STATISTICAL ANALYSIS PLAN

Study Title: A Phase 2b, Randomized, Double-Blind, Placebo-Controlled

Multi-Center Study Evaluating Antiviral Effects,
Pharmacokinetics, Safety, and Tolerability of GS-5806 in
Hematopoietic Cell Transplant (HCT) Recipients with
Respiratory Syncytial Virus (RSV) Infection of the Lower
Respiratory Tract

Name of Test Drug: Presatovir (GS-5806)

Study Number: GS-US-218-1502

Protocol Version: Amendment 7

Protocol Date: 28 March 2016

Analysis Type: Final

Analysis Plan Version: Version 1.0

Analysis Plan Date: 27 June 2017

Analysis Plan Author: PPD

CONFIDENTIAL AND PROPRIETARY INFORMATION

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TABLE OF CONTENTS
TABLE OF CONTENTS .............................................................................................................................................. 2
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 3
LIST OF ABBREVIATIONS........................................................................................................................................ 4
1. INTRODUCTION ................................................................................................................................................ 6
1.1. Study Objectives ...................................................................................................................................... 6
1.2. Study Design ............................................................................................................................................ 6
1.3. Sample Size and Power ............................................................................................................................ 7
2. TYPE OF PLANNED ANALYSIS ...................................................................................................................... 8
2.1. Data Monitoring Committee Analyses ..................................................................................................... 8
2.2. Final Analysis .......................................................................................................................................... 8
3. GENERAL CONSIDERATIONS FOR DATA ANALYSES .............................................................................. 9
3.1. Analysis Sets ............................................................................................................................................ 9
3.1.1. All Randomized Analysis Set ................................................................................................. 9
3.1.2. Full Analysis Set .................................................................................................................... 9
3.1.3. Per Protocol Analysis Set ....................................................................................................... 9
3.1.4. Safety Analysis Set............................................................................................................... 10
3.1.5. Pharmacokinetic Analysis Set .............................................................................................. 10
3.2. Subject Grouping ................................................................................................................................... 10
3.3. Strata and Covariates.............................................................................................................................. 10
3.4. Examination of Subject Subgroups ........................................................................................................ 11
3.5. Multiple Comparisons ............................................................................................................................ 11
3.6. Missing Data and Outliers ...................................................................................................................... 12
3.6.1. Missing Data ........................................................................................................................ 12
3.6.2. Outliers ................................................................................................................................. 12
3.7. Data Handling Conventions and Transformations ................................................................................. 12
3.8. Analysis Visit ......................................................................................................................................... 13
3.8.1. Definition of Study Day ....................................................................................................... 13
3.8.2. Analysis Visit ....................................................................................................................... 13
3.8.3. Selection of Data in the Event of Multiple Records ............................................................. 14
4. SUBJECT DISPOSITION .................................................................................................................................. 15
4.1. Subject Enrollment and Disposition ....................................................................................................... 15
4.2. Extent of Study Drug Exposure and Adherence..................................................................................... 16
4.2.1. Duration of Exposure to Study Drug .................................................................................... 16
4.2.2. Adherence to Study Drug ..................................................................................................... 16
4.3. Protocol Deviations ................................................................................................................................ 17
5. BASELINE CHARACTERISTICS .................................................................................................................... 18
5.1. Demographics ........................................................................................................................................ 18
5.2. Other Baseline Characteristics ............................................................................................................... 18
5.3. Medical History...................................................................................................................................... 19
6. EFFICACY ANALYSES ................................................................................................................................... 20
6.1. Primary Efficacy Endpoint ..................................................................................................................... 20
6.1.1. Definition of the Primary Efficacy Endpoint ....................................................................... 20
6.1.2. Analysis for the Primary Efficacy Endpoint......................................................................... 20
6.1.3. Sensitivity Analysis for Primary Efficacy Endpoint ............................................................ 21

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6.1.4. Imputation of Missing Data .................................................................................................. 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 .......................................................... 21
6.2.3. Sensitivity Analysis for Secondary Efficacy Endpoints ....................................................... 22
6.3. Exploratory Efficacy Endpoints ............................................................................................................. 22
6.3.1. Definition of Exploratory Efficacy Endpoints ...................................................................... 22
6.3.2. Analysis Methods for Exploratory Efficacy Endpoints ........................................................ 22
6.4. Changes From Protocol-Specified Efficacy Analyses............................................................................ 24
7. SAFETY ANALYSES ........................................................................................................................................ 25
7.1. Adverse Events and Deaths .................................................................................................................... 25
7.1.1. Adverse Event Dictionary .................................................................................................... 25
7.1.2. Adverse Event Severity ........................................................................................................ 25
7.1.3. Relationship of Adverse Events to Study Drug .................................................................... 25
7.1.4. Serious Adverse Events ........................................................................................................ 25
7.1.5. Treatment-Emergent Adverse Events................................................................................... 25
7.1.6. Summaries of Adverse Events and Deaths ........................................................................... 26
7.1.7. Additional Analysis of Adverse Events ............................................................................... 27
7.2. Laboratory Evaluations .......................................................................................................................... 27
7.2.1. Summaries of Numeric Laboratory Results ......................................................................... 28
7.2.2. Graded Laboratory Values ................................................................................................... 28
7.2.3. Liver-related Laboratory Evaluations................................................................................... 29
7.3. Body Weight and Vital Signs ................................................................................................................. 30
7.4. Prior and Concomitant Medications ....................................................................................................... 30
7.4.1. Prior Medications ................................................................................................................. 31
7.4.2. Concomitant Medications..................................................................................................... 31
7.5. Electrocardiogram Assessment .............................................................................................................. 32
7.6. Other Safety Measures ........................................................................................................................... 32
7.7. Changes From Protocol-Specified Safety Analyses ............................................................................... 33
8. PHARMACOKINETIC (PK) ANALYSES ........................................................................................................ 34
9. REFERENCES ................................................................................................................................................... 35
10. SOFTWARE ....................................................................................................................................................... 36
11. SAP REVISION.................................................................................................................................................. 37
12. PROPOSED TABLES, FIGURES AND LISTINGS ......................................................................................... 38
12.1. Tables ..................................................................................................................................................... 38
12.2. Figures .................................................................................................................................................... 44
12.3. Listings ................................................................................................................................................... 46
13. APPENDICES .................................................................................................................................................... 48

Appendix 1. Study Procedures Table .......................................................................................................... 48

Appendix 2. Cardiac Adverse Events of Interest ........................................................................................ 51
Appendix 3. Sample SAS Code for MMRM Model ................................................................................... 52
Appendix 4. Sample SAS Code for Negative Binomial Model .................................................................. 53

LIST OF IN-TEXT FIGURES

Figure 1-1. Study Visits .............................................................................................................................. 7

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LIST OF ABBREVIATIONS

AE adverse event
ALT alanine aminotransferase
ANCOVA analysis of covariance
AST aspartate aminotransferase
ATC Anatomical Therapeutic Chemical (drug class)
BLQ below the limit of quantification
BMI body mass index
CI confidence interval
CSR clinical study report
DAVG difference between time-weighted average post-baseline and baseline
DMC Data Monitoring Committee
ECG electrocardiogram
eCRF electronic case report forms
EOT end of treatment
FAS Full Analysis Set
HCT hematopoietic cell transplant
HLT high level term
HLGT high level group term
ICH International Conference on Harmonisation
ICU Intensive Care Unit
ID identification
IMP investigational medicinal product
IWRS interactive web response system
LLT lower level term
LOQ limit of quantification
LRTI lower respiratory tract infection
MedDRA medical dictionary for regulatory activities
ml milliliter
MMRM mixed-effect model with repeated measures
PK pharmacokinetics
PP Per Protocol
PT preferred term
Q1 first quartile
Q3 third quartile
RSV respiratory syncytial virus
RT-qPCR quantitative real time polymerase chain reaction
SAP statistical analysis plan
SD standard deviation

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SE standard error
SOC system organ class
TEAE treatment-emergent adverse event
TFLs tables, figures, and listings
WHO World Health Organization

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1. INTRODUCTION

This statistical analysis plan (SAP) describes the statistical analysis methods and data
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR)
for Study GS-US-218-1502. This SAP is based on the study protocol Amendment 7 dated
28 March 2016 and the electronic case report forms (eCRF) for this study. The SAP will be
finalized before the database finalization. Any changes made after the finalization of the SAP
will be documented in the CSR.

