of the inclusion/exclusion criteria and completion of 
all screening procedures as outlined in Table 6-1.
Once eligibility is confirmed, the study site will complete an eligibility worksheet for each 
screened subject and submit for Sponsor review. The sponsor will assign a unique subject 
number for each eligible subject and provide the subject number information to the site prior 
to Day 1 visit. 
6.2.2.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and 
whether condition(s) is currently ongoing, and medication history will be collected on all 
subjects during screening. Information related to HCV infection will be collected. In 
addition, a cirrhosis determination will be made as follows:
Cirrhosis determination

Cirrhosis is defined as any one of the following:
— Liver biopsy showing cirrhosis
— Fibroscan (in countries where locally approved) showing cirrhosis or results 
> 12.5 kPa
— FibroTest® score of > 0.75 AND an AST:platelet (APRI) ratio of > 2 during 
Screening

Absence of cirrhosis is defined as any one of the following:
— Liver biopsy within 2 years of Screening showing absence of cirrhosis
— Fibroscan (in countries where locally approved) with a result of ≤12.5 kPa within 
≤6 months of Day 1
— FibroTest® score of ≤ 0.48 AND APRI of ≤1 during Screening
In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above 
criteria, a liver biopsy is required.


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6.3.
Day 1 Assessments
Subjects meeting all eligibility criteria following the screening evaluation will return to the 
study site within 35 days for Day 1 assessments as outlined in Table 6-1.
6.3.1.
Dosing Diary
Subjects will be provided with self-administration instructions and study drug diaries to 
record the exact date, time and number of tablets of study drug administration.  The site staff 
will record the information from the study drug dosing diary into the eCRF.  In the event that 
the dosing diary is not available, the site may obtain dosing information via subject interview 
and record this information in the source notes
6.4.
Treatment Assessments
Study visits will occur at the end of Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24.
Study procedures and assessments are outlined in Table 6-1. 
6.5.
Safety Assessments
Safety will be evaluated throughout the study. Refer to Table 6-1 for a schedule of 
assessments.
6.5.1.
Safety ECGs
Subjects should rest quietly in the supine position for a minimum of 10 minutes prior to each 
scheduled ECG acquisition and should remain in that position until the recording is complete. 
There must be no environmental distractions (television, radio, conversation, etc.) while the 
subjects are resting prior to and during the recordings.
ECGs will be recorded at a sampling frequency of 500+ Hz, at a speed of 25 mm/sec and at a 
standard duration of 10 seconds. All ECGs will be obtained using instruments that analyze 
data using the same algorithms and produce the same data for interpretation. When ECGs are 
performed on an ECG machine, site standard operating procedures (SOPs) will be used.
ECG measurements will be collected pre-dose at time-points as per Table 6-1.
The Investigator or other qualified individuals at the study center will review ECGs to assess 
for changes in ECG intervals and morphology as compared to pre-dose ECGs. Collection of 
additional ECGs for routine safety monitoring at additional time-points or days is at the 
discretion of the Investigator based on GCP.
6.5.2.
Physical Examination
Complete physical examinations or a symptom directed physical examination will be 
conducted pre-dose as outlined in Table 6-1. A complete physical examination must include 
source documentation of general appearance, and the following body systems: head, neck 
and thyroid; eyes, ears, nose, throat, mouth and tongue; chest (excluding breasts); respiratory; 
cardiovascular; lymph nodes, abdomen; skin, hair, nails; musculoskeletal; neurological. 


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6.5.3.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, 
respiratory rate, and temperature and will be conducted pre-dose as outlined in Table 6-1.
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.
6.5.4.
BMI
Height and weight will be collected at the times shown in the schedule of assessments 
Table 6-1.
BMI is calculated by the following equation.
BMI = weight (pounds) 703           or            weight in kilograms
   (height in inches)2                                (height in meters)2
6.5.5.
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)
6.5.6.
Clinical Laboratory Tests/Assessments
In addition to the PK blood samples that will be collected, blood samples will be collected 
pre-dose as outlined in the schedule of assessments, Table 6-1 for the following laboratory 
analyses:
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, MCV, 
and Coagulation Panel (PT, PTT, and INR).


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Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase 
(AST/SGOT), Albumin, Alkaline phosphatase, Creatinine, Total Bilirubin (reflex to Direct 
Bilirubin), Glucose, Total Protein, Bicarbonate, BUN, Calcium, Chloride, Phosphorus, 
Magnesium, Potassium and Sodium. 
Thyroid-stimulating hormone (TSH)
Haemoglobin A1C (HbA1c)
Virological Tests: Serologies for HCV, HBV and HIV. HCV RNA will be measured using 
the COBAS® TaqMan® HCV Test, v2.0 for Use with the High Pure System. HCV genotype 
and subtype will be determined using the Siemens VERSANTHCV Genotype INNO-LiPA 
2.0 Assay. Gilead reserves the right to use alternate assays for HCV RNA and HCV genotype 
should the above assays become unavailable or are not definitive.
Viral RNA Sequencing / Phenotyping plasma samples will be collected to confirm virologic 
breakthrough. Untested samples may be archived.
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: All females of childbearing potential will have serum or urine pregnancy 
testing every 4 weeks during the dosing period and for a minimum of 6 months following the 
last dose of RBV. If required by local regulations, additional pregnancy tests may be 
collected. In the event of a positive urine pregnancy result, subjects will be instructed to stop 
study drugs immediately and return to the clinic as soon as possible for a serum pregnancy 
test.
Pregnancy tests must be completed for all females of childbearing potential (see Appendix 2 
for definition) as specified in Table 6-1. When feasible for subjects, a urine pregnancy test 
may also be taken. During post treatment of the study, subject will be contacted by telephone 
monthly to confirm that the serum or urine pregnancy testing has been performed post-
treatment during non-clinic visits.. Alternatively, if required by local regulations or preferred 
by the investigator or subject, the subject may return to the clinic for urine or serum 
pregnancy tests post treatment.
6.5.7.
Adverse Events/ Concomitant Medications/ Protocol Restrictions
Evaluation for adverse events, review of concomitant medications, and review of protocol 
restrictions will occur at the times shown in the schedule of assessments Table 6-1. See 
Section 7 for more information regarding adverse events and Section 5 for more information 
about concomitant medications.


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6.6.
Pharmacokinetic (PK) Assessments
Subjects will be instructed to take their SOF dose on the day prior to clinic visits, 20-28 
hours before the clinic visit. On the day of clinic visits, subjects should bring their 
medication with them to the clinic and take their dose after the trough PK sample is 
collected, or after the predose intensive PK sample is taken.
In Part 2 (ESRD subjects on dialysis), the Week 2 and 12 visits (intensive PK assessments) 
must be conducted the same number of days after the previous dialysis session.
The exact time of the dose taken prior to collection of the PK sample and the exact time the 
PK sample is drawn will be recorded on the appropriate eCRF.
Trough PK blood samples will be collected pre-dose for all subjects at each on-treatment 
visit after Day 1 and archived for PK analysis of SOF (and its metabolites GS-566500 and 
GS-331007) and/or RBV as appropriate.
6.7.
Early Termination (ET)/Unscheduled Visit 
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. 
The assessments at the unscheduled visits are at the investigator’s discretion. At all 
unscheduled visits initiated for the purpose of confirming virologic failure a Viral RNA 
Sequencing / Phenotyping Sample must be collected. 
The Sponsor (e.g. Medical Monitor and Clinical Program Manager)/CRO must be informed, 
as soon as possible, when a subject prematurely discontinues treatment.  The primary reason 
for premature treatment discontinuation must be provided to the Sponsor/CRO.  
If a subject discontinues treatment early for any reason then the following assessments for the 
Early Termination (ET) Visit must be performed: 

Perform complete physical examination

Obtain body weight

Obtain vital signs

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Obtain blood samples for:
— Hematology & Chemistry
— Coagulation (PT, PTT, and INR)
— HCV RNA


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Viral Sequencing I Phenotyping Sample 
-
TroughPK 
-
Semm pregnancy test (females of childbearing potential only) 
Final 
Original 
• 
Review study dmg adherence with subject including recording the date and time of the 
subject's last dose of study dmg prior to the PK draw (subject should retum all study 
dtugs at this visit) 
All subjects will attend the 4-Week Post-Treatment Visit. 
6.8. 
Post-Treatment Assessments 
Subjects with HCV RNA < LLOQ at the 4-Week Post-Treatment Visit will attend the 
12-Week Post-Treatment Visit. 
Subjects with HCV RNA ~ LLOQ do not need to retum for additional visits and they will be 
tenninated early from the study. 
Subjects with HCV RNA < LLOQ at the Post-Treatment Week 12 Visit will retum at the 
post-treatment Week 24 Visit. 
6.9. 
Optional Samples for Pharmacogenetic Testing 
PD 
6.10. 
Archived Plasma Sample 
Archive plasma samples will be collected at the study visits, indicated in Table 6-1. Archive 
plasma samples are being collected for possible additional analyses, including but not limited 
to, study dtug or metabolite measurements, viral load, safety/efficacy assessments, HCV 
gene sequencing, HCV resistance testing and other possible predictors of response as 
detennined by Gilead. 
In the event of a subject's death or loss of competence, the subject's specimens and data. will 
continue to be used as prui of the optimal future biomru·ker reseru·ch. 
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6.11. 
Blood Storage 
Final 
Original 
Archived blood samples will be collected for future testing. These samples will be frozen and 
stored. The stored blood samples may be used by the Sponsor or its research pruiner for 
future clinical laborat01y testing to provide additional clinical data. At the conclusion of this 
study, these samples may be retained in storage by Gilead Sciences, Inc. at its reseru·ch 
pruiner facility for a period up to 10 yeru·s. 
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7.
ADVERSE EVENTS MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with the treatment. An AE can therefore be any unfavorable and/or unintended sign, 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. AEs may also include pre- or post treatment 
complications that occur as a result of protocol specified procedures, lack of efficacy, 
overdose, drug abuse/misuse reports, or occupational exposure. Preexisting events that 
increase in severity or change in nature during or as a consequence of participation in the 
clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and 
transfusion. The condition that led to the procedure may be an adverse event and must be 
reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before 
the screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not 
an AE. It is considered to be pre-existing and should be documented on the medical 
history CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the 
following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer 
to an event that hypothetically might have caused death if it were more severe.)


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
In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; and development of drug 
dependency or drug abuse. For the avoidance of doubt, infections resulting from 
contaminated medicinal product will be considered a medically important event and 
subject to expedited reporting requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event 
information and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to 
IMP therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, 
an alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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It should be emphasized that ineffective treatment should not be considered as causally 
related in the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or 
biopsy) should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study 
procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading 
Scale for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs 
associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in 
agreement with the grading of the laboratory abnormality.
7.3.
Investigator Requirements and Instructions for Reporting Adverse 
Events and Serious Adverse Events to Gilead.
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required 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 from 
screening onwards.
All AEs, regardless of cause or relationship, that occur from initiation of study medication 
until 4 weeks after last administration of study IMP must be reported to the CRF/eCRF 
database as instructed. 
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of 
the last dose of study IMP, regardless of causality, should also be reported.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the post-treatment 
follow-up period.
Investigators are not obligated to actively seek SAEs after the post treatment follow-up 
period. However, if the investigator learns of any SAEs that occur after study participation 
has concluded and the event is deemed relevant to the use of IMP, he/she should promptly 
document and report the event to Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines 
outlined in the CRF/eCRF completion guideline. 

At the time of study start, SAEs will be reported using a paper serious adverse event 
reporting form. During the study conduct, sites may transition to an electronic SAE 
(eSAE) system. Gilead will notify sites in writing and provide training and account 
information prior to implementing an eSAE system.


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Serious Adverse Event Paper Repmiing Process 
Final 
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• 
All SAEs will be recorded on the serious adverse event repmi fonn and submitted by 
faxing the report fmm within 24 hours of the investigator's knowledge of the event to the 
attention of Gilead DSPH. 
Electronic Serious Adverse Event (eSAE) Repmiing Process 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit the SAE 
infmmation to Gilead DSPH within 24 hours of the investigator's knowledge of the 
event. Detailed instructions can be fmmd in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE infmmation electr·onically, ie, the 
eCRF database is not fimctioning, record the SAE on the paper serious adverse event 
repmiing fmm and submit within 24 hours as described above. 
• 
As soon as it is possible to do so, any SAE reported via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repmied via a paper fonn because the eCRF database has been 
locked, no fmiher action is necessaty. 
Gilead DSPH: 
Fax: 
+ 1-650-522-5477 
E-mail: 
safety_ fc@gilead.com 
Gilead Sciences 
Name: 
Diana Brainard, MD 
Medical Monitor: 
Phone: 
PPD 
Mobile 
PPD 
Fax: 
PPD 
E-mail: 
PPD 
I 
• 
For fatal or life-threatening events, copies of hospital case repmis, autopsy repmis, and 
other documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the tr·aceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensure the timely completion of accurate 
safety repmis. 
Any medications necessruy for tr·eatlnent of the SAE must be recorded onto the concomitant 
medication section of the subject's CRF/eCRF and the event description section of the SAE 
fmm. 
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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to 
expedite to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions 
(SADRs), or suspected unexpected serious adverse reactions (SUSARs). In accordance with 
the EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify 
worldwide regulatory agencies and the relevant IEC in concerned Member States of 
applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. 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. 
7.5.
Toxicity Management 
7.5.1.
Stopping Rules for Toxicity
Subjects who meet any of the following criteria should be instructed to immediately stop all 
study drugs and return for an Early Termination Visit

Confirmed elevation of ALT and/or AST > 5x Day 1 or nadir, confirmed by immediate 
repeat testing

Confirmed elevation of ALT >3x Day 1 and total bilirubin >2 x ULN

Confirmed elevation of ALT >15 x ULN

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event assessed as related to treatment 
7.5.2.
Sofosbuvir (SOF)
Administration of SOF may be discontinued due to a clinical or laboratory event.  In the 
event that SOF is stopped, RBV should also be discontinued. 
7.5.3.
Ribavirin (RBV)
Dose reduction or interruption of RBV due to toxicity should be performed based on the 
clinical experience of the Investigator. RBV may be permanently discontinued due to toxicity 
without stopping SOF. 


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7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, and 
pregnancy reports regardless of an associated AE.  Also includes reports of adverse reactions 
in infants following exposure from breastfeeding, and reports of adverse reactions associated 
with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following maternal or paternal exposure 
to the medicinal product.
Medication error is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by 
a subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not 
in accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a 
medicinal product given per administration or cumulatively which is above the maximum 
recommended dose as per protocol or in the product labelling (as it applies to the daily dose 
of the subject in question). In cases of a discrepancy in drug accountability, overdose will be 
established only when it is clear that the subject has taken the excess dose(s). Overdose 
cannot be established when the subject cannot account for the discrepancy except in cases in 
which the investigator has reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the 
manufacture, packaging, or distribution of the medicinal product.  
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first 
consents to participate in the study (ie, signs the informed consent) and throughout the study, 
including the post study drug follow-up period, to the Gilead DSPH using the pregnancy 
report form within 24 hours of becoming aware of the pregnancy. Refer to Section 7.3 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.


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Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as 
an SAE. The underlying medical reason for this procedure should be recorded as the AE 
term.
A spontaneous abortion is always considered to be an SAE and will be reported as described 
in Sections 7.1.1 and 7.1.2 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. 
Clinical staff should also report any pregnancies to the Ribavirin Pregnancy Registry at 
1-800-593-2214 (see also http://www.ribavirinpregnancyregistry.com).
Refer to Appendix 2 for Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the 
situation. These reports must consist of situations that involve study IMP, but do not apply to 
concomitant medications. Except for situations that result in AEs, special situations involving 
concomitant medications will not be reported. Any inappropriate use of medications 
prohibited by this protocol should not be reported as “misuse,” but may be more 
appropriately documented as a protocol deviation.
Refer to Section 7.3 and the 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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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The prima1y objectives of this study are as follows: 
Final 
Original 
• 
To evaluate the safety of SOF 200 mg or 400 mg + RBV for 24 weeks as assessed by 
review of the accumulated safety data in each treatment rum 
• 
To evaluate the efficacy of SOF 200 mg or 400 mg + RBV for 24 weeks measured by the 
prop01iion of subjects with renal insufficiency who have achieved a SVR12 after 
treatment discontinuation in each treatment ann 
• 
To evaluate the steady state PK ofSOF and its metabolites upon dosing SOF 200 mg or 
400 mg in subjects with renal insufficiency 
The secondruy objectives of this study ru·e as follows: 
• 
To evaluate the prop01iion of subjects with renal insufficiency who attain SVR4 and 
SVR24 weeks after discontinuation of treatment 
• 
To evaluate the kinetics of plasma HCV RNA during and after treatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF during and after treatment 
discontinuation 
The explorat01y objective ofthis study is: 
PPO 
8.1.2. 
Primary Endpoint 
The prima1y safety endpoints include incidences of AEs, laborat01y, 12-lead ECG, and vital 
sign abn01malities. 
The primru·y PK endpoints ru·e pru·ameters AUCtau, Cmax, and Ctau for analytes SOF, 
GS-566500, GS-331007, and RBV as applicable. 
The prima1y efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after discontinuation 
of therapy). 
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8.1.3.
Secondary Endpoint
Secondary PK endpoints are parameters AUClast, Clast, Tmax, Tlast, λz, and t1/2 for analytes SOF, 
GS-566500, GS-331007, and RBV as applicable.
Secondary efficacy endpoints include the proportion of subjects with SVR4 and SVR24, the 
proportion of subjects with virologic failure including viral breakthrough and relapse.
8.1.4.
Other Endpoints of Interest
Additional efficacy evaluations may include HCV RNA change from baseline; ALT 
normalization; viral kinetic parameters, and the health related quality of life endpoints.
8.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses 
will be performed using SASsoftware (SAS Institute, Cary, North Carolina, USA).
The study drugs in this study include SOF and RBV. Last dose of study drug refers to the last 
dose of any of the study drugs in a treatment group and will be used in the definition of 
treatment-emergent AEs and laboratory abnormalities as well as the efficacy endpoints of 
SVR at various post-treatment time points.
All analyses will be presented by treatment in each renal function subgroup (study part). 
Subjects who receive study drug other than that to which they were assigned will be analyzed 
according to the study drug received.
8.2.1.
Analysis Sets
8.2.1.1
Efficacy
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which 
includes subjects who were enrolled and received at least one dose of study drug. 
8.2.1.2
Safety
The primary analysis set for safety analyses will be the Safety Analysis Set which includes
subjects who received at least one dose of study drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose of 
study drug through the date of the last dose of study drug plus 30 days.
8.2.1.3
Pharmacokinetics
The PK analysis set will include all subjects who are enrolled and have received at least one 
dose of study drug and for whom PK concentration data of interested analytes (SOF, 
GS-566500, GS-331007, or RBV) are available. The PK analysis set will be used for 
analyses of general PK.


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8.2.2.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. In general, values 
for missing data will not be imputed. 
For the analysis of post-baseline categorical efficacy endpoints, if a data point is missing and 
is immediately preceded and followed in time by values that are deemed successes, then the 
missing data point will be termed a success; otherwise the data point will be termed a failure.
Any subject with missing data due to premature discontinuation of the study medication will 
be considered a failure at the time points on, or following, the date of discontinuation. If no 
HCV RNA values are obtained after the last dose of study medication, the subject will be 
considered a treatment failure for the SVR endpoints. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject received study medication, the subject will be included in a summary of 
adverse events according to the treatment received; otherwise, if the subject is not dosed 
then they will be excluded from the summary.

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 predose value, then the subject will be excluded from the 
calculation of summary statistics for the predose value and the change from predose 
values.
Values for missing safety laboratory data will not be imputed; however, a missing baseline 
result will be replaced with a screening result, if available. If no pretreatment laboratory 
value is available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) 
for the summary of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for 
calculation of summary statistics for the actual HCV RNA values and the change from 
baseline values by study visit. The reported values will be provided in the HCV RNA listing.
For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed 
to the logarithmic (base 10) scale (log10 IU/mL).
PK concentration values below the lower limit of quantitation (BLQ) will be treated as zero
for determination of summary and order statistics. Individual values that are BLQ will be 
presented as “BLQ” in the concentration data listing. For the presentation of summary and 
order statistics, if at least 1 subject has a concentration value BLQ for the time point, then the 


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minimum value will be displayed as “BLQ.” If more than 50% of the subjects have a 
concentration data value BLQ for the time point, then the minimum and median values will 
be displayed as “BLQ.” If more than 75% of the subjects have a concentration data value of 
BLQ for a given time point, then the minimum. 1st quartile [q1], median, and 3rd quartile 
[Q3] values will be displayed as “BLQ.” If all subjects have concentration data values BLQ 
for the time point, then all order statistics (minimum, first quartile [Q1], median, third 
quartile [Q3], maximum) will be displayed as “BLQ”.
Exposure parameters that are selected for statistical analysis will be natural log-transformed. 
Concentration values that are BLQ will be excluded for any ratio or natural log-transformed 
statistical analysis.
8.2.3.
Interim Analysis
No formal interim analyses are planned for this study. For the purpose of making the decision 
to proceed with Part 2, an informal data review of available safety, efficacy, and PK data will 
be conducted by the Sponsor to facilitate the decision of doses and the timing of initiating 
Part 2.
8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline characteristics will be summarized using standard descriptive 
methods by treatment in each study part.
Demographic data will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include body weight/body mass index, HCV RNA level 
(log10 IU/mL), IL28B genotype, baseline ALT level, creatinine clearance estimated by 
Cockcroft-Gault, and additional endpoints as necessary.
8.4.
Efficacy Analysis
8.4.1.
Primary Analysis
The primary efficacy endpoint is SVR12 in the FAS population. The primary analysis will be 
performed after all enrolled subjects have been followed through 12 weeks post-treatment or 
discontinued from study.
A point estimate with a 2-sided 95% exact confidence interval (CI) using the exact binomial 
distribution (Clopper-Pearson method) will be constructed for the SVR12 rate by treatment 
and study part.
No statistical hypothesis testing will be performed.


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8.4.2. 
Secondary Analysis 
Final 
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The prop01tion of subjects with HCV RNA below the LLOQ over time (including SVR12) 
will be presented by treatment and study pmt in tabulm· and graphical f01m . 
Descriptive summm·ies and listings will be provided for additional efficacy evaluations 
including the prop01tion of subjects who experience virologic failure, ALT n01m alization, 
sennn HCV RNA actual values and change from baseline, other endpoints of interest 
including AL T nonnalization and health related quality of life endpoints. 
PPD 
Details on efficacy analyses will be described in the statistical analysis plan (SAP). 
8.5. 
Safety Analysis 
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, 
vital signs measurements, at vm·ious time points during the study, and by the doclnnentation 
of AEs. 
All safety data collected on or after the first dose of study dmg adminisu·ation up to 30 days 
after the last dose of study dm g will be summm·ized according to the study dmg received. 
Safety endpoints will be sUIIllnm·ized as the number (proportion) of subjects with events or 
abn01m alities for categorical data or as an 8-number summmy (n, mean, standai·d deviation, 
minimum, Ql, median, Q3, maximum) for continuous data .. 
8.5.1. 
Extent of Exposure 
A subject's extent of exposure to study dmg will be generated from the study dmg 
adminisu·ation page of the CRF. Exposure data will be summm·ized by u·eatment and study 
pmt. 
8.5.2. 
Adverse Events 
Clinical and laborat01y AEs will be coded using the Medical Dictionmy for Regulat01y 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Te1m (HLGT), 
High-Level Te1m (HLT), Prefen ed Te1m (PT), and Lower-Level Te1m (LLT) will be 
attached to the clinical database. 
Events will be sUIIllnarized on the basis of the date of onset for the event. A 
u·eatment-emergent adverse event will be defined as any new or worsening adverse event that 
begins on or after the date of first dose of study dmg up to the date of last dose of study dmg 
plus 30 days. 
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Summaries (number and percentage of subjects) of treatment-emergent adverse events (by 
SOC and preferred term) will be provided by treatment and study part:

All AEs,

All study drug-related AEs,

Combined Grade 2, 3 and 4 AEs,

Combined Grade 3 and 4 AEs,

Combined Grade 2, 3 and 4 study drug-related AEs,

Combined Grade 3 and 4 study drug-related AEs,

All AEs that caused permanent discontinuation from study drug,

All AEs that caused change in dose or temporary interruption of study drug,

All SAEs (including death), and

All study drug-related SAEs
All AEs collected during the course of the study will be presented in data listings.
8.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, minimum, Q1, median, Q3, 
maximum) by study visit along with corresponding change from baseline.
Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme 
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 baseline at 
any time post-baseline up to the date of last dose of study drug plus 30 days will be 
summarized by treatment and study part. 
Values for missing safety laboratory data will not be imputed; however, a missing baseline 
result will be replaced with a screening result, if available. If no pretreatment laboratory 
value is available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) 
for the summary of graded laboratory abnormalities. Thus, any post-baseline graded 
abnormality (i.e., at least Grade 1) will be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.