1.1. Study Objectives

Primary Objective

• To evaluate the effect of presatovir on RSV viral load in autologous or allogeneic

hematopoietic cell transplant (HCT) recipients with an acute RSV lower respiratory tract
infection (LRTI)

Secondary Objectives

• To evaluate the effect of presatovir on being free of any supplemental oxygen, and rates of
respiratory failure and all-cause mortality

• To evaluate the PK, safety, and tolerability of presatovir

1.2. Study Design

This is a randomized, double-blind, placebo-controlled study evaluating the effect of presatovir

on efficacy, PK, safety, and tolerability in HCT recipients with RSV LRTI.

All subjects will be permitted to receive the standard of care therapy for RSV infection per their
local medical practices, in addition to the investigational medicinal product (IMP).

Approximately 60 subjects will be enrolled from approximately 45 international HCT centers.

Subjects will be randomized in a 1:1 ratio to receive IMP (presatovir or placebo) and will be
stratified by 2 factors:

• Supplemental O2 requirement (≤ 2 L/min or > 2 L/min) at the time of randomization

• Treatment of current RSV infection (yes or no) with ribavirin (oral, intravenous, or
aerosolized)

A single dose of 200 mg (four 50 mg tablets) of presatovir or placebo will be administered on

Study Days 1, 5, 9, 13, and 17. The study will consist of the following visits: screening (Day -1),
baseline/randomization/IMP administration (Day 1), optional Visit 3 (Day 3), Visit 4 (Day 5),

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Visit 5 (Day 7), Visit 6 (Day 9), Visit 7 (Day 13), Visit 8 (Day 17), Visit 9 (Day 22), and end of
study (Day 28). Four additional visits at Days 35, 42, 49, and 56 will only be completed for
subjects who consent to the optional extended viral monitoring and test positive for RSV at Visit
9 (Day 22) (see Figure 1-1).

Figure 1-1. Study Visits

1.3. Sample Size and Power

Sample size calculations are based on results observed in a study that evaluated the efficacy of
oral and aerosolized ribavirin treatment for preventing progression from upper to lower
respiratory tract infection in hematopoietic cell transplant recipients with RSV infections
(unpublished data from Dr. PPD ). The sample size calculation assumes the
time-weighted average change in RSV log 10 viral load from Day 1 to Day 9 in the placebo group
will be -1.5 log 10 copies/mL with a corresponding standard deviation (SD) of 1.75, and that 85%
of the subjects will be evaluable. Based on these assumptions, with 25 subjects per group there is
approximately 85% power to detect a 1.5 log difference in time-weighted average change in
log 10 viral load between treatment groups using a 2-sided 0.05-level test. Given an evaluable rate
of 85%, a total of 60 subjects will need to be randomized into the study.

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Visit 5 (Day 7), Visit 6 (Day 9), Visit 7 (Day 13), Visit 8 (Day 17), Visit 9 (Day 22), and end of
study (Day 28). Four additional visits at Days 35, 42, 49, and 56 will only be completed for
subjects who consent to the optional extended viral monitoring and test positive for RSV at Visit
9 (Day 22) (see Figure 1-1).

Figure 1-1. Study Visits

1.3. Sample Size and Power

Sample size calculations are based on results observed in a study that evaluated the efficacy of
oral and aerosolized ribavirin treatment for preventing progression from upper to lower
respiratory tract infection in hematopoietic cell transplant recipients with RSV infections
(unpublished data from Dr. PPD ). The sample size calculation assumes the
time-weighted average change in RSV log 10 viral load from Day 1 to Day 9 in the placebo group
will be -1.5 log 10 copies/mL with a corresponding standard deviation (SD) of 1.75, and that 85%
of the subjects will be evaluable. Based on these assumptions, with 25 subjects per group there is
approximately 85% power to detect a 1.5 log difference in time-weighted average change in
log 10 viral load between treatment groups using a 2-sided 0.05-level test. Given an evaluable rate
of 85%, a total of 60 subjects will need to be randomized into the study.

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2. TYPE OF PLANNED ANALYSIS

2.1. Data Monitoring Committee Analyses

An external multidisciplinary Data Monitoring Committee (DMC) will review the progress of
the study and perform interim reviews of safety data in order to protect subject welfare and
preserve study integrity. To ensure the best interests of the participants, the DMC will
recommend to the sponsor if the nature, frequency, and severity of adverse effects associated
with study treatment warrant the early termination of the study, the continuation of the study, or
the continuation of the study with modifications.

The DMC’s role and responsibilities and the scope of analysis to be provided to the DMC are
provided in a mutually agreed upon charter, which defines the DMC membership, meeting
logistics, and meeting frequency.

The initial safety review occurred after approximately 25% of the planned 60 subjects were
enrolled and completed Day 28 visit or discontinued the study. No additional meetings were
scheduled due to the reasons specified in Section 7.7.

2.2. Final Analysis

After all subjects have completed the study, outstanding data queries have been resolved, and the
data have been cleaned and finalized, the study blind will be broken and 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 relevant 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. The treatment group to which
subjects were randomized will be used in the listings. 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. Subjects included in each analysis set will be determined before the
study blind is broken for analysis. 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, will be summarized by treatment group.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1. All Randomized Analysis Set
All Randomized Analysis Set includes all subjects who were randomized in the study.
3.1.2. Full Analysis Set
The Full Analysis Set (FAS) includes all randomized subjects who received at least 1 full dose of
study drug, and have an RSV viral load greater than or equal to the lower limit of quantification
of the RT-qPCR assay in the Day 1 nasal sample, as determined by RT-qPCR at the central lab.
This is the primary analysis set for efficacy analyses.
3.1.3. Per Protocol Analysis Set
The Per-Protocol (PP) Analysis Set includes subjects in the FAS who meet the following criteria:

• Did not violate the following major inclusion criteria (IC)

 IC #2: Received an autologous or allogeneic HCT using any conditioning regimen

 IC #3: Chest X-ray obtained < 48 hours prior to Screening

 IC #4: Documented RSV in both the upper and lower respiratory tract as determined by
local testing collected ≤ 6 days prior to Day 1

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• Did not administered invalid (eg, expired, damaged, quarantined, improperly stored) study
drug

• Not be dispensed incorrect study drug (wrong bottle) or drug from another study

• Missed < 1 dose (200 mg) in the first 9 study days

• Missed < 3 nasal swab samples over the course of the study

The PP Analysis Set is the secondary analysis set for efficacy analyses.

3.1.4. Safety Analysis Set

The Safety Analysis Set includes subjects who took at least 1 full dose of study drug. This is the
primary analysis set for safety analyses.

3.1.5. Pharmacokinetic Analysis Set

The Pharmacokinetic (PK) Analysis Set includes all subjects in the Safety Analysis Set who have
evaluable on-study PK measurements. This is the primary analysis set for all PK analyses.