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8.6.
Pharmacokinetic Analysis
Plasma concentrations of the study drug over time will be listed and summarized using 
descriptive statistics. PK parameters (e.g., AUCtau, Cmax, and Ctau) will be listed and 
summarized for study drug [SOF and metabolite(s)] and/or RBV using descriptive statistics 
(e.g., sample size, arithmetic mean, geometric mean, % coefficient of variation [%CV], SD, 
minimum, Q1, median, Q3, maximum). Details of the analysis plan will be provided in the 
SAP.
8.7.
Stopping Rules for Individual Groups
There are no predetermined futility criteria which would require enrollment to be halted or 
treatment discontinued.
8.8.
Sample Size
Due to the exploratory nature of this study, no formal power or sample size calculations were 
used to determine treatment group size. The total sample size of 40 i.e., 10 enrolled to obtain 
8 evaluable for each treatment in each study part) is largely based on feasibility.


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


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written informed consent. Each informed consent (or assent as applicable) will be 
appropriately signed and dated by the subject or the subject’s legally authorized 
representative and the person conducting the consent discussion, and also by an impartial 
witness if required by IRB or IEC or local requirements. The consent form will inform 
subjects about pharmacogenomic testing and sample retention, and their right to receive 
clinically relevant pharmacogenomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties. Only subject initials, date of birth, 
another unique identifier (as allowed by local law) and an identification code will be 
recorded on any form or biological sample submitted to the Sponsor, IRB or IEC, or 
laboratory. Laboratory specimens must be labeled in such as way as to protect subject 
identity while allowing the results to be recorded to the proper subject. Refer to specific 
laboratory instructions. NOTE: The investigator must keep a screening log showing codes, 
names, and addresses for all subjects screened and for all subjects enrolled in the trial. 
Subject data will be processed in accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to 
the investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study 
information, remain the sole and exclusive property of Gilead during the conduct of the study 
and thereafter. This information is not to be disclosed to any third party (except employees or 
agents directly involved in the conduct of the study or as required by law) without prior 
written consent from Gilead. The investigator further agrees to take all reasonable 
precautions to prevent the disclosure by any employee or agent of the study site to any third 
party or otherwise into the public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully 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 should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria);


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
Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and 
return;

Record of all adverse events and other safety parameters (start and end date, and 
including causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing 
application in an ICH region (ie, United States, Europe, or Japan) and until there are no 
pending or planned marketing applications in an ICH region; or, if no application is filed or if 
the application is not approved for such indication, until 2 years after the investigation is 
discontinued and regulatory authorities have been notified. Investigators may be required to 
retain documents longer if specified by regulatory requirements, by local regulations, or by 
an agreement with Gilead. The investigator must notify Gilead before destroying any clinical 
study records.
Should the investigator wish to assign the study records to another party or move them to 
another location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all 
of the documents, special arrangements must be made between the investigator and Gilead to 
store these records securely away from the site so that they can be returned sealed to the 
investigator in case of an inspection. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should 
be completed on the day of the subject visit to enable the sponsor to perform central 
monitoring of safety data.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system. Original entries as well as any changes to data 


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


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, 
may be made only by Gilead Sciences. All protocol modifications must be submitted to the 
Competent Authorities, IRB or IEC in accordance with local requirements. Approval must be 
obtained before changes can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). 
Gilead will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report 
may be prepared in certain cases. 
Investigators in this study may communicate, orally present, or publish in scientific journals 
or other scholarly media only after the following conditions have been met:

the results of the study in their entirety have been publicly disclosed by or with the 
consent of Gilead in an abstract, manuscript, or presentation form or the study has been 
completed at all study sites for at least 2 years

The investigator will submit to Gilead any proposed publication or presentation along 
with the respective scientific journal or presentation forum at least 30 days before 
submission of the publication or presentation. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).

The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to 
withhold publication or presentation for an additional 60 days in order to obtain patent 
protection if deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to 
the investigator’s source documentation in order to verify the accuracy of the data recorded 
in the CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals 
throughout the study to verify adherence to the protocol and the completeness, consistency, 
and accuracy of the data being entered on them. The monitor should have access to any 
subject records needed to verify the entries on the CRF/eCRF. The investigator agrees to 
cooperate with the monitor to ensure that any problems detected through any type of 
monitoring (central, on site) are resolved.


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9.3.2.
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.
9.3.3.
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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10.
REFERENCES
2202
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16:31-41.
12557
Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. 
Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks 
versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic 
infection with hepatitis C virus. International Hepatitis Interventional Therapy 
Group (IHIT). Lancet 1998;352 (9138):1426-32.
12558
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et 
al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for 
chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 
1998;339 (21):1485-92.
13693
Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and 
treatment of hepatitis C: an update. Hepatology 2009;49 (4):1335-74.
15572
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
Laboratories Inc., Nutley, NJ. Revised: January 2010.
15668
Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
Characteristics. Roche Products Limited, Welwyn Garden City, United Kingdom. 
Revised: March 2010.
17940
Craxi A. EASL clinical practice guidelines: management of hepatitis C virus 
infection, European association for the study of the liver. J Hepatol 2011;55:245-
64.
19705
Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus 
infection in Europe. J Hepatol 2008;48 (1):148-62.
23275
Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. 
Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J 
Med 2013;368 (1):34-44.
24149
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
Laboratories Inc., Nutley, NJ. Revised: February 2013.
24713
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, 
Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without 
treatment options. N Engl J Med 2013;368 (20):1867-77.


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24715
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et 
al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 
2013;368 (20):1878-87.
24913
Abboud O, Becker G, Bellorin-Font E, Field M, Johnson R, Li PK, et al. KDIGO 
clinical practice guidelines on hepatitis C in chronic kidney disease acknowledged 
by ISN. Nature clinical practice 2008;4 (12):648-9.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities


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Appendix 1. 
Investigator Signatut·e Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DIUVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2b Randomized, Open-Label Study of200mg or 400mg Sofosbuvir+RBV for 
24 Weeks in Genotype 1 or 3 HCV-Infected Subjects with Renal Insufficiency 
GS-US-334-0154, Original, 11 July 2013 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Diana Brainard, 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 infonned about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 65 
l l July 2013 


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Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
11.1.1.
Background
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects 
have been demonstrated in all animal species tested. Pregnancy must be excluded before the 
start of treatment with study drugs and prevented thereafter by reliable contraceptive 
methods. Pregnancy tests will be performed regularly throughout this study. Furthermore, 
RBV is known to accumulate intracellularly where it is cleared slowly, and is also excreted in 
semen. Therefore, extreme care must be taken to avoid pregnancy during RBV therapy and 
for up to 6 months following completion of treatment (7 months for males). Please refer to 
the latest version of the product insert for additional information. 
Non-clinical toxicity studies of SOF demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of SOF in pregnant 
women. Please refer to the latest version of the investigator’s brochure for additional 
information. 
11.1.2.
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 randomization. They must also 
agree to one of the following from 3 weeks prior to Day 1 until 6 months after last dose of 
RBV:

Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) is not permitted.
Or

Consistent and correct use of 1 of the following methods of birth control listed below, in 
addition to a male partner who correctly uses a condom, from the date of Screening until 
6 months after the last dose of RBV: 
— intrauterine device (IUD) with a failure rate of < 1% per year
— female barrier method: cervical cap or diaphragm with spermicidal agent


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— tubal sterilization
— vasectomy in male partner
— implants of levonorgestrel
— injectable progesterone
— oral contraceptives (either combined or progesterone only)
— contraceptive vaginal ring 
— transdermal contraceptive patch
11.1.3.
Contraceptive Requirements for Male Subjects (and their female 
partners)
All male study participants must agree to consistently and correctly use a condom from 
Baseline until 7 months after the last dose of RBV. If their female partner is of childbearing 
potential (as defined above), their female partner must use 1 of the methods of birth control 
listed above from the date of Screening until 7 months after last dose of RBV.
Male subjects must agree to refrain from sperm donation for at least 7 months after the last 
dose of RBV.
11.1.4.
Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any 
time during the study, or if they become pregnant within 6 months (7 months for 
partners of male subjects) of last RBV dose. Subjects who become pregnant or who 
suspect that they are pregnant must report the information to the investigator and 
discontinue study drug immediately. Subjects whose partner has become pregnant 
or suspects she is pregnant must report the information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined 
in Section 7.6.2. 


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


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Protocol GS-US-334-0154
Final
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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


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Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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11 July 2013
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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Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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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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Protocol GS-US-334-0154
Final
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Original
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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
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


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Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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


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Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 
Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to Dipstick 
Hematuria.
With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for the 
AE.


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Protocol GS-US-334-0154
Final
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Original
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated


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


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Original
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11 July 2013
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70% to 80%
FEV1 or peak flow 50% to 69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak flow 
25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in affected 
eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in affected 
eye(s)


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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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Protocol GS-US-334-0154
Final
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Original
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11 July 2013
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening consequences 
OR Aggressive intervention 
indicated [eg, tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (eg, diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening consequences 
(eg, sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock


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Protocol GS-US-334-0154
Final
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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)


Sofosbuvir
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 83
11 July 2013
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood (eg, 
agitation, anxiety, 
depression, mania, 
psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities 
Alteration causing greater than 
minimal interference with 
usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional activities 
Behavior potentially harmful 
to self or others (eg, 
suicidal/homicidal ideation or 
attempt, acute psychosis) OR 
Causing inability to perform 
basic self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no 
or minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities 
Disabling ataxia causing 
inability to perform basic self-
care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater than 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 


Sofosbuvir
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 84
11 July 2013
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate 
for the setting
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting 
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or 
other neurologic function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic self-
care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual 
social & functional activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social & 
functional activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions


Sofosbuvir
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 85
11 July 2013
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase 
from Previous Level of 
Control to Any of These 
Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (eg, 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 5–20 
minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated 
with a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic self-
care functions


Sofosbuvir
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 86
11 July 2013
MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia
See also Arthritis
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing greater than 
minimal interference with usual 
social & functional activities
Joint pain causing inability 
to perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic self-
care functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional activities
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0 
BMD t-score or z-score –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Pediatric 21 Years
BMD z-score 
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Myalgia
(non-injection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities
Muscle pain causing 
inability to perform usual 
social & functional activities
Disabling muscle pain causing 
inability to perform basic self-
care functions
Osteonecrosis
NA
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention 
indicated
Disabling bone pain with 
radiographic findings causing 
inability to perform basic self-
care functions


Sofosbuvir
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 87
11 July 2013
SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Acute Systemic Allergic 
Reaction 
Localized urticaria 
(wheals) with no medical 
intervention indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR Life-
threatening bronchospasm OR 
laryngeal edema
Chills
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & 
functional activities
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7C to 38.6C
99.8F to 101.5F
38.7C to 39.3C
101.6F to 102.8F
39.4C to 40.5C
102.9F to 104.9F
40.5C 
104.9F
Pain- Indicate Body Site
See also Injection Site 
Pain, Headache, 
Arthralgia, and Myalgia
Pain causing no or 
minimal interference with 
usual social & functional 
activities
Pain causing greater than minimal 
interference with usual social & 
functional activities
Pain causing inability to 
perform usual social & 
functional activities
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization (other than ER 
visit) indicated
Unintentional Weight 
Loss
NA
5% to 9% loss in body weight from 
baseline
10% to 19% loss in body 
weight from baseline
20% loss in body weight 
from baseline OR  Aggressive 
intervention indicated [eg, 
tube feeding or total parenteral 
nutrition]


Sofosbuvir
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 88
11 July 2013
INJECTION SITE REACTION
Grade 1
Grade 2
Grade 3
Grade 4
Injection Site Pain (pain 
without touching)
Or Tenderness (pain when 
area is touched) 
Pain/tenderness causing no 
or minimal limitation of use 
of limb
Pain/tenderness limiting use of 
limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social 
& functional activities
Pain/tenderness causing 
inability to perform usual
social & functional activities
Pain/tenderness causing inability 
to perform basic self-care 
function OR Hospitalization 
(other than ER visit) indicated 
for management of 
pain/tenderness
Injection Site Reaction 
(Localized), 15 Years
Erythema OR Induration
of 5 5 cm to 9 9 cm (or 
2581 cm2)
Erythema OR Induration OR 
Edema 9 cm any diameter 
(or 81 cm2)
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis and 
deeper tissue)
Pediatric 15 Years
Erythema OR Induration 
OR Edema present but 
2.5 cm diameter
Erythema OR Induration 
OR Edema > 2.5 cm 
diameter but < 50% surface 
area of the extremity 
segment (eg, upper 
arm/thigh)
Erythema OR Induration 
OR Edema involving 
50% surface area of the 
extremity segment (eg, 
upper arm/thigh) OR 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR 
Drainage
Necrosis (involving dermis and 
deeper tissue)
Pruritis Associated with 
Injection 
See also Skin: Pruritis 
(itching—no skin lesions)
Itching localized to injection 
site AND Relieved 
spontaneously or with 
48 h treatment 
Itching beyond the injection 
site but not generalized OR 
Itching localized to injection 
site requiring 48 h treatment 
Generalized itching causing 
inability to perform usual 
social & functional activities
NA


Sofosbuvir
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 89
11 July 2013
ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, back 
of neck, breasts, 
abdomen)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current meds to regain glucose 
control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences 
(eg, ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, myxedema coma)
Lipoatrophy (eg, fat loss 
from the face, extremities, 
buttocks)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


Sofosbuvir
Protocol GS-US-334-0154
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 90
11 July 2013
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

SAP_005.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2b, Open-Label Study of 200 mg or 400 mg 
Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 and 
Ledipasvir/Sofosbuvir (LDV/SOF) Fixed-Dose Combination 
(FDC) Tablet for 12 weeks in Genotype 1 or 4 HCV-Infected 
Subjects with Renal Insufficiency
Name of Test Drugs:
Sofosbuvir, Ledipasvir/Sofosbuvir Fixed-Dose Combination
Study Number:
GS-US-334-0154 (Cohorts 1 & 2)
Protocol Version/Date:
Original:
11 July 2013
Amendment 1:
05 September 2013
Amendment 2:
20 February 2014
Amendment 3:
23 February 2015
Amendment 4:
23 April 2015
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
05 February, 2016
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD


Sofosbuvir 
Study GS-US-334-0154 (Cohorts 1 & 2)
Statistical Analysis Plan
Final
CONFIDENTIAL
Page 2
05 February 2016
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
1.1.1.
Primary Study Objectives.......................................................................................................6
1.1.2.
Secondary Study Objectives...................................................................................................6
1.1.3.
Exploratory Study Objective ..................................................................................................6
1.2.
Study Design ............................................................................................................................................7
1.2.1.
Design Configuration, Subject Population and Treatment Cohorts........................................7
1.2.2.
Study Duration .......................................................................................................................7
1.2.3.
Schedule of Assessments........................................................................................................7
1.3.
Sample Size and Power............................................................................................................................7
2.
TYPE OF PLANNED ANALYSIS ......................................................................................................................8
2.1.
DMC Analyses .........................................................................................................................................8
2.2.
Final Analysis for Cohorts 1 and 2...........................................................................................................8
2.3.
Final Analysis for Cohorts 3.....................................................................................................................8
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES...............................................................................9
3.1.
Analysis Sets ............................................................................................................................................9
3.1.1.
All Enrolled Subjects..............................................................................................................9
3.1.2.
Full Analysis Set.....................................................................................................................9
3.1.3.
Safety Analysis Set.................................................................................................................9
3.1.4.
PK Analysis Set......................................................................................................................9
3.2.
Subject Groups.........................................................................................................................................9
3.3.
Data Handling Conventions and Transformations....................................................................................9
3.4.
Missing Data and Outliers......................................................................................................................10
3.4.1.
Missing Data.........................................................................................................................10
3.4.2.
Outliers.................................................................................................................................11
3.5.
Visit Windows........................................................................................................................................11
3.5.1.
Definition of Study Day 1, First/Last Dosing Date, and Baseline Value..............................11
3.5.2.
Analysis Windows................................................................................................................12
3.5.3.
Selection of Data in the Event of Multiple Records in a Window........................................14
4.
SUBJECT DISPOSITION..................................................................................................................................15
4.1.
Subject Enrollment.................................................................................................................................15
4.2.
Disposition of Subjects...........................................................................................................................15
4.3.
Extent of Exposure.................................................................................................................................16
4.3.1.
Duration of Exposure to Study Drug....................................................................................16
4.3.2.
Exposure to RBV (mg).........................................................................................................16
4.3.3.
Adherence to Study Drug .....................................................................................................16
4.4.
Protocol Deviations................................................................................................................................18
5.
BASELINE DATA .............................................................................................................................................19
5.1.
Demographics and Baseline Characteristics...........................................................................................19
5.2.
Medical History......................................................................................................................................20
6.
EFFICACY ANALYSES....................................................................................................................................21


Sofosbuvir 
Study GS-US-334-0154 (Cohorts 1 & 2)
Statistical Analysis Plan
Final
CONFIDENTIAL
Page 3
05 February 2016
6.1.
Primary Efficacy Endpoint.....................................................................................................................21
6.2.
Secondary Efficacy Endpoints................................................................................................................21
6.2.1.
Definition of Secondary Efficacy Endpoints ........................................................................21
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints...........................................................22
7.
SAFETY ANALYSES........................................................................................................................................23
7.1.
Adverse Events.......................................................................................................................................23
7.1.1.
Adverse Event Dictionary ....................................................................................................23
7.1.2.
Adverse Event Severity ........................................................................................................23
7.1.3.
Relationship of Adverse Events to Study Drug ....................................................................23
7.1.4.
Serious Adverse Events........................................................................................................23
7.1.5.
Treatment-Emergent Adverse Events...................................................................................24
7.1.6.
Summaries of Adverse Events and Deaths ...........................................................................24
7.2.
Laboratory Evaluations ..........................................................................................................................25
7.2.1.
Summaries of Numeric Laboratory Results..........................................................................26
7.2.2.
Graded Laboratory Values ...................................................................................................26
7.3.
Body Weight, Height, BMI and Vital Signs...........................................................................................27
7.4.
Electrocardiogram (ECG) Results..........................................................................................................27
7.5.
Echocardiogram Results.........................................................................................................................27
7.6.
Concomitant Medications.......................................................................................................................28
7.7.
Other Safety Measures ...........................................................................................................................28
8.
PHARMACOKINETIC ANALYSES.................................................................................................................29
9.
SOFTWARE.......................................................................................................................................................31
10.
APPENDICES ....................................................................................................................................................32
Appendix 1.
Tables, Figures, and Listings..................................................................................................33
Appendix 2.
Schedule of Assesments for Cohorts 1 and 2..........................................................................39
LIST OF IN-TEXT TABLES
Table 1.
On-Treatment Visit Windows for Selected Tests ...................................................................13
Table 2.
Posttreatment Visit Windows for Selected Tests....................................................................13
Table 3.
On-Treatment Visit Windows for ECGs.................................................................................14
Table 4.
Number of Prescribed Tablets................................................................................................17


Sofosbuvir 
Study GS-US-334-0154 (Cohorts 1 & 2)
Statistical Analysis Plan
Final
CONFIDENTIAL
Page 4
05 February 2016
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
BUN
blood urea nitrogen
%CV / CV
(percent) coefficient of variation
CI
confidence interval
CrCl
creatinine clearance
CRF
case report form(s)
CSR
clinical study report
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic case report form(s)
eGFR
estimated glomerular filtration rate
FAS
full analysis set
FU
follow-up
HCV
hepatitis C virus
HLT
high-level term
IBW
ideal body weight
INR
International Normalized Ratio of prothrombin time
IL28B
IL28B gene
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
nadir
the lowest point
PK
pharmacokinetic
PT
preferred term 
Q1
first quartile
Q3
third quartile
QD
once daily
RBV
ribavirin
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SAS
statistical analysis software
SD
standard deviation
SOC
system organ class
SOF
sofosbuvir, GS-7977
SVR
sustained virologic response


Sofosbuvir 
Study GS-US-334-0154 (Cohorts 1 & 2)
Statistical Analysis Plan
Final
CONFIDENTIAL
Page 5
05 February 2016
TFL
tables, figures, and listings
TND
target not detected
ULN
upper limit of the normal range
ULOQ
upper limit of quantitation
VF
virologic failure
WHO
World Health Organization


Sofosbuvir 
Study GS-US-334-0154 (Cohorts 1 & 2) 
Statistical Analysis Plan 
L 
INTRODUCTION 
Final 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in the summruy and analysis of data for subjects in coh01is 1 and 2 from 
Study GS-US-334-0154. This SAP was based on the protocol amendment dated 23 April 2015. 
Related documents ru·e the study protocol, study protocol amendments and elecu·onic case rep01i 
f01m (eCRF). Any changes made after the finalization of the SAP will be documented in the 
clinical study rep01i (CSR). 
1.1. 
Study Objectives 
1.1.1. 
Primary Study Objectives 
The primruy objectives of this study are: 
• 
To evaluate the safety of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks and LDV/SOF for 12 weeks as assessed by review of the accumulated safety data in 
each u·eatment rum 
• 
To evaluate the efficacy ofSOF 200 mg or 400 mg + RBV for 24 weeks and LDV/SOF for 
12 weeks measured by the prop01iion of subjects with renal insufficiency who have achieved 
a sustained viral response 12 weeks after u·eatment discontinuation (SVR12) in each 
u·eatment rum 
• 
To evaluate the steady state phrum acokinetics of SOF and its metabolites and LDV upon 
dosing SOF 200 mg or 400 mg or LDV/SOF in subjects with renal insufficiency 
1.1.2. 
Secondary Study Objectives 
The secondaty objectives of this study are: 
• 
To evaluate the prop01iion of subjects with renal insufficiency who attain SVR at 4 and 
24 weeks after discontinuation ofu·eatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of plasma HCV RNA during and after u·eatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV during and after u·eatment 
discontinuation 
1.1.3. 
Exploratory Study Objective 
PD 
I 
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05 Febmary 2016 


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~----------------------------------------------------~ 
1.2. 
Study Design 
1.2.1. 
Design Configuration, Subject Population and Treatment Cohorts 
This is a multicenter, open label study that will evaluate the safety, tolerability, and antiviral 
efficacy of SOF with RBV or LDV/ SOF in chronic renal insufficiency and HCV infection 
subjects with genotype 1, 3 or genotype 4 HCV infection, including those with compensated 
cinhosis. 
This study will have 3 coh01ts. 
Approximately 35 subjects with severe renal insufficiency will be enrolled. 
• 
Coh01t 1: 10 subjects will receive SOF 200 mg QD + RBV 200 mg QD for 24 weeks. 
Final 
• 
Coh01t 2: Following review of safety, efficacy and PK data through posttreatment Week 4 of 
Coh01t 1, 10 additional subjects will receive SOF 400 mg QD + RBV 200 mg QD for 
24 weeks. 
• 
Coh01t 3: Following review of safety and available PK data through Week 12 of Coh01t 2, 
15 additional subjects will receive LDV/SOF QD for 12 weeks. 
1.2.2. 
Study Duration 
The total time to complete all study visits is approximately 54 weeks (Cohorts 1 and 2) or 
42 weeks (Coh01t 3) including the following periods: 
• 
Up to 42-day (6-week) screening period 
• 
An 24-week (Coh01ts 1 and 2) or 12-week (Coh01t 3) treatment period 
• 
Up to 24-week postu·eatment period 
1.2.3. 
Schedule of Assessments 
The schedule of assessments is provided as an appendix to the SAP (Appendix 2). 
1.3. 
Sample Size and Power 
Due to the explorat01y nature of this study, no fonnal power or sample size calculations were 
perf01med to detennine u·eatment group size. The total sample size of 35 is largely based on 
feasibility. 
CONFIDENTIAL 
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2.
TYPE OF PLANNED ANALYSIS
2.1.
DMC Analyses
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety, efficacy, and PK data for each cohort of the study 
before proceeding to the next. Specifically, all of the data through posttreatment week 4 from the 
SOF 200 mg group (Cohort 1) will be reviewed before screening, enrollment and dosing for the 
SOF 400 mg group (Cohort 2). A similar review and initiation process will occur between 
SOF 400 mg (Cohort 2) and LDV/SOF dose group (Cohort 3), with review of safety and PK data 
through Week 12 from Cohort 2 prior to initiating Cohort 3. The DMC will provide 
recommendations to Gilead whether the nature, frequency, and severity of adverse effects 
associated with study treatment warrant the early termination of the study in the best interests of 
the participants, whether the study should continue as planned, or the study should continue with 
modifications. The DMC may also provide recommendations as needed regarding the need for 
additional meetings or an alternative meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.
2.2.
Final Analysis for Cohorts 1 and 2
The final analysis for Cohorts 1 and 2 will be conducted when all subjects in Cohorts 1 and 2 
have completed the 24 week posttreatment visit or have prematurely discontinued from study. 
The data will be finalized after all data queries are resolved for study visits through completion 
of the 24-week posttreatment visit. At the conclusion of data finalization for Cohorts 1 and 2, the 
final version of tables, figures and listings (TFLs) for Cohorts 1 and 2 will be generated.
2.3.
Final Analysis for Cohorts 3
A separate SAP will be written to describe the analysis for data from Cohort 3.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
3.1.
Analysis Sets
Analysis sets define which subjects are included in an analysis. A summary of the number and 
percentage of subjects in each analysis set will be provided by treatment cohort and in total as 
part of the subject disposition summary.
3.1.1.
All Enrolled Subjects
All enrolled subjects are defined as subjects who were enrolled into the study.
3.1.2.
Full Analysis Set
The full analysis set (FAS) includes subjects who were enrolled and received at least 1 dose of 
study drug. The study drugs for the Cohorts 1 and 2 in this study are SOF and RBV.
3.1.3.
Safety Analysis Set
The safety analysis set includes subjects who received at least 1 dose of study drug.
3.1.4.
PK Analysis Set
The PK analysis sets for SOF, its metabolites (GS-566500, GS-331007), and RBV will include 
all subjects who were enrolled, received at least one dose of study drug and for whom PK 
concentration data of interested analytes are available.
3.2.
Subject Groups
Subjects will be grouped for analyses according to enrolled treatment cohort for efficacy analysis 
using the FAS. For safety analyses using the safety analysis set, subjects will be grouped 
according to their enrolled treatment cohort except when their actual treatment differs from 
enrolled treatment for the entire treatment duration. In this case, the subject is grouped based on 
actual treatment received.
3.3.
Data Handling Conventions and Transformations
The COBAS® AmpliPrep/COBAS® TaqMan® HCV Test will be 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, 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.