3.2. Subject Grouping

For analyses based on the FAS and PP Analysis Set, subjects will be grouped according to the
treatment to which they were randomized. For analyses based on the Safety Analysis Set,
subjects will be grouped according to the actual treatment received. The actual treatment
received will differ from the randomized treatment only when their actual treatment differs from
randomized treatment for the entire treatment duration.

For the PK Analysis Set, subjects will be grouped according to the actual treatment they
received.

3.3. Strata and Covariates

Subjects will be randomly assigned to treatment groups via the interactive web response system
(IWRS) in a 1:1 ratio using a stratified randomization schedule. Stratification will be based on
the following parameters:

• Supplemental O2 requirement (≤ 2 L/min or > 2 L/min) at the time of randomization

• Treatment of current RSV infection (yes or no) with ribavirin (oral, intravenous, or
aerosolized)

If there are discrepancies in stratification factor values between the IWRS and the clinical
database, the values recorded in the clinical database will be used for analyses.

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Efficacy endpoints will be evaluated using stratification factors as covariates for analyses, as
specified in Section 6. In the event the number of subjects within a stratum of the stratification
factor is small (eg. ≤ 4 subjects), the stratum will be collapsed with the adjacent stratum for the
analysis.

For efficacy endpoints, the baseline value of the efficacy variables will be included as a covariate
in the efficacy analysis model.

3.4. Examination of Subject Subgroups

The primary and secondary efficacy endpoints will be examined using the following subgroups:

• Actual ribavirin use at the first dosing date (Yes or No)

• Supplemental O2 requirement (≤ 2 L/min or > 2 L/min) at the time of randomization

The primary efficacy endpoint will also be examined by RSV type (RSV A or RSV B).

The safety endpoints will be examined using the following subgroups:

• Age (< 65 years and ≥ 65 years)

• Sex (male and female)

3.5. Multiple Comparisons

In order to account for multiple hypothesis testing of endpoints, a sequential testing procedure
will be used to control the Type 1 error rate of 0.05 across the primary and secondary endpoints.
The primary endpoint analysis will serve as the gatekeeper for the secondary analyses, ie, the
primary efficacy hypothesis must be rejected at the 2-sided 0.05 significance level before the
efficacy hypotheses for the secondary efficacy endpoints can be evaluated.

If the primary null hypothesis is rejected, then the following secondary endpoints will be tested
sequentially at 2-sided α = 0.05 significance level in the order listed below based upon the closed
testing procedure {Dmitrienko 2003}.

• Number of supplemental O 2 free days through Day 28

• Proportion of subjects developing respiratory failure (of any cause) requiring mechanical
ventilation (invasive or noninvasive) through Day 28

• Proportion of all-cause mortality among all subjects through Day 28

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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 7.4. The handling of missing data in analyses of the
efficacy endpoints is discussed in Section 6.

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 analyses.

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
randomization 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 eCRF, “01 January” 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).

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If methods based on the assumption that the data are normally distributed are not adequate,
analyses may be performed on transformed data (eg, log-transformed data) or nonparametric
analysis methods may be used, as appropriate.

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 LOQ at post-baseline time points.

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.”

3.8. Analysis Visit

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 post-dose 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.

3.8.2. Analysis Visit

The nominal visit as recorded on the eCRF will be used when data are summarized by visit. Any
data relating to unscheduled visits will not be assigned to a particular visit or time point.
However, the following exception will be made:

• An unscheduled visit prior to the first dosing of study drug may be included in the calculation
of the baseline value, if applicable.

• Unscheduled visits after the first dose of study drug will be included in determining the
maximum post-baseline toxicity grade.

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• For subjects who prematurely discontinue from the study, early termination (ET) data will be
assigned to the next scheduled visit where the respective data were scheduled to be collected.

• Data collected on an extended viral load monitoring visit will be summarized as a separate
visit, and labeled as Day 35, 42, 49, or 56.

3.8.3. Selection of Data in the Event of Multiple Records

Depending on the statistical analysis method, single values may be required for each analysis
visit. If multiple valid, nonmissing, continuous measurements exist in one visit, 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 the efficacy endpoints, if no measurements occur prior to
the time of first dosing of study drug, the first nonmissing value on the first dosing date of
study drug will be considered as 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, non-missing, categorical measurements exist for one visit, 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 at the same time or no time recorded on the
same day, the value with the lowest severity will be selected unless otherwise specified.

• 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 value with the worst severity will
be used.

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4. SUBJECT DISPOSITION

4.1. Subject Enrollment and Disposition

A summary of subject enrollment will be provided by treatment group for each country,
investigator within a country, and overall. The summary will present the number and percentage
of subjects enrolled. For each column, the denominator for the percentage calculation will be the
total number of subjects analyzed for that column.

A similar enrollment table will be provided by randomization stratum. The denominator for the
percentage of subjects in the stratum will be the total number of randomized subjects. If there are
discrepancies in the value used for stratification assignment between the IWRS and the clinical
database or other source documents, the value collected in the clinical database will be used for
the summary. A listing of subjects with discrepancies in the value used for stratification
assignment between the IWRS and the clinical database at the time of data finalization will be
provided.

The randomization schedule used for the study will be provided as an appendix to the CSR.

A summary of subject disposition will be provided by treatment group. This summary will
present the number of subjects screened, the number of subjects who met all eligibility criteria
but were not randomize with reasons subjects not randomized, the number of subjects
randomized, and the number of subjects in each of the categories listed below:

• Full Analysis Set

• Safety Analysis Set

• Per-Protocol Analysis Set

• 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

• Completed Extended Viral Load Monitoring Period

• Did not complete the Extended Viral Load Monitoring Period with reasons for premature
discontinuation of Extended Viral Load Monitoring Period

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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
corresponding to that column.

The following by-subject listings will be provided by subject identification (ID) number in
ascending order to support the above summary tables:

• Reasons for premature study drug or study discontinuation

• Reasons for screen failure (will be provided by screening ID number in ascending order)

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 the 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 4, regardless of any temporary interruptions in study drug administration, and will be
expressed in days using up to 1 decimal place (eg, 4.5 days). 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 (n,
mean, SD, median, Q1, Q3, minimum, and maximum), and using the number and percentage of
subjects exposed through the following time periods: Day 1 (Baseline), Day 5, Day 9, Day 13,
and Day 17. Summaries will be provided by treatment group for the Safety Analysis Set.

No formal statistical testing is planned.

4.2.2. Adherence to Study Drug

The total number of tablets administered will be summarized using descriptive statistics.

The presumed total number of tablets administered to a subject will be determined by the data
collected on the drug accountability eCRF using the following formula:

Total Number of Tablets Administered

= (∑ No. of Tablets Dispensed at Study Dosing Visits )
The level of prescribed adherence to the study drug regimen 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.

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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 

Descriptive statistics for adherence (sample size, mean, SD, median, Q1, Q3, minimum, and
maximum) along with the number and percentage of subjects belonging to adherence categories
(eg, < 80% and ≥ 80%) will be provided by treatment group 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

Subjects who did not meet the eligibility criteria for study entry, but enrolled in the study will be
summarized regardless of whether they were exempted by the sponsor or not. The summary will
present the number and percentage of subjects who did not meet at least 1 eligibility criterion and
the number of subjects who did not meet specific entry criteria by treatment group based on the
All Randomized Analysis Set. A by-subject listing will be provided for those subjects who did
not meet at least 1 eligibility (inclusion or exclusion) criterion. The listing will present the
eligibility criterion (or criteria if more than 1 deviation) that subjects did not meet and related
comments, if collected.

Protocol deviations occurring after subjects entered the study are documented during routine
monitoring. The number and percentage of subjects with important protocol deviations by
deviation reason (eg, nonadherence to study drug, violation of selected inclusion/exclusion
criteria) will be summarized by treatment group for All Randomized Analysis Set. A by-subject
listing will be provided for those subjects with any protocol deviation.

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5. BASELINE CHARACTERISTICS

5.1. Demographics

Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized by treatment
group and overall using descriptive statistics for age, and using number and percentage of
subjects for sex, race, and ethnicity. The summary of demographic data will be provided for the
Safety Analysis Set.

In addition, a similar summary table will be provided by the consent status of participation in the
Extended Viral Load Monitoring (yes or no).

A by-subject demographic listing, including the informed consent date, will be provided by
subject ID number in ascending order.

5.2. Other Baseline Characteristics

Other baseline characteristics include:

• Weight (kg)

• Height (cm)

• Body mass index (BMI; in kg/m2)

• RSV types (RSV A or RSV B)

• Vital signs (pulse rate, systolic and diastolic blood pressure, body temperature, and
respiratory rate)

• Smoking history

• Viral load

• Detectable RSV in nasal swab samples

• Co-pathogen types

• Duration of respiratory symptoms prior to the first dosing date

• Stratification factors

• Hospitalization (including hospitalization on the date of the first study drug administration
Yes/No, hospitalized types, duration of hospitalization prior to the date of the first study drug
administration, hospitalization reasons, hospitalization related to RSV infection)

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These baseline characteristics will be summarized by treatment groups and overall using
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for continuous
variables and using number and percentage of subjects for categorical variables. In addition,
baseline characteristics will be summarized by the consent status of participation in the Extended
Viral Load Monitoring (yes or no) in a separate table. The summary of baseline characteristics
will be provided for the Safety Analysis Set. No formal statistical testing is planned.

A by-subject listing of the baseline characteristics will be provided by subject ID number in

ascending order.

5.3. Medical History

Medical history will be collected at screening for disease-specific and general conditions
(ie, conditions not specific to the disease being studied).

HCT-specific medical history (eg, transplant type, graft versus host disease [GVHD], cell source,
cytomegalovirus [CMV] status, and time from transplant to the first dosing date) will be
summarized by treatment group and overall using descriptive statistics (n, mean, SD, median,
Q1, Q3, minimum, and maximum) for continuous variables and using the numbers and
percentages of subjects for categorical variables. A summary of HCT-specific medical history
will be provided for the Safety Analysis Set. No formal statistical testing is planned.

General medical history will not be coded, but will be listed only.

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6. EFFICACY ANALYSES

6.1. Primary Efficacy Endpoint

6.1.1. Definition of the Primary Efficacy Endpoint

The primary efficacy endpoint for this study is the time-weighted average change in log 10 RSV
viral load from Baseline (Day 1) to Day 9, defined as:

where Y i is the change from Baseline in RSV log 10 viral load at Visit i, t is the time at the
specified timepoint (the actual study day), a is the baseline assessment at Day 1, and b is the last
assessment at or prior to Day 9.

The time-weighted average change, often referred to as the DAVG, provides the average viral
burden change from baseline.

6.1.2. Analysis for the Primary Efficacy Endpoint

The primary analysis will test for the superiority of the presatovir group compared to the placebo
group based on the time-weighted average change in log 10 RSV viral load from Day 1 to Day 9
in the Full Analysis Set at the 2-sided 0.05 level. The null and alternative hypotheses for the
superiority test on the primary efficacy endpoint are as follows:

• H 0 : There is no difference between presatovir and placebo in the time-weighted average

change in RSV log 10 viral load from Day 1 to Day 9

• H 1 : There is difference between presatovir and placebo in the time-weighted average change
in RSV log 10 viral load from Day 1 to Day 9

To test the null hypothesis above, a parametric analysis of covariance (ANCOVA) model with
corresponding baseline viral load and stratification factors (supplemental O 2 use and treatment of
current RSV infection) as covariates will be used, at a 2-sided 0.05 level. Adjusted means and
95% confidence intervals (CIs) will be provided. The stratified Wilcoxon rank sum test will be
implemented as a sensitivity analysis.

Viral load values below the limit of detection (LOD) will be assigned as 0 if it is reported in the
form of ‘not detected’. A value of 1 unit less than the LOQ will be used for analysis if the viral
load is reported in the form of “< x” (where x is considered the LOQ). Viral load data will be
transformed using the base 10 logarithm for the analyses and summaries. To account for
0 values, 1 will be added to each viral load measurement before being transformed.

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6.1.3. Sensitivity Analysis for Primary Efficacy Endpoint

Sensitivity analyses of the primary efficacy endpoint will be performed in the PP analysis set.

6.1.4. Imputation of Missing Data

Missing viral load data due to premature discontinuation of the study will not be imputed as all
available data will be included in the time-weighted average calculations. Intermediate missing
viral load data will be imputed using the trapezoidal rule for the time-weighted average
calculations.

6.2. Secondary Efficacy Endpoints

6.2.1. Definition of Secondary Efficacy Endpoints

Secondary efficacy endpoints include:

• Number of supplemental O 2 free days through Day 28

• Proportion of subjects developing respiratory failure (of any cause) requiring mechanical
ventilation (invasive or noninvasive) through Day 28

• Proportion of all-cause mortality among subjects through Day 28

6.2.2. Analysis Methods for Secondary Efficacy Endpoints

In order to account for multiple hypothesis testing of endpoints, a sequential testing procedure
described in Section 3.5 will be used to control the overall Type 1 error rate of 0.05 across the
primary and secondary endpoints.

The FAS will be used for all summaries and analyses of secondary endpoints. All secondary
endpoints will be analyzed using 2-sided tests to compare treatment differences.

The number of supplemental O 2 -free days through Day 28 will be analyzed using a negative
binomial model with stratification factors as covariates and an offset parameter to account for the
on-study duration. Subjects who die prior to Day 28 (inclusive) or are receiving supplemental O 2
on all days of the study period are assigned 0 supplemental O 2 -free days. All survivors accrue 1
supplemental O 2 -free day for each day that they are both alive and on the use of supplemental O 2
less than 12 hours per 24 hours (0:00 to 23:59) when they are on study.

The proportion of subjects who develop respiratory failure requiring mechanical ventilation and
the proportion of subjects with all-cause mortality will be analyzed using
Cochran-Mantel-Haenszel (CMH) test adjusting for the stratification factors at the 2-sided
0.05-level. The 2-sided 95% exact CI of the respiratory failure rate or mortality rate based on the
Clopper-Pearson method will be provided for each treatment group. In the case of a small
number of events, the exact method will be used.

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6.2.3. Sensitivity Analysis for Secondary Efficacy Endpoints

Sensitivity analyses of the seconda~y efficacy endpoints, the number of supplemental 0 2-free
days through Day 28, the prop01iion of subjects who develop respirat01y failure requi1ing
mechanical ventilation through Day 28, and the prop01iion of subjects with all-cause mo1iality
through Day 28,will be perf01m ed in the PP analysis set.

6.3. Exploratory Efficacy Endpoints

6.3.1. Definition of Exploratory Efficacy Endpoints

PPD
I
I
I
I
I
I
I
I
I
I
I
6.3.2. Analysis Methods for Exploratory Efficacy Endpoints

PPD

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PPD
I

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PD

6.4. C hanges From Protocol-Specified Efficacy Analyses

PD

I
I
I

• The number of supplemental 0 2-free days through Day 28 will be analyzed using a negative
binomial model with stratification factors as covariates. An offset parameter will be included
to accmmt for differential study durations.