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When HCV RNA is not detected, the result is reported as “HCV RNA not 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.”
For numerical HCV RNA data, values below LLOQ will be set to the LLOQ minus 1 
(ie, 14 HCV RNA IU/mL, or 1.15 on the log10 scale). HCV RNA values returned as “target not
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).
Total bilirubin values entered as < 0.2 mg/dL will be analyzed as 0.1 mg/dL; direct bilirubin 
values entered as < 0.1 mg/dL will be analyzed as 0.05 mg/dL. In general, other than the above 
2 exceptions, laboratory data that are continuous in nature but are less than the LLOQ or above 
the upper limit of quantitation (ULOQ) will be imputed to the value of the lower or upper limit 
minus or plus 1 significant digit, respectively (e.g., if the result of a continuous laboratory test is 
< 20, a value of 19 will be assigned; if it is < 0.2 mg/dL a value of 0.1 mg/dL will be assigned).
In addition, laboratory data that are continuous in nature but are ≤ LLOQ or ≥ ULOQ will be 
imputed to the value of the lower or upper limit, respectively (e.g., if the result of a continuous 
laboratory test is ≤20, a value of 20 will be assigned)
PK concentration values below the limit of quantitation (BLQ) will be treated as zero for the 
determination of summary and order statistics. Individual values that are BLQ will be presented 
as “BLQ” in the concentration data listing. For the presentation of summary and order statistics, 
if at least 1 subject has a concentration value BLQ for the time point, then the minimum value 
will be displayed as “BLQ”. If more than 25% of subjects have a concentration data value of 
BLQ for a given time point, then the minimum and the first quartile [Q1] will be displayed as 
“BLQ”. If more than 50% of the subjects have a concentration data value of BLQ for a given 
time point, then the minimum and median values will be displayed as “BLQ”. If more than 75% 
of the subjects have a concentration value of BLQ for a given time point, the minimum, Q1, 
median, and third quartile [Q3] values will be displayed as “BLQ”. If all subjects have 
concentration data values BLQ for a given time point, then all order statistics (minimum, Q1, 
median, Q3, and maximum) will be displayed as “BLQ”.
Exposure parameters selected for statistical analysis will be natural log-transformed. 
Concentration values that are BLQ will be considered missing for any ratio or natural 
log-transformed statistical analyses.
3.4.
Missing Data and Outliers
3.4.1.
Missing Data
A missing data point for a given study visit may be due to any one of the following reasons:


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
A visit occurred but data were not collected or were unusable

A visit did not occur

A subject permanently discontinued from the study before reaching the window
For analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have the 
missing data always imputed. Missing on-treatment HCV RNA data will have the missing data 
imputed up to the time of the last dose (for on-treatment displays). If the study day associated 
with the last dosing date is greater than or equal to the lower bound of a visit window, and the
value at the visit is missing, the value will be imputed. If the study day associated with the last 
dosing date is less than the lower bound of a visit window then the on-treatment value at that 
visit will remain missing.
If a data point is missing and is preceded and followed in time by values that are “< LLOQ 
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/numerical value will be imputed to LLOQ-1 
IU/mL.
Except for the imputation rules described above, values for other missing data (including all 
safety data) will not be imputed.
3.4.2.
Outliers
Outliers will be identified during data management and data analysis process, but no sensitivity 
analyses will be done to evaluate the impact of outliers on efficacy or safety outcomes. All data 
will be included in the data analysis.
3.5.
Visit Windows
3.5.1.
Definition of Study Day 1, First/Last Dosing Date, and Baseline Value
The first dose date of individual study drug will be calculated separately for each study drug
(ie, SOF, RBV) in a treatment cohort. Study Day 1 is defined as the first dose date of any 
study drug, which is the minimum of the first dose dates of individual study drugs in a treatment 
cohort. 


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The last dose date of individual study drug will be calculated separately for each study drug in a 
treatment cohort. The last dose date for an individual study drug will be the end date on study 
drug administration CRF for the record where the “subject permanently discontinued” flag is 
‘Yes’. The last dose date of any study drug will be defined as the maximum of the last dosing 
dates of individual study drugs in a treatment cohort. 
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). 
In general, the baseline value will be the last nonmissing value on or prior to the first dose date 
of study drug. If multiple measurements occur on the same day, the last nonmissing value prior to 
the time of first dose of study drug will be considered as the baseline value. If these multiple 
measurements occur at the same time or time is not available, the average of these measurements 
(for continuous data) or the worst among these measurements (for categorical data) will be 
considered as 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.
3.5.2.
Analysis Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purposes of data 
analysis, visit windows will be utilized when a single value at a visit is required for analysis.
Visit windows are defined for HCV RNA, vital signs, safety laboratory, and ECG. No analysis 
windows will be defined for echocardiogram data.
All available HCV RNA data will be included in efficacy analysis, unless a subject starts 
alternative HCV medication. HCV RNA data collected after starting alternative HCV medication 
will be excluded. Imputation for missing HCV RNA values are described in Section 3.4.1. For 
safety data, subjects who are permanently discontinued from study drug will be included in safety 
analyses up to the last dose date of any study drug + 30 days, unless otherwise specified. For 
interim DMC analyses, subjects still on study drug will have all available data included in the 
interim snapshot database included in analysis.
HCV RNA, vital signs, and safety laboratory data collected up to the last dose date of any study 
drug + 2 days are considered to be on-treatment data, and HCV RNA, vital signs and safety 
laboratory data collected after the last dose date of any study drug + 2 days are considered 
posttreatment data. On-treatment and posttreatment data will follow 2 different sets of visit 
windows.
On-treatment visit windows will be calculated from Study Day 1 (ie, Study Day = collection 
date minus date of Study Day 1; +1 if result is ≥ 0) for HCV RNA, vital signs and other safety 
laboratory data as shown in Table 1.


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Table 1.
On-Treatment Visit Windows for Selected Tests
Visit ID
On-Treatment Visit Windows for HCV RNA, 
Vital Signs and Other Safety Labs
Baseline
Study Day 1
Week 1
2 Study Day 11
Week 2
12 Study Day 21
Week 4
22 Study Day 35
Week 6
36 Study Day 49
Week 8
50 Study Day 63
Week 10
64 Study Day 77
Week 12
78 Study Day 98
Week 16
99 Study Day 126
Week 20
127 Study Day 154
Week 24
155 Study Day 182
HCV RNA, vital sign, and safety laboratory data collected after the last dose date of any study 
drug + 2 days will be assigned to the posttreatment FU visit windows. Windows will be 
calculated from the last dose date of any study drug (ie, FU Day = collection date minus the last 
dose date of any study drug) as shown in Table 2.
Table 2.
Posttreatment Visit Windows for Selected Tests
FU Visit ID
Posttreatment Visit Windows for 
HCV RNAa
Posttreatment Visit Windows for ECG, Vital 
Signs and Other Safety Labsb
FU-4
21 FU Day 69
3 FU Day 30
FU-12
70 FU Day 146
N/A
FU-24
147 FU Day 190
N/A
a
SVR follow-up visit window (lower bound) must occur within 7, 14, and 21 days of target for SVR4, SVR12, and SVR24, 
respectively.
b
Vital signs and safety labs will only be summarized for the 4-week follow-up visit (up to last dose date of any study 
drug + 30 days).
ECG data collected up to the last dose date of any study drug + 2 days are considered to be 
on-treatment data. The following visit windows shown in Table 3 will be used.


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Table 3.
On-Treatment Visit Windows for ECGs
Visit ID
On-Treatment Visit Windows for ECG Data
Baseline
Study Day 1
Week 4
2Study Day 42
Week 8
43 Study Day 70
Week 12
71 Study Day 98
Week 16
99 Study Day 126
Week 20
127 Study Day 154
Week 24
155 Study Day 182
3.5.3.
Selection of Data in the Event of Multiple Records in a 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. When a single value is 
needed, the following rules will be used:

Select the record closest to the nominal day (ie, visit weeks x 7 days) for that visit except for 
HCV RNA posttreatment follow-up visits, for which the latest record in the analysis window 
should be selected.

If there are 2 visits equidistant from the nominal day within the analysis window, take the 
latest.

If there is more than 1 record on the selected day, take the average (for continuous data) or 
the worst (for categorical data). If there are 2 values on the same day, the second may be a 
retest because there was a problem with the first test (eg, specimen hemolyzed). In cases 
where the first test is cancelled, the retest value should be used.

For ECG end of treatment value, select the last value on/prior to last dose date of any study 
drug +2.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment
The number and percentage of subjects enrolled and treated in each country and by each 
investigator within a country will be summarized by treatment cohort and overall. The 
denominator for this calculation will be the number of subjects in the safety analysis set. 
4.2.
Disposition of Subjects
A summary of subject disposition will be provided by treatment cohort and overall. This 
summary will present the number of subjects screened, subjects not enrolled, enrolled, in safety 
analysis set, in FAS, in PK analysis set, and the number and percentage of subjects meeting the 
following criteria:

Completed study treatment

Discontinued study treatment (with summary of reasons for not completing the study 
treatment)

Completed the study 

Did not complete the study (with summary of reasons for not completing the study)
Among subjects who completed study treatment and who discontinued study treatment, the 
number of subjects will be summarized for:

Who had no HCV posttreatment Week 4 assessment and thereafter (No HCV FU-4 
Assessment 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 Assessment and thereafter)
If a subject did not have any HCV RNA assessment beyond 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 Assessment and thereafter”. If a subject had the HCV FU-4 assessment 
but did not have any HCV RNA assessment beyond 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 Assessment and thereafter”.
The denominator for the percentages of subjects in each category will be the number of subjects 
in the safety analysis set. 
No inferential statistics will be presented.


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A data listing of date of informed consent, first dose date, last dose date of any study drug (study 
day), completed study treatment (yes/no), completed study (yes/no) and reasons for premature 
study treatment/study discontinuation will be provided. The last available observed nonmissing 
HCV RNA value prior to discontinuation and for up to 2 days after last dose will be included in 
this listing.
4.3.
Extent of Exposure
4.3.1.
Duration of Exposure to Study Drug
Duration of exposure to study regimen will be defined as (last dose date of any study drug – first 
dose date of any study drug + 1), regardless of temporary interruptions in study drug 
administration and will be expressed in weeks (recorded to 1 decimal place, eg, 10.1 weeks).
Duration of exposure to individual study drug is defined as (last dose date of individual study 
drug – first dose date of individual study drug + 1 day), regardless of temporary interruptions in 
study drug administration. For subjects ongoing at the time of a DMC analysis, the last dosing 
date will be estimated based on the last available eCRF or laboratory date available in the 
snapshot database. 
Duration of exposure to study regimen will be summarized using descriptive statistics (sample 
size, mean, standard deviation [SD], minimum, first quartile [Q1], median, third quartile [Q3], 
and maximum) and as the number of subjects exposed to study regimen through (ie, cumulative 
counts): Baseline (Day 1); Week 1 (Day 7); Week 2 (Day 14); Week 4 (Day 28); Week 6 
(Day 42); Week 8 (Day 56); Week 10 (Day 70); Week 12 (Day 84); Week 16 (Day 112); 
Week 20 (Day 140); and Week 24 (Day 168). 
Summaries will be provided by treatment cohort for the safety analysis set.
4.3.2.
Exposure to RBV (mg)
Descriptive summary statistics will be provided for the daily dose of RBV administered by weeks 
(ie, first dose, and at Week 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24). The daily dose of RBV on study 
day 1, 8, 15, 29, 43, 57, 71, 85, 113, 141 and 165 will be summarized across all subjects who 
were on RBV on that day.
Descriptive summary statistics will be provided for the mean daily dose of RBV, with mean daily 
dose for each subject calculated by total RBV dose during study treatment divided by number of 
total RBV exposure days.
Summaries will be provided by treatment cohort for the safety analysis set.
4.3.3.
Adherence to Study Drug
Adherence will be calculated separately for SOF (tablets) and RBV (tablets) as:
(Number of tablets taken) ÷ (Number of tablets prescribed for study drug at baseline) × 100%


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Note: If calculated adherence is greater than 100%, the result will be set to 100%.
4.3.3.1.
Calculation of Number of Tablets Prescribed for Study Drug
For subjects who complete study drug or prematurely discontinue study drug for a reason other 
than virologic failure (ie, met virologic failure stopping criteria) number of tablets prescribed is
displayed in Table 4.
Table 4.
Number of Prescribed Tablets
Cohort 1
(SOF 200mg +RBV 200 mg)
Cohort 2
(SOF 400mg +RBV 200 mg)
SOF  tablet
2×168 (336) 
SOF 100 mg tablet
1×168 (168)
SOF 400 mg tablet
RBV 200 mg tablet
1×168 (168)
1×168 (168)

For Cohort 1, prescribed SOF (100 mg) would require 336 tablets for the 24-week treatment 
period (2 tablets/day ×168 days) and prescribed RBV (200 mg) would require 168 tablets for 
the 24-week treatment period (1 tablet/day × 168 days).

For Cohort 2, prescribed SOF (400 mg) would require 168 tablets for the 24-week treatment 
period (1 tablets/day × 168 days) and prescribed RBV (200 mg) would require 168 tablets for 
the 24-week treatment period (1 tablet/day ×168 days).
Subjects who prematurely discontinue study drug for lack of efficacy (ie, virologic failure) will 
have prescribed medications calculated for the number of study days at the first date when 
virologic stopping criteria were met (ie, substitute number of days to virologic failure [date of 
first of 2 consecutive measurements or a last available value meeting criteria] for 168 days).
4.3.3.2.
Calculation of Number of Tablets Taken
The number of tablets taken for SOF and RBV during the treatment period will be calculated as 
the sum of (number of tablets dispensed – number of tablets returned) at each distinct dispensing 
period across all bottles dispensed. For subjects who discontinue for virologic failure, bottles 
dispensed after the subject first met virologic failure criteria will not be included in calculations. 
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 adherence to each study drug (sample size, mean, SD, minimum, Q1, 
median, Q3, and maximum) along with the number and percentage of subjects belonging to 
adherence categories (eg, < 80%, ≥ 80 to < 90%, ≥ 90%) will be provided by treatment cohort for 
the safety analysis set. Categorical displays will be presented for the number of subject who are 
at least 80% adherent to their drug regimen (ie, adherence is ≥ 80% for each of the study drugs).


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No inferential statistics will be provided.
4.4.
Protocol Deviations
A summary of major protocol violations will be provided by the Clinical Operations group for 
subjects in the safety analysis set.


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5.
BASELINE DATA
5.1.
Demographics and Baseline Characteristics
The following subject demographic and baseline characteristics will be summarized by treatment 
cohort and overall using descriptive statistics (sample size, mean, standard deviation, median, 
Q1, Q3, minimum and maximum) for continuous data and by the number and percent of subjects 
for categorical data. Variables to be summarized include the following:

age (on date of first dose of any study drug) as a continuous variable

sex at birth (male, female)

race 

ethnicity (hispanic or latino, non-hispanic or latino)

body weight and height

body mass index as a continuous variable and for categories (< 30 kg/m2, ≥ 30 kg/m2)

HCV genotype

cirrhosis (presence, absence)

IL28B (CC, CT, TT) 

baseline HCV RNA as a continuous variable and for categories (< 6log10 IU/mL, ≥  6log10 
IU/mL)

baseline ALT as a continuous variable and for categories (≤1.5 x ULN, > 1.5 x ULN)

estimated glomerular filtration rate using the Cockcroft-Gault equation

prior HCV treatment experience (treatment naïve, treatment experienced)

prior HCV treatment response for treatment experienced subjects

most recent HCV treatment regimen for treatment experienced subjects

fibrotest score as a continuous variable  and fibrotest stage as a categorical variable


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Age is calculated as the integer of age in years at first dose of study regimen. eGFR will be 
calculated by the Cockcroft-Gault method using ideal body weight (IBW): eGFRCG (mL/min) = 
[(140 – age (yrs)) × IBW (kg) × (0.85 if female)] / (serum creatinine (mg/dL) × 72).
The summary of demographic data and baseline characteristics will be provided for the safety 
analysis set. 
5.2.
Medical History
General medical history data will be listed only. General medical history data will not be coded.


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is SVR 12 weeks after treatment discontinuation (SVR12) defined 
as HCV RNA < LLOQ (ie, < 15 IU/mL) 12 weeks after study drug cessation for the FAS. The 
COBAS® AmpliPrep/COBAS® TaqMan® HCV Test will be used to determine HCV RNA results 
in this study.
The 2-sided 95% exact confidence interval (CI) based on Clopper-Pearson method will be 
provided for the SVR12 rate for each treatment cohort.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints include the following:

The proportion of subjects who attain SVR at 4 and 24 weeks after treatment discontinuation, 
defined as HCV RNA < LLOQ (ie, < 15 IU/mL) 4 and 24 weeks after stopping treatment 
(SVR 4 and SVR 24)

The proportion of subjects with HCV RNA below LLOQ (ie, < 15 IU/mL) by study visit

HCV RNA (log10 IU/mL) and change from baseline in HCV RNA (log10 IU/mL) through end 
of treatment

The proportion of subjects with virologic failure as the following:
On-treatment virologic failure
o
HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ, while on 
treatment, confirmed with 2 consecutive values (note, second confirmation value can 
be posttreatment), or last available on-treatment measurement with no subsequent 
follow up values (ie, breakthrough)
o
> 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)
o
HCV RNA persistently ≥ LLOQ through 8 weeks of treatment (ie, nonresponse)
Relapse 
o
HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV 
RNA < LLOQ at end of treatment, confirmed with 2 consecutive values or last 
available posttreatment measurement


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6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
For analyses of HCV RNA < LLOQ (ie, < 15 IU/mL) 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 categorical imputation rules described in Section 3.4.1. The 2-sided 95% exact confidence 
interval based on Clopper-Pearson method will be provided for the proportion within each 
treatment cohort. The overall category for “HCV RNA < LLOQ” will be split into the following 
2 subcategories: “< LLOQ TND” for subjects with target not detected and “< LLOQ detected” 
for subjects with < LLOQ in tabular displays. 
Graphs for the proportion of subjects with HCV RNA < LLOQ over time during treatment will 
be displayed.
Summary statistics will be presented for absolute values and change from baseline in HCV RNA 
(log10 IU/mL) by visit through end of treatment (EOT). Imputation rules 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”. Otherwise, a missing = excluded 
analysis will be performed. 
For the SVR12 endpoint analysis, a summary table of the number and percentage of subjects with 
SVR12, virologic failure (VF), and Other will be created. All subjects who achieve SVR12 will 
be categorized as SVR12. Virologic failure will be descriptively summarized as “on-treatment 
virologic failure” and relapse (which will be broken down by study drug completed yes/no). 
Subjects who do not achieve SVR12 and do not meet criteria for VF will be categorized as Other. 
The denominator for relapse will be the number of subjects who had HCV RNA < LLOQ on 
their last observed on-treatment HCV RNA measurement; otherwise, the denominator will be the 
number of subjects in the FAS. Point estimates and 95% Clopper-Pearson exact confidence 
intervals will be presented for the overall virologic failure.
A concordance table between SVR12 and SVR24 will be provided by treatment cohort.
In addition, the proportion of subjects with ALT normalization (defined as ALT > ULN at 
baseline and ALT ≤ ULN at each visit) will be presented by study visit. Tables for ALT 
normalization by visit will use similar methodology to the analyses of HCV RNA < LLOQ, but 
will use a missing = excluded analysis. Only those subjects with ALT greater than the ULN range 
at baseline (defined as the last ALT value collected prior to first dose of study drug) will be 
included in the analysis of ALT normalization. 


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7.
SAFETY ANALYSES
Safety data will be summarized for subjects included in the safety analysis set. Summaries of 
safety data (treatment-emergent [TE] adverse events [AEs], TE maximum toxicity grades,
changes from baseline in laboratory tests and vital signs parameters) will include all data 
collected on or after the first dose date of any study drug through the last dose date of any study
drug plus 30 days for subjects who have stopped all study drugs, and all available data at the time 
of the database snapshot for subjects still on treatment at the time of a DMC interim analysis.
All safety data (except for laboratory tests with results that were cancelled by the lab) will be 
included in data listings based on the safety analysis set.
7.1.
Adverse Events
7.1.1.
Adverse Event Dictionary
Clinical and laboratory AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). System organ class (SOC), high level group term (HLGT), high level term (HLT), 
preferred term (PT), and lower level term (LLT) will be attached to the clinical database.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator according to the Gilead Sciences, Inc. (Gilead) 
Grading Scale for Severity of Adverse Events and Laboratory Abnormalities as specified in the 
clinical study 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 will be 
considered the least severe for the purposes of sorting for data presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
The relationship of AE to study drug will be assessed by investigators as “Yes” or “No”.
Events for which the investigator did not record the relationship to study drug will be considered 
to be related to study drug for summary purposes. However, data listings will present the 
relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) are those identified as serious in the clinical database. The clinical 
database will be reconciled with the SAE database from the Drug Safety and Public Health 
Department before database finalization.


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7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent
Treatment-emergent AEs are 

Any AEs with an onset date of on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug or

Any AEs leading to premature discontinuation of study drug
7.1.5.2.
Incomplete Dates
If the date of onset is incomplete, then the month and year (or year alone if month is not 
recorded) of onset determine whether the AE is treatment emergent. The event is treatment 
emergent if the month and year of onset (or year of onset) of the event meets both of the 
following criteria:

The same as or after the month and year (or year) of the first dose of any study drug

The same as or before the month and year (or year) of the 30th day after the date of the last 
dose of any study drug 
7.1.6.
Summaries of Adverse Events and Deaths
A brief summary of AEs will show, by treatment cohort, the number and percentage of subjects 
who (1) had any TE AE, (2) had any Grade 3 or 4 TE AE, (3) had any Grade 2, 3, or 4 TE AE, 
(4) had any TE treatment-related AE, (5) had any Grade 3 or 4 TE treatment-related AE, (6) had 
any Grade 2, 3 or 4 TE treatment-related AE, (7) had any TE SAE, (8) had any TE treatment-
related SAE, (9) had any AE leading to permanent discontinuation from any study drug,  (10) had 
any AE leading to permanent discontinuation from SOF, (11) had any AE leading to 
modification or interruption of any of the study drugs, (12) had any AE leading to interruption of 
SOF and (13) TE death during the study
Summaries (number and percentage of subjects) of adverse events (by SOC and PT) will be 
provided by treatment cohort using the safety analysis set as follows:

All TE AEs

Combined Grade 3 or 4 TE AEs

Combined Grade 2, 3 or 4 TE AEs

TE non-serious AEs occurring in at least 5% of subjects in any treatment cohort (this will be 
produced for ClinicalTrials.gov website)

TE treatment-related  AEs


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
Combined Grade 3 or 4 TE treatment-related AEs

Combined Grade 2, 3 or 4 TE treatment-related AEs

TE SAEs

TE treatment-related SAEs 

AEs leading to permanent discontinuation from any of the study drugs

AEs leading to modification or interruption of any of the study drugs
Multiple events will be counted once only per subject in each summary. For data presentation, 
SOC will be ordered alphabetically, with PT sorted by decreasing total frequency within an SOC. 
For summaries by severity grade, the most severe event will be selected. 
In addition to the presentation by SOC and preferred term, summaries will also be presented by 
preferred term only, ordered by decreasing total frequency for All TE AEs.
Data listings, with a variable indicating whether the event is treatment-emergent, will be 
provided for the following:

All AEs

SAEs

Deaths

AEs leading to permanent discontinuation of any of the study drugs

Grade 3 or 4 AEs
7.2.
Laboratory Evaluations
Summaries of laboratory data will be provided for the safety analysis set and will include data 
collected up to last dose of any study drug plus 30 days for subjects who have stopped all study 
drugs and all available data at the time of the database snapshot for subjects who are ongoing at 
the time of interim DMC analysis. Analysis will be based on values reported in conventional 
units. Laboratory results cancelled by the central laboratory will not be included in analysis.
No inferential statistics will be generated.