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7. SAFETY ANALYSES

7.1. Adverse Events and Deaths

7.1.1. Adverse Event Dictionary

Clinical and laboratory AEs will be coded using the current version of the Medical Dictionary
for Regulatory Activities (MedDRA). System organ class (SOC), high level group term (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

Severity of adverse events will be determined by the investigator as Grade 1 (mild), Grade 2
(moderate), Grade 3 (severe), or Grade 4 (life-threatening). The severity 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 eCRF 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
relationships to study drug will be considered related to study drug for summary purposes.
However, by-subject data listings will show the relationship as missing.

7.1.4. Serious Adverse Events

Serious adverse events will be identified and captured as SAEs if 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 database finalization.

7.1.5. Treatment-Emergent Adverse Events

7.1.5.1. Definition of Treatment-Emergent Adverse Events

Treatment-emergent adverse events (TEAE) are defined as 1 or both of the following:

• Any AEs with an onset date on or after the study drug start date up to the Day 28, or up to 28
days if a subject withdraws early (prior to Day 28) from the study

• Any AEs leading to premature discontinuation of study drug

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7.1.5.2. Incomplete Dates

If the onset date of the AE is incomplete 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 Day 28

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 (TE) AEs will be summarized based on the Safety Analysis Set.

The number and percentage of subjects who experienced at least 1 TEAE will be provided and
summarized by SOC and PT, and treatment group. For other AEs described below, summaries
will be provided by SOC, PT, and treatment group:

• TEAE by maximum severity

• TEAEs of Grade 3 or higher (by maximum severity)

• TEAEs of Grade 2 or higher

• All TE treatment-related AEs

• All TE treatment-related AEs by maximum severity

• TE treatment-related AEs of Grade 3 or higher (by maximum severity)

• TE treatment-related AEs of Grade 2 or higher

• All TE SAEs

• All TE treatment-related SAEs

• All TEAEs leading to premature discontinuation of study drug

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• All TEAEs leading to premature discontinuation of study

• All AEs leading to death (ie, outcome of death)

A brief, high-level summary of AEs described above will be provided by treatment group and by
the number and percentage of subjects who experienced the above AEs. All deaths observed in
the study will be also 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 HLT within each SOC (if applicable),
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, TE treatment-related AEs, and TE SAE will
be summarized by PT only, in descending order of total frequency.

In addition, data listings will be provided for the following:

• All AEs, indicating whether the event is treatment emergent

• All AEs of Grade 3 or higher

• All AEs of Grade 2 or higher

• SAEs

• Deaths

• All AEs leading to death (ie, outcome of death)

• AEs leading to premature discontinuation of study drug

• AEs leading to premature discontinuation of study

7.1.7. Additional Analysis of Adverse Events

Summaries (number and percentage) of subjects who experienced any cardiac related events will
be provided for each treatment group using the Safety Analysis Set by AE of interest categories
and the associated PTs (see Appendix 2).

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 Day 28. The analysis will be based on
values reported in conventional units. When values are below the LOQ, they will be listed as

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such, and the closest imputed value will be used for the purpose of calculating summary statistics
as 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 and serum chemistry separately. Values falling outside of the
relevant reference range and/or having a severity grade of 1 or higher on the Gilead Grading
Scale for Severity of Adverse Events and Laboratory Abnormalities will be flagged in the data
listings, as appropriate.

No formal testing will be generated.

7.2.1. Summaries of Numeric Laboratory Results

Descriptive statistics will be provided by treatment group for each laboratory test specified in the
study protocol as follows:

• Baseline values

• Values at each postbaseline visit

• Change from baseline at each postbaseline visit

A baseline laboratory value will be defined as the 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
will be displayed to the reported number of digits; SD values will be displayed to the reported
number of digits plus 1.

Median (Q1, Q3) of the observed values for the laboratory tests will be plotted using a line plot
by treatment group and visit.

In the case of multiple values in an analysis visit, data will be selected for analysis as described
in Section 3.8.3.

7.2.2. Graded Laboratory Values

The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be
used for assigning toxicity grades (0 to 4) to laboratory results for analysis. Grade 0 includes all
values that do not meet the criteria for an abnormality of at least Grade 1. 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 Day 28. 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. Treatment-Emergent Marked Laboratory Abnormalities

Treatment-emergent marked laboratory abnormalities are defined as values that increase from
baseline by at least 3 toxicity grades at any postbaseline time point, up to and including Day 28.
If the relevant baseline laboratory value is missing, then any Grade 3 or 4 values observed within
the timeframe specified above will be considered treatment-emergent marked abnormalities.
7.2.2.3. 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 treatment group; subjects will be categorized according to the
most severe postbaseline abnormality grade for a given lab test:

• Graded laboratory abnormalities

• Grade 3 or 4 laboratory abnormalities

• Marked laboratory abnormalities

For all summaries of laboratory abnormalities, the denominator is the number of subjects with
nonmissing postbaseline values up to and including Day 28.
A by-subject listing of treatment-emergent Grade 3 or 4 laboratory abnormalities and marked
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.

7.2.3. Liver-related Laboratory Evaluations

Liver-related abnormalities after initial study drug dosing will be examined and summarized
using the number and percentage of subjects who were reported to have the following laboratory
test values for post-baseline measurements:

• Aspartate aminotransferase (AST): (a) > 3 times of the upper limit of reference range
(ULN); (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x ULN

• Alanine aminotransferase (ALT): (a) > 3 x ULN; (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x
ULN

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• AST or ALT: (a) > 3 x ULN; (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x ULN

• Total bilirubin: (a) > 1 x ULN; (b) > 2 x ULN

• Alkaline phosphatase (ALP) > 1.5 x ULN

• AST or ALT > 3 x ULN and total bilirubin: (a) > 1.5 x ULN; (b) > 2 x ULN

• AST or ALT > 3 x ULN, total bilirubin > 2 x ULN and ALP < 2 x ULN

The summary will include data from all post-baseline visits up to and including Day 28. For
individual laboratory tests, subjects will be counted once based on the most severe post-baseline
values. For both the composite endpoint of AST or ALT and total bilirubin, subjects will be
counted once when the criteria are met at the same post-baseline visit date. The denominator is
the number of subjects in the Safety Analysis Set who have nonmissing post-baseline values of
all relevant tests at the same post-baseline visit date. A listing of subjects who met at least 1 of
the above criteria will be provided.

7.3. Body Weight and Vital Signs

Descriptive statistics will be provided by treatment group for body weight and vital signs as
follows:

• Baseline value

• Values at each postbaseline time point

• Change from baseline at each postbaseline time point

Median (Q1, Q3) of the observed values for vital signs will be plotted by treatment group and
visit.

A baseline value will be defined as the last available value collected on or prior to the date/time
of first dose of study drug. Change from baseline to a post-baseline visit will be defined as the
post-baseline value minus the baseline value.

In the case of multiple values at a visit assessment, data will be selected for analysis as described
in Section 3.8.3. No inferential statistics will be generated.

A by-subject listing of vital signs will be provided by subject ID number and visit in
chronological order. Body weight will be included in the vital signs listing, if space permits. If
not, they will be provided separately.

7.4. 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.

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7.4.1. Prior Medications

Prior medications are defined as any medications taken before a subject took the first study drug.

Prior medications will be summarized by Anatomical Therapeutic Chemical (ATC) drug class
Level 2 and preferred name using the number and percentage of subjects for each treatment
group and overall. A subject reporting the same medication more than once will be counted only
once when calculating the number and percentage of subjects who received that medication. The
summary will be ordered alphabetically by ATC classes and then by preferred term in order of
descending overall frequency within each ATC medical class. For drugs with the same
frequency, sorting will be done alphabetically.

For the purposes of analysis, any medication with a start date prior to the first dosing date of
study drug will be included in the prior medication summary regardless of when the stop date is.
If a partial start date is entered the medication will be considered prior unless the month and year
(if day is missing) or year (if day and month are missing) of the start date are after the first
dosing date. Medications with a completely missing start date will be included in the prior
medication summary, unless otherwise specified. Summaries will be based on the Safety
Analysis Set. No formal statistical testing is planned.

Prior ribavirin use will be summarized separately from other prior general medications.

7.4.2. Concomitant Medications

Concomitant medications are defined as medications taken while a subject took study drug. 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 for each
treatment group. 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 the purposes of analysis, any medication with a start date prior to or on the first dosing date
of study drug and continued to take after the first dosing date, or started after the first dosing date
but prior to or on the last dosing date of study drug will be considered concomitant medications.
Medications started and stopped on the same day as the first dosing date or the last dosing date of
study drug will also be considered concomitant. Medications with a stop date prior to the date of
first dosing date of study drug or a start date after the last dosing date of study drug will be
excluded from the concomitant medication summary. If a partial stop date is entered, any
medication with the month and year (if day is missing) or year (if day and month are missing)
prior to the date of first study drug administration will be excluded from the concomitant
medication summary. If a partial start date is entered, any medication with the month and year
(if day is missing) or year (if day and month are missing) after the study drug stop date will be
excluded from the concomitant medication summary. Medications with completely missing start

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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.

Concomitant ribavirin use will be summarized separately from other concomitant general
medications.

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.

7.5. Electrocardiogram Assessment

Number and percent of subjects with new ECG abnormalities at postbaseline visits including
those assessments obtained for the purpose of standard of care will by summarize by treatments.
Only subjects with baseline ECG assessments will be included in this analysis.

A shift table of the central assessment of ECG results at postbaseline visit including those
assessments obtained for the purpose of standard of care compared with baseline values will be
presented by treatment group using the following categories: normal, no new abnormality, new
abnormality, or missing. The number and percentage of subjects in each cross-classification
group of the shift table will be presented. Subjects with a missing value at baseline or
postbaseline will not be included in the denominator for percentage calculation. No formal
statistical testing is planned.

A by-subject listing for ECG central assessment and ECG abnormalities, including those not
required by the protocol (ie. standard of care), will be provided by subject ID number and time
point in chronological order.

7.6. Other Safety Measures

A shift table of troponin results at postbaseline visit including those obtained for the purposes of
standard of care compared with baseline values will be presented by treatment group using the
following categories: normal, abnormal, or missing. The number and percentage of subjects in
each cross-classification group of the shift table will be presented. Subjects with a missing value
at baseline or postbaseline will not be included in the denominator for percentage calculation. No
formal statistical testing is planned.

If multiple troponin results exist for one visit due to multiple troponin assay tests performed, the
results obtained from Troponin I test will be used for the analysis.

A by-subject listing for all troponin results, including those not required by the protocol
(ie, standard of care), will be provided by subject ID number and visit in chronological order.

A data listing will be provided for subjects experiencing pregnancy during the study.

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7.7. Changes From Protocol-Specified Safety Analyses

In accordance with the DMC Charter, the additional safety DMC meetings were scheduled to
occur after approximately 50% and 75% of the subjects were enrolled. The winter 2016/2017
RSV season resulted in higher rates of enrollment for this study compared to previous RSV
seasons. The enrollment was completed in this study on 20 March 2017 with 60 subjects
enrolled. Due to quicker than expected enrollment and the time required to prepare for a DMC
meeting, it would not have been possible to hold the planned DMC meeting prior to all subjects
completing treatment with presatovir. Since the findings of the DMC would not have been
actionable upon subjects in the study, the DMC Chairperson agreed to forgo the meeting

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8. PHARMACOKINETIC (PK) ANALYSES

Individual subject concentration data for presatovir will be listed and summarized using
descriptive statistics. Summary statistics (n, mean, SD, coefficient of variation [%CV], median,
min, max, Q1, and Q3) will be calculated for individual subject concentration data by time point.

Individual concentration data listings and summaries will include all subjects with concentration
data. The sample size for each time point will be based on the number of subjects with
nonmissing concentration data at that time point. The number of subjects with concentration
BLQ will be presented for each time point. For summary statistics, BLQ values will be treated as
0 at pre-dose and one-half of the lower LOQ for post-dose time points.

The following table will be provided for presatovir:

• Individual subject concentration data and summary statistics

The following figures will be provided for presatovir:

• Mean (± SD) concentration data versus time (on linear and semilogarithmic scales)

Individual, mean, and median post-dose concentration values that are ≤ lower LOQ will not be
displayed in the figures and remaining points connected.

PK sampling details by subject, including procedures, differences in scheduled and actual draw
times, and sample age will be provided in listings.

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Statistical Analysis Plan Version 1.0

9. REFERENCES

Dmitrienko A, Offen WW, Westfall PH. Gatekeeping strategies for clinical trials that do not
require all primary effects to be significant. Statist Med 2003;22 (15):2387-400.

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Statistical Analysis Plan Version 1.0

10. SOFTWARE

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

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Presatovir (GS-5806)
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Statistical Analysis Plan Version 1.0

11. SAP REVISION

Revision Date
(dd month, yyyy) Section Summary of Revision Reason for Revision

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Statistical Analysis Plan Version 1.0

12. PROPOSED TABLES, FIGURES AND LISTINGS

12.1. Tables

Table Number Title Analysis Set

15.8.1.1 Enrollment by Country and Investigator All Randomized Analysis Set
15.8.1.2 Enrollment by Randomization Stratum All Randomized Analysis Set
15.8.1.3 Subject Disposition All Screened Subjects
15.8.2.1 Eligibility Criteria Deviations All Randomized Analysis Set
15.8.2.2 Important Protocol Deviations All Randomized Analysis Set
15.8.3.1.1 Demographics Safety Analysis Set
Demographics by Consent for Participating in the
15.8.3.1.2 Safety Analysis Set
Extended Viral Load Monitoring
15.8.3.2.1 Baseline Characteristics Safety Analysis Set
Baseline Characteristics by Consent for Participating in
15.8.3.2.2 Safety Analysis Set
the Extended Viral Load Monitoring
15.8.3.3 Hematopoietic Cell Transplant Medical History Safety Analysis Set
15.8.4 Adherence to Study Drug Safety Analysis Set
15.8.5 Analysis Sets All Randomized Analysis Set
Time-Weighted Average Change in Nasal RSV Viral
15.9.1.1 Full Analysis Set
Load (log 10 copies/ml) from Baseline to Day 9
Time-Weighted Average Change in Nasal RSV Viral
15.9.1.2 Per Protocol Analysis Set
Load (log 10 copies/ml) from Baseline to Day 9
Time-Weighted Average Change in Nasal RSV Viral
15.9.1.3 Load (log 10 copies/ml) from Baseline to Day 9 by Actual Full Analysis Set
Ribavirin Use at Date of First Study Drug Administration
Time-Weighted Average Change in Nasal RSV Viral
15.9.1.4 Load (log 10 copies/ml) from Baseline to Day 9 by Full Analysis Set
Supplemental O 2 Use at Randomization
Time-Weighted Average Change in Nasal RSV Viral
15.9.1.5 Load (log 10 copies/ml) from Baseline to Day 9 by RSV Full Analysis Set
Type
15.9.2.1.1 Number of Supplemental O 2 Free Days through Day 28 Full Analysis Set
15.9.2.1.2 Number of Supplemental O 2 Free Days through Day 28 Per Protocol Analysis Set
Number of Supplemental O 2 Free Days through Day 28
15.9.2.1.3 by Actual Ribavirin Use at Date of First Study Drug Full Analysis Set
Administration
Number of Supplemental O 2 Free Days through Day 28
15.9.2.1.4 Full Analysis Set
by Supplemental O 2 Use at Randomization