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7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum and maximum) will be 
provided by treatment cohort for ALT, AST, total bilirubin, alkaline phosphatase, white blood 
cell (WBC) counts, neutrophils, lymphocytes, hemoglobin, platelets, reticulocytes, creatinine, 
INR, and creatinine clearance (calculated by the Cockcroft-Gault equation, using IBW) as 
follows:

Baseline values 

Values at each postbaseline analysis window

Change from baseline at each postbaseline analysis window 
The mean, median, Q1, Q3, minimum and maximum will be displayed to reported number of 
digits, standard deviation to reported number of digits +1 for visits up to end of treatment. The 
posttreatment week 4 safety follow-up visit will be presented as an additional separate visit.
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 treatment cohort.
7.2.2.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
used for assignment of toxicity grades to laboratory results for purposes of analysis as Grade 0, 
Grade 1 (mild) , Grade 2 (moderate), Grade 3 (severe) or Grade 4 (potentially life threatening). 
Grade 0 includes all values that do not meet criteria for an abnormality of at least Grade 1. 
Some laboratory tests have laboratory toxicity criteria for both increased and decreased levels; 
analyses for each direction (ie, increased, decreased) will be presented separately.
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 1 
toxicity grade from baseline at any time postbaseline up to the last dose of any study drug plus 
30 days for subjects who have stopped all study drugs or all available data in the database 
snapshot for subjects still on treatment at the time of a DMC interim analysis.
If the relevant baseline laboratory data are missing, then any abnormality of at least Grade 1 will 
be considered treatment emergent.


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7.2.2.2.
Summaries of Laboratory Abnormalities
The following summaries (number and percentage of subjects) of laboratory abnormalities using 
the Gilead Grading Scale will be provided by treatment cohort (subjects categorized according to 
most severe postbaseline abnormality grade):

TE graded laboratory abnormalities

TE Grade 3 or 4 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 any study drug) for the 
laboratory parameter of interest.
A listing of TE Grade 3 or Grade 4 laboratory abnormalities will be provided. This listing will 
include the complete laboratory test profile for each laboratory test with the graded result 
throughout the study.
All valid laboratory values will be listed. Values falling outside of the relevant reference range 
and/or meeting Gilead Grading Scale will be flagged, as appropriate, in the data listings.
7.3.
Body Weight, Height, BMI and Vital Signs
Absolute value and change from baseline in vital signs (systolic blood pressure [SBP], diastolic 
blood pressure [DBP] and pulse) at each visit will be summarized for the safety analysis set using 
descriptive statistics by treatment cohort for each post baseline analysis window. In the case of 
multiple values in an analysis window, data will be selected for analysis as described in 
Section 3.5.3. No inferential statistics will be generated.
A listing of height (at screening), body weight, and BMI, and a listing of SBP, DBP, pulse, 
respiration and temperature will be provided.
7.4.
Electrocardiogram (ECG) Results
Absolute value and change from baseline in PR interval, QRS interval, QT interval and QTcF at
each visit will be summarized for the safety analysis set using descriptive statistics by treatment 
cohort for each post baseline analysis window. A listing of PR interval, QRS interval, QT 
interval, and QTcF will be provided.
A listing of overall assessment of ECG results including description regarding clinically 
significant abnormalities will be provided.
7.5.
Echocardiogram Results
Absolute value and change from baseline in ejection fraction, fractional shortening, left 
ventricular end diastolic volume (LVEDV) and left ventricular internal dimension in diastole 
(LVIDd) at each visit will be summarized for the safety analysis set using descriptive statistics by 


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treatment cohort for each post baseline visit. A shift table of diastolic function score assessment 
at baseline versus each on-treatment visit will be presented by treatment cohort.
A listing of ejection fraction, fractional shortening, LVEDV, LVIDd and diastolic function score 
will be provided.
7.6.
Concomitant Medications
Concomitant medications (ie, medications other than study drug that are taken while receiving 
study treatment) will be coded using the World Health Organization (WHO) Drug Dictionary. 
The WHO preferred name and drug code will be attached to the clinical database. Use of 
concomitant medications will be summarized (number and percentage of subjects) by treatment 
cohort, WHO drug class, and WHO generic name. Multiple drug use (by preferred name) will be 
counted once only per subject. The summary will be sorted alphabetically by drug class and then 
by decreasing total frequency within a class.
For purposes of programming, any medication with a stop date that is on/prior to first dosing date 
or start date that is after the last dose of any study drug will be excluded from this summary. 
Otherwise, dates that are completely missing will be included in the summary. If a partial stop 
date is entered, then the month and year (if day is missing) or year (if day and month are missing) 
that is prior to the study drug start date will be excluded from the summary. If a partial start date 
is entered, then the month and year (if day is missing) or year (if day and month are missing) that 
is after the study drug stop date will be excluded from the summary. 
Summaries of concomitant medications will be provided for the safety analysis set.  No 
inferential statistics will be generated.
A listing of all concomitant medications reported during the study will be provided.
7.7.
Other Safety Measures
A data listing of cirrhosis determination will be provided.
A data listing will be provided for subjects who received dialysis during the study.
A data listing will be provided for subjects’ prior HCV treatment and response.
A data listing will be provided for subjects who become pregnant during the study.


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8.
PHARMACOKINETIC ANALYSES
Steady-state PK over dosing interval will be determined from intensive PK assessments at the 
Week 2 and Week 12 on-treatment visits.
Concentration of SOF (and its metabolites GS-566500 and GS-331007) and RBV in plasma will 
be determined using validated bioanalytical assays. The PK parameters for these analytes will be 
computed for all subjects with evaluable PK profiles.  For each subject, the following PK 
parameters will be calculated, as appropriate:
Parameter
Description
AUCtau
area under the concentration versus time curve over the dosing interval
Clast
last observed quantifiable concentration of the drug in plasma
Cmax
maximum observed concentration of drug in plasma
Ctau
observed drug concentration at the end of the dosing interval
T1/2
estimate of the terminal elimination half-life of the drug in plasma, calculated by dividing the 
natural log of 2 by the terminal elimination rate constant (z)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination phase 
of the plasma concentration of drug versus time curve
PK parameters will be estimated by application of a nonlinear model using standard 
noncompartmental methods (WinNonlinsoftware v6.3). The linear up/log down trapezoidal 
rule will be used in conjunction with the appropriate noncompartmental model (usually input 
Model 200 for oral dosing), with input values for dose, time of dose, plasma concentration, and 
corresponding real time values, based on drug dosing times whenever possible. 
All predose sample times of less than time zero will be converted to zero. Samples below the 
limit of quantitation of the bioanalytical assays that occur prior to the achievement of the first 
quantifiable concentration will be assigned a concentration value of zero to prevent 
overestimation of the initial AUC. Samples that are BLQ at all other time points will be treated 
as missing data. The nominal time point for a key event or dosing interval (tau) may be used to 
permit direct calculation of AUC over specific time intervals. The appropriateness of this 
approach will be assessed by the pharmacokineticist on a profile-by-profile basis.
Accurate estimation of several PK parameters, such as λz and T½, are dependent on the measured 
terminal elimination phase of the drug. The appropriateness of calculating these parameters will 
be assessed by the pharmacokineticist on a profile-by-profile basis.


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Ten descriptive statistics (sample size, mean, SD, coefficient of variation [%CV], median, Q1, 
Q3, minimum, maximum, and geometric mean and its 95% CI) will be presented for PK 
concentration data and PK parameter data. For concentration values BLQ, the number of subjects 
with values of BLQ will be presented.
Plasma concentrations of SOF (and its metabolites GS-566500 and GS-331007) and RBV over 
time from the intensive PK assessments will be plotted in linear and semi-logarithmic scales as 
mean ± SD and as Q1, median, and Q3 by treatment cohort and visit.


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9.
SOFTWARE
SAS, Version 9.2, SAS Institute Inc., Cary, NC, USA.
PhoenixWinNonlin, Version 6.2, Pharsight Corporation, Mountain View, CA, USA.


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10.
APPENDICES
Appendix 1.
Tables, Figures, and Listings
Appendix 2.
Schedule of Assesments for Cohorts 1 and 2


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Appendix 1.
Tables, Figures, and Listings
Table 
Number
Title
Analysis Set
1
Subjects Enrolled and Treated by Country and Investigator
Safety Analysis Set 
2
Subject Disposition
Screened Subjects
3
Reasons for Screen Failure
Screened Subjects
4
Demographics and Baseline Characteristics
Safety Analysis Set
5
Duration of Exposure to Study Regimen
Safety Analysis Set
6
Concomitant Medications
Safety Analysis Set
7
Adherence to Study Drug
Safety Analysis Set
8
Daily Dose of Ribavirin (mg) by Week
Safety Analysis Set
9
Summary of Mean Daily Dose of Ribavirin (mg)
Safety Analysis Set
10
SVR12
Full Analysis Set
11
Virologic Outcomes
Full Analysis Set
12
Concordance between SVR12 and SVR24
Full Analysis Set
13
SVR by Visit During Posttreatment Follow Up
Full Analysis Set
14
Proportion of Subjects with HCV RNA Less than LLOQ (15 IU/mL) While 
on Treatment by Visit
Full Analysis Set
15
HCV RNA (log10 IU/mL) and Change from Baseline by Visit Through End 
of Treatment
Full Analysis Set
16
Proportion of Subjects with ALT Normalization by Visit
Full Analysis Set with 
ALT>ULN at Baseline
17
Adverse Events: Brief Summary
Safety Analysis Set
18
All Treatment-Emergent Adverse Events
Safety Analysis Set
19
All Treatment-Emergent Adverse Events by Preferred Term
Safety Analysis Set
20
Treatment-Emergent Treatment-Related Adverse Events
Safety Analysis Set
21
Grade 3 or 4 Treatment-Emergent Adverse Events
Safety Analysis Set
22
Grade 3 or 4 Treatment-Emergent Treatment-Related Adverse Events
Safety Analysis Set
23
Grade 2, 3, or 4 Treatment-Emergent Adverse Events
Safety Analysis Set
24
Grade 2, 3, or 4 Treatment-Emergent Treatment-Related Adverse Events
Safety Analysis Set
25
Adverse Events Leading to Permanent Discontinuation from Any Study 
Drug
Safety Analysis Set
26
Treatment-Emergent Serious Adverse Events
Safety Analysis Set
27
Treatment-Emergent Treatment-Related Serious Adverse Events
Safety Analysis Set
28
Treatment-Emergent Non-Serious AEs Occurring in At Least 5% of 
Subjects in Any Treatment Cohort
Safety Analysis Set
29
Adverse Events Leading to Modification or Interruption of Any Study Drug
Safety Analysis Set