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Statistical Analysis Plan Version 1.0

Table Number Title Analysis Set

Proportion of Subjects Developing Respiratory Failure
15.9.2.2.1 Full Analysis Set
Requiring Mechanical Ventilation Through Day 28
Proportion of Subjects Developing Respiratory Failure
15.9.2.2.2 Per Protocol Analysis Set
Requiring Mechanical Ventilation Through Day 28
Proportion of Subjects Developing Respiratory Failure
Requiring Mechanical Ventilation Through Day 28 by
15.9.2.2.3 Full Analysis Set
Actual Ribavirin Use at Date of First Study Drug
Administration
Proportion of Subjects Developing Respiratory Failure
15.9.2.2.4 Requiring Mechanical Ventilation Through Day 28 by Full Analysis Set
Supplemental O 2 Use at Randomization
Proportion of All-cause Mortality Among Subjects
15.9.2.3.1 Full Analysis Set
Through Day 28
Proportion of All-cause Mortality Among Subjects
15.9.2.3.2 Per Protocol Analysis Set
Through Day 28
Proportion of All-cause Mortality Among Subjects
15.9.2.3.3 Through Day 28 by Actual Ribavirin Use at Date of First Full Analysis Set
Study Drug Administration
Proportion of All-cause Mortality Among Subjects
15.9.2.3.4 Through Day 28 by Supplemental O 2 Use at Full Analysis Set
Randomization
RSV Viral Load (log 10 copies/ml) and Change from
15.9.3.1.1 Full Analysis Set
Baseline in Nasal Samples
RSV Viral Load (log 10 copies/ml) and Change from
15.9.3.1.2 Baseline in Nasal Samples for the Extended Viral Load Full Analysis Set
Monitoring
RSV Viral Load (log 10 copies/ml) and Change from
15.9.3.1.3 Baseline in the Nasal Samples by Consent for Full Analysis Set
Participating in the Extended Viral Load Monitoring
Time-weighted Average and Time-weighted Average
15.9.3.2 Change from Baseline in Nasal RSV Viral Load (log 10 Full Analysis Set
copies/ml)
Proportion of Subjects with Detectable RSV in Nasal
15.9.3.3.1 Full Analysis Set
Samples by Visit
Proportion of Subjects with Detectable RSV in Nasal
15.9.3.3.2 Samples by Consent for Participating in the Extended Full Analysis Set
Viral Load Monitoring
Proportion of Subjects on Supplemental O 2 (≥ 2 L/min
15.9.3.4 Full Analysis Set
for > 24 hours ) through Day 28
Proportion of Subjects whose O 2 Saturation Drops ≤ 88%
15.9.3.5 Full Analysis Set
by Day 28
15.9.3.6 O 2 Saturation and Change from Baseline in O 2 Full Analysis Set

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Table Number Title Analysis Set

Saturation
Time-weighted Average O 2 Saturation and Time-
15.9.3.7 weighted Average Change from Baseline in O 2 Full Analysis Set
Saturation
Proportion of Subjects Requiring ICU Admission or
15.9.3.8 Equivalent of ICU Care (due to Any Cause) through Day Full Analysis Set
28
15.9.3.9 Number of ICU Free Days through Day 28 Full Analysis Set
Number of Mechanical Ventilation (Invasive or Non-
15.9.3.10 Full Analysis Set
invasive) Free Days through Day 28
15.9.3.11 Number of Hospital Free Days through Day 28 Full Analysis Set
Individual Data and Summary Statistics of Plasma
15.10.1.1 Concentration (ng/mL) at Protocol Specified Sampling PK Analysis Set
Time
15.11.1.1 Extent of Exposure to Study Drug Safety Analysis Set
15.11.2.1.1.1 Treatment Emergent Adverse Events: Overall Summary Safety Analysis Set
Treatment Emergent Adverse Events by Age Group (<65
15.11.2.1.1.2 Safety Analysis Set
Years or ≥65 Years): Overall Summary
Treatment Emergent Adverse Events by Sex (Male or
15.11.2.1.1.3 Safety Analysis Set
Female): Overall Summary
Treatment Emergent Adverse Events by System Organ
15.11.2.1.2.1 Safety Analysis Set
Class and Preferred Term
Treatment Emergent Adverse Events by System Organ
15.11.2.1.2.2 Class and Preferred Term by Age Group (<65 Years or Safety Analysis Set
≥65 Years)
Treatment Emergent Adverse Events by System Organ
15.11.2.1.2.3 Safety Analysis Set
Class and Preferred Term by Sex (Male or Female)
15.11.2.1.3 Treatment Emergent Adverse Events by Preferred Term Safety Analysis Set
Treatment Emergent Adverse Events by System Organ
15.11.2.2.1 Safety Analysis Set
Class, Preferred Term, and Severity
Treatment-Emergent Adverse Events with Severity of
15.11.2.2.2.1 Grade 3 or Above by System Organ Class and Safety Analysis Set
Preferred Term
Treatment-Emergent Adverse Events with Severity of
15.11.2.2.2.2 Grade 2 or Above by System Organ Class and Safety Analysis Set
Preferred Term
Treatment-Emergent Adverse Events with Severity of
15.11.2.2.2.3 Safety Analysis Set
Grade 3 or Above by Preferred Term
Treatment-Emergent Adverse Events with Severity of
15.11.2.2.2.4 Safety Analysis Set
Grade 2 or Above by Preferred Term

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Table Number Title Analysis Set

Treatment-Emergent Treatment-Related Adverse Events
15.11.2.3.1.1 Safety Analysis Set
by System Organ Class and Preferred Term
Treatment-Emergent Treatment-Related Adverse Events
15.11.2.3.1.2 Safety Analysis Set
by Preferred Term
Treatment-Emergent Treatment-Related Adverse Events,
15.11.2.3.2 Safety Analysis Set
Preferred Term, and Severity
Treatment-Emergent Treatment-Related Adverse Events
15.11.2.3.3.1 with Severity of Grade 3 or Above by System Organ Class Safety Analysis Set
and Preferred Term
Treatment-Emergent Treatment-Related Adverse Events
15.11.2.3.3.2 with Severity of Grade 2 or Above by System Organ Class Safety Analysis Set
and Preferred Term
Treatment-Emergent Treatment-Related Adverse Events
15.11.2.3.3.3 Safety Analysis Set
with Severity of Grade 3 or Above by Preferred Term
Treatment-Emergent Treatment-Related Adverse Events
15.11.2.3.3.4 Safety Analysis Set
with Severity of Grade 2 or Above by Preferred Term
Treatment-Emergent Adverse Events of Interest (Cardiac
15.11.2.4 Adverse Event) by System Organ Class and Preferred Safety Analysis Set
Term
Treatment-Emergent Adverse Events Leading to Death
15.11.3 Safety Analysis Set
by System Organ Class and Preferred Term
Treatment Emergent Serious Adverse Event by System
15.11.4.1 Safety Analysis Set
Organ Class and Preferred Term
Treatment Emergent Serious Adverse Event by Preferred
15.11.4.2 Safety Analysis Set
Term
Treatment Emergent Treatment-Related Serious Adverse
15.11.4.3.1 Safety Analysis Set
Events by System Organ Class and Preferred Term
Treatment Emergent Treatment-Related Serious Adverse
15.11.4.3.2 Safety Analysis Set
Events by Preferred Term
Treatment-Emergent Serious Adverse Events of Interest
15.11.4.4 (Cardiac Adverse Event) by System Organ Class and Safety Analysis Set
Preferred Term
Treatment-Emergent Adverse Events Leading to
15.11.5.1 Premature Discontinuation of Study Drug by System Safety Analysis Set
Organ Class and Preferred Term
Treatment-Emergent Adverse Events Leading to
15.11.5.2 Premature Discontinuation of Study by System Organ Safety Analysis Set
Class and Preferred Term
Hematology Test: Hemoglobin (g/dL) and Change from
15.11.6.1.1 Safety Analysis Set
Baseline
Hematology Test: Lymphocytes (x10^3/µL) and Change
15.11.6.1.2 Safety Analysis Set
from Baseline

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Statistical Analysis Plan Version 1.0

Table Number Title Analysis Set

Hematology Test: Lymphocytes (%) and Change from
15.11.6.1.3 Safety Analysis Set
Baseline
Hematology Test: Monocytes (x10^3/µL) and Change
15.11.6.1.4 Safety Analysis Set
from Baseline
Hematology Test: Monocytes (%) and Change from
15.11.6.1.5 Safety Analysis Set
Baseline
Hematology Test: Neutrophils (x10^3/µL) and Change
15.11.6.1.6 Safety Analysis Set
from Baseline
Hematology Test: Neutrophils (%) and Change from
15.11.6.1.7 Safety Analysis Set
Baseline
Hematology Test: Platelets (x10^3/µL) and Change from
15.11.6.1.8 Safety Analysis Set
Baseline
Hematology Test: Leukocytes (x10^3/µL) and Change
15.11.6.1.9 Safety Analysis Set
from Baseline
15.11.6.2.1 Chemistry Test: ALT (U/L) and Change from Baseline Safety Analysis Set
15.11.6.2.2 Chemistry Test: AST (U/L) and Change from Baseline Safety Analysis Set
Chemistry Test: ALP (SGPT) (U/L) and Change from
15.11.6.2.3 Safety Analysis Set
Baseline
Chemistry Test: Total Bilirubin (mg/dL) and Change
15.11.6.2.4 Safety Analysis Set
from Baseline
Chemistry Test: Blood Urea Nitrogen (mg/dL) and
15.11.6.2.5 Safety Analysis Set
Change from Baseline
Chemistry Test: Creatinine (mg/dL) and Change from
15.11.6.2.6 Safety Analysis Set
Baseline
Chemistry Test: Creatinine Clearance (mL/min) and
15.11.6.2.7 Safety Analysis Set
Change from Baseline
Chemistry Test: Albumin (g/dL) and Change from
15.11.6.2.8 Safety Analysis Set
Baseline
Chemistry: Creatinine (mg/dL) and Change from
15.11.6.2.9 Safety Analysis Set
Baseline by Hourly Timepoint for Hospitalized Subjects
15.11.6.4.1.1 Treatment Emergent Laboratory Abnormalities Safety Analysis Set
Treatment Emergent Laboratory Abnormalities by Age
15.11.6.4.1.2 Safety Analysis Set
Group (<65 Years or ≥65 Years)
Treatment Emergent Laboratory Abnormalities by Sex
15.11.6.4.1.3 Safety Analysis Set
(Male or Female)
Treatment Emergent Grade 3 or Above Laboratory
15.11.6.4.2 Safety Analysis Set
Abnormalities
15.11.6.4.3 Treatment Emergent Marked Laboratory Abnormalities Safety Analysis Set
15.11.6.5 Liver-Related Laboratory Abnormalities Safety Analysis Set

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Statistical Analysis Plan Version 1.0

Table Number Title Analysis Set

15.11.6.6 Shift in Troponin Results Safety Analysis Set
Vital Signs: Diastolic Blood Pressure (mmHg) and
15.11.7.1.1 Safety Analysis Set
Change from Baseline
Vital Signs: Systolic Blood Pressure (mmHg) and
15.11.7.1.2 Safety Analysis Set
Change from Baseline
Vital Signs: Pulse (beats per minute) and Change from
15.11.7.1.3 Safety Analysis Set
Baseline
Vital Signs: Respiratory Rate (breaths per minute) and
15.11.7.1.4 Safety Analysis Set
Change from Baseline
Vital Signs: Temperature (Celsius) and Change from
15.11.7.1.5 Safety Analysis Set
Baseline
15.11.7.2.1 Body Weight (kg) and Change from Baseline Safety Analysis Set
Prior Medications by Drug Class and Preferred Drug
15.11.7.3.1 Safety Analysis Set
Name
Concomitant Medications by Drug Class and
15.11.7.3.2 Safety Analysis Set
Preferred Drug Name
15.11.7.3.3 Prior Ribavirin Safety Analysis Set
15.11.7.3.4 Concomitant Ribavirin Safety Analysis Set
15.11.9.1 Shift in Electrocardiogram Results Safety Analysis Set
15.11.9.2 Subject with New Abnormalities ECG at Postbaseline Safety Analysis Set

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12.2. Figures

Figure Title Analysis Set

15.8.1 Histogram of Number of Subjects Enrolled by Site All Randomized Analysis Set
15.8.2 Histogram of Number of Subjects Enrolled by Country All Randomized Analysis Set
15.9.1.1 Mean (SD) Viral Load (log 10 copies/ml) at Each Visit Full Analysis Set
Mean (SD) Change from Baseline in Viral Load (log 10
15.9.1.2 Full Analysis Set
copies/ml) at Each Visit
15.9.2.1 Mean (SD) O 2 Saturation at Each Visit Full Analysis Set
15.9.2.2 Mean (SD) Change from Baseline in O 2 Saturation at Each Visit Full Analysis Set
15.10.1.1 Mean (SD) Plasma Concentrations vs. Time PK Analysis Set
Median (Q1, Q3) Hematology Test: Hemoglobin (g/dL) by
15.11.6.1.1 Safety Analysis Set
Visit
Median (Q1, Q3) Hematology Test: Lymphocytes (x10^3/µL)
15.11.6.1.2 Safety Analysis Set
by Visit
15.11.6.1.3 Median (Q1, Q3) Hematology Test: Lymphocytes (%) by Visit Safety Analysis Set
Median (Q1, Q3) Hematology Test: Monocytes (x10^3/µL) by
15.11.6.1.4 Safety Analysis Set
Visit
15.11.6.1.5 Median (Q1, Q3) Hematology Test: Monocytes (%) by Visit Safety Analysis Set
Median (Q1, Q3) Hematology Test: Neutrophils (x10^3/µL) by
15.11.6.1.6 Safety Analysis Set
Visit
15.11.6.1.7 Median (Q1, Q3) Hematology Test: Neutrophils (%) by Visit Safety Analysis Set
Median (Q1, Q3) Hematology Test: Leukocytes (x10^3/uL) by
15.11.6.1.8 Safety Analysis Set
Visit
Median (Q1, Q3) Hematology Test: Platelet Count (x10^3/uL)
15.11.6.1.9 Safety Analysis Set
by Visit
15.11.6.2.1 Median (Q1, Q3) Chemistry Test: ALT (U/L) by Visit Safety Analysis Set
15.11.6.2.2 Median (Q1, Q3) Chemistry Test: AST (U/L) by Visit Safety Analysis Set
Median (Q1, Q3) Chemistry Test: Alkaline Phosphatase (U/L)
15.11.6.2.3 Safety Analysis Set
by Visit
Median (Q1, Q3) Chemistry Test: Total Bilirubin (mg/dL) by
15.11.6.2.4 Safety Analysis Set
Visit
Median (Q1, Q3) Chemistry Test: Blood Urea Nitrogen
15.11.6.2.5 Safety Analysis Set
(mg/dL) by Visit
15.11.6.2.6 Median (Q1, Q3) Chemistry Test: Creatinine (mg/dL) by