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Table 
Number
Title
Analysis Set
30.1
ALT (U/L) and Change from Baseline by Visit
Safety Analysis Set
30.2
AST (U/L) and Change from Baseline by Visit
Safety Analysis Set
30.3
Total Bilirubin (mg/dL) and Change from Baseline by Visit
Safety Analysis Set
30.4
Alkaline Phosphatase (U/L) and Change from Baseline by Visit
Safety Analysis Set
30.5
Hemoglobin (g/dL) and Change from Baseline by Visit
Safety Analysis Set
30.6
Subjects with Postbaseline Hemoglobin < 10 g/dL and < 8.5 g/dL
Safety Analysis Set
30.7
Reticulocytes (x10^3 /uL) and Change from Baseline by Visit
Safety Analysis Set
30.8
WBC (x10^3 /uL) and Change from Baseline by Visit
Safety Analysis Set
30.9
Neutrophils (x10^3 /uL) and Change from Baseline by Visit
Safety Analysis Set
30.10
Lymphocytes (x10^3 /uL) and Change from Baseline by Visit
Safety Analysis Set
30.11
Platelets (x10^3 /uL) and Change from Baseline by Visit
Safety Analysis Set
30.12
INR and Change from Baseline by Visit
Safety Analysis Set
30.13
Creatinine (mg/dL) and Change from Baseline by Visit
Safety Analysis Set
30.14
Estimated Glomerular Filtration Rate by Cockcroft-Gault (mL/min) and 
Change from Baseline by Visit
Safety Analysis Set
31
Treatment-Emergent Graded Laboratory Abnormalities
Safety Analysis Set
32
Treatment-Emergent Grade 3 or 4 Laboratory Abnormalities
Safety Analysis Set
33.1
Systolic Blood Pressure (mmHg) and Change from Baseline by Visit
Safety Analysis Set
33.2
Diastolic Blood Pressure (mmHg) and Change from Baseline by Visit
Safety Analysis Set
33.3
Pulse (bpm) and Change from Baseline by Visit
Safety Analysis Set
34.1
PR Interval (ms) and Change from Baseline by Visit
Safety Analysis Set
34.2
QRS Interval (ms) and Change from Baseline by Visit
Safety Analysis Set
34.3
QT Interval (ms) and Change from Baseline by Visit
Safety Analysis Set
34.4
QTcF (ms) and Change from Baseline by Visit
Safety Analysis Set
34.5
Summary of On-Treatment ECG Abnormality
Safety Analysis Set
35.1
Echocardiogram: Ejection Fraction (%) and Change from Baseline by Visit
Safety Analysis Set
35.2
Echocardiogram: Fractional Shortening (%) and Change from Baseline by 
Visit
Safety Analysis Set
35.3
Echocardiogram: LVEDV (mL) and Change from Baseline by Visit
Safety Analysis Set
35.4
Echocardiogram: LVIDd (cm) and Change from Baseline by Visit
Safety Analysis Set
35.5
Echocardiogram: Shift Table of Baseline versus On-Treatment Diastolic 
Function Score Assessment by Visit
Safety Analysis Set
36.1
Individual Data and Summary Statistics of Plasma Intensive Concentration 
(ng/mL) at Protocol-Specified Sampling Times by Visit
SOF PK Analysis Set
36.2
Individual Data and Summary Statistics of Plasma Intensive Concentration 
(ng/mL) at Protocol-Specified Sampling Times by Visit
GS-566500 PK Analysis 
Set


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Table 
Number
Title
Analysis Set
36.3
Individual Data and Summary Statistics of Plasma Intensive Concentration 
(ng/mL) at Protocol-Specified Sampling Times by Visit
GS-331007 PK Analysis 
Set
36.4
Individual Data and Summary Statistics of Plasma Intensive Concentration 
(ng/mL) at Protocol-Specified Sampling Times by Visit
RBV PK Analysis Set
36.5
Individual Data and Summary Statistics of Plasma Intensive Concentration 
(ng/mL) at Protocol-Specified Sampling Times by Visit - With Specified 
Sampling Data Removed
RBV PK Analysis Set
37.1
Individual Data and Summary Statistics of Plasma Trough Concentration 
(ng/mL) by Visit
SOF PK Analysis Set
37.2
Individual Data and Summary Statistics of Plasma Trough Concentration 
(ng/mL) by Visit
GS-566500 PK Analysis 
Set
37.3
Individual Data and Summary Statistics of Plasma Trough Concentration 
(ng/mL) by Visit
GS-331007 PK Analysis 
Set
37.4
Individual Data and Summary Statistics of Plasma Trough Concentration 
(ng/mL) by Visit
RBV PK Analysis Set
37.5
Individual Data and Summary Statistics of Plasma Trough Concentration 
(ng/mL) by Visit –With Specified Sampling Data Removed
RBV PK Analysis Set
38.1
Individual Estimate and Summary Statistics for Pharmacokinetic Parameters 
by Visit
SOF PK Analysis Set
38.2
Individual Estimate and Summary Statistics for Pharmacokinetic Parameters 
by Visit
GS-566500 PK Analysis 
Set
38.3
Individual Estimate and Summary Statistics for Pharmacokinetic Parameters 
by Visit
GS-331007 PK Analysis 
Set
38.4
Individual Estimate and Summary Statistics for Pharmacokinetic Parameters 
by Visit
RBV PK Analysis Set
38.5
Individual Estimate and Summary Statistics for Pharmacokinetic Parameters 
by Visit –With Specified Sampling Data Removed
RBV PK Analysis Set


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Figure 
Number
Title
Analysis Set
1
Subject Disposition
Safety Analysis Set
2
Proportion of Subjects with HCV RNA < LLOQ While on Treatment by 
Visit
Full Analysis Set
2.1
Proportion of Subjects with SVR (HCV RNA < LLOQ) by Posttreatment 
Visit
Full Analysis Set
3.1
Mean (SD) Plasma Concentration - Time (0 hour - 12 hours) Profiles by Visit
SOF PK Analysis Set
3.2
Mean (SD) Plasma Concentration - Time (0 hour - 12 hours) Profiles by Visit
GS-566500 PK Analysis 
Set
3.3
Mean (SD) Plasma Concentration - Time (0 hour - 12 hours) Profiles by Visit
GS-331007 PK Analysis 
Set
3.4
Mean (SD) Plasma Concentration - Time (0 hour - 12 hours) Profiles by Visit
RBV PK Analysis Set
3.5
Median (Q1, Q3) Plasma Concentration - Time (0 hour - 12 hours) Profiles 
by Visit
SOF PK Analysis Set
3.6
Median (Q1, Q3) Plasma Concentration - Time (0 hour - 12 hours) Profiles 
by Visit
GS-566500 PK Analysis 
Set
3.7
Median (Q1, Q3) Plasma Concentration - Time (0 hour - 12 hours) Profiles 
by Visit
GS-331007 PK Analysis 
Set
3.8
Median (Q1, Q3) Plasma Concentration - Time (0 hour - 12 hours) Profiles 
by Visit
RBV PK Analysis Set


Sofosbuvir 
Study GS-US-334-0154 (Cohorts 1 & 2)
Statistical Analysis Plan
Final
CONFIDENTIAL
Page 37
05 February 2016
Listing 
Number
Title
Analysis Set
1
Inclusion and Exclusion Criteria
Subjects Not Treated
2
Subjects Enrolled and Treated Who Did Not Meet Eligibility Criteria
Safety Analysis Set
3
Subject Disposition
Safety Analysis Set
4
Subject Demographics and Baseline Characteristics
Safety Analysis Set
5
Cirrhosis Determination
Safety Analysis Set
6
Medical History
Safety Analysis Set
7
Study Drug Administration
Safety Analysis Set
8
Study Drug Accountability and Adherence
Safety Analysis Set
9
Prior and Concomitant Medications
Safety Analysis Set
10
HCV RNA (log10 IU/mL) and Change from Baseline 
Safety Analysis Set
11
Subjects with Virologic Failure
Safety Analysis Set
12
Subjects with ‘Other’ Virologic Outcome
Safety Analysis Set
13
Subjects with Postbaseline Hemoglobin < 10 g/dL and <8.5 g/dL
Safety Analysis Set
14
All Adverse Events
Safety Analysis Set
15
Grade 3 or 4 Adverse Events
Safety Analysis Set
16
Serious Adverse Events
Safety Analysis Set
17
Adverse Events Leading to Premature Discontinuation from Any Study 
Drug
Safety Analysis Set
18
Deaths
Safety Analysis Set
19
Central Laboratory (Covance) Reference Ranges
Safety Analysis Set
20
Subjects with Treatment-Emergent Grade 3 or 4 Laboratory Abnormalities
Safety Analysis Set
21
Screen Labs: HBsAg, Anti-HIV Ab, Anti-HCV Ab, HbA1c,
and Serum Beta hCG
Safety Analysis Set
22
Hematology: Hematocrit, Hemoglobin, Reticulocyte Count,
MCV, RBC, WBC, and Platelets
Safety Analysis Set
23
Hematology: WBC, Neutrophils, and Lymphocytes
Safety Analysis Set
24
Hematology: Eosinophils, Basophils, and Monocytes
Safety Analysis Set
25
Chemistry: Sodium, Potassium, Serum Creatinine,
Estimated GFR (Cockcroft-Gault), and Glucose
Safety Analysis Set
26
Chemistry: AST, ALT, Total Bilirubin, Direct Bilirubin,
Alkaline Phosphatase, GGT, and Albumin
Safety Analysis Set
27
Coagulation and Other Laboratory Tests: INR, APTT, and TSH
Safety Analysis Set
28
Vital Signs
Safety Analysis Set
29
Height, Weight, and BMI
Safety Analysis Set
30
Overall Assessment of  Electrocardiogram Results
Safety Analysis Set
30.1
Electrocardiogram measurements
Safety Analysis Set


Sofosbuvir 
Study GS-US-334-0154 (Cohorts 1 & 2)
Statistical Analysis Plan
Final
CONFIDENTIAL
Page 38
05 February 2016
Listing 
Number
Title
Analysis Set
31
Echocardiogram Results
Safety Analysis Set
32
Echocardiogram: Ejection Fraction and LVEDV
Safety Analysis Set
33
Dialysis
Safety Analysis Set
34
Pregnancy
Safety Analysis Set
35
Prior HCV Treatment and Response
Safety Analysis Set
36
Plasma PK Sampling Details and PK Concentrations
PK Analysis Set


Sofosbuvir 
Study GS-US-334-0154 (Cohorts 1 & 2)
Statistical Analysis Plan
Final
CONFIDENTIAL
Page 39
05 February 2016
Appendix 2.
Schedule of Assesments for Cohorts 1 and 2
Study 
Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Written 
Informed 
Consent
X
Medical History 
X
HCV RNA 
Genotype
X
IL28B 
Genotyping
X
HbA1c
X
HCV, HBV, 
HIV Serology
X
TSH
X
Physical Exam, 
including 
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram 
X
X
X
Height
X
Weight
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Sofosbuvir 
Study GS-US-334-0154 (Cohorts 1 & 2)
Statistical Analysis Plan
Final
CONFIDENTIAL
Page 40
05 February 2016
Study 
Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Coagulation 
(PT, PTT, and 
INR)
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA Viral 
Load
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA 
Sequencing 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum 
Pregnancy Teste
X
X
X
X
X
X
X
X
X
X
X
X
Creatinine 
Clearance
X
Optional 
Pharmacogenetic 
Samplek
X
Intensive PK
Xf
Xf
Trough PK 
Sampleg
X
X
X
X
X
X
X
X
X
Archive Plasma 
Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
Administration
X
Weeks 1-24


Sofosbuvir 
Study GS-US-334-0154 (Cohorts 1 & 2)
Statistical Analysis Plan
Final
CONFIDENTIAL
Page 41
05 February 2016
Study 
Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Review Dosing 
Diary/Perform 
Accountabilityh
X
X
X
X
X
X
X
X
X
X
AEs/
Concomitant 
Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Screening evaluations must be completed within 42 days prior to Day 1.
b
Day 1 tests and procedures must be completed prior to administration of the first dose of study drugs 
c
Within 72 hours of permanently discontinuing study drug.
d
Full PE at Day 1 and ET visits only; symptom-directed PE at all other timepoints. Vital signs include blood pressure, pulse, respiration rate, and temperature
e
Females of childbearing potential only. To confirm eligibility at Day 1, a urine pregnancy test may be collected for subjects able to pass urine. For subjects unable to pass 
urine, a serum pregnancy test at Day 1 must be performed at a local lab prior to dosing to confirm eligibility along with sample collected and send to central lab. During 
post-treatment of the study, serum or urine pregnancy testing will occur every month during non-clinic post treatment visits. The subject will be contacted by telephone to 
confirm that pregnancy testing has been performed post-treatment during non-clinic visits.
f
Intensive plasma PK evaluations will be assessed at the following timepoints: 0 (predose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose. 
g
Trough plasma PK samples will be drawn prior to dosing. 
h
Dosing Diaries will be completed for all non-observed doses and will be reviewed at every visit. Unused study drug will be returned to perform study drug accountability in 
the original container at each visit following Day 1 for study drug compliance assessment.
i
A window of ± 2 days is allowed for the treatment visits on weeks 1, 2, and 12.  A window of ± 4 days is allowed for the treatment visits weeks, 4-10, and 16-24. Subjects 
who cannot complete their study visit per the visit schedule should ensure they do not run out of study drug prior to their next study visit.  Compliance is critical to ensure 
adequate drug exposure.
j
A window of ± 7 days is allowed for the post treatment visits. 
k
The sample should be collected on Day 1 prior to dosing, but may be collected at any time during the study or at a separate post-study visit, if necessary.
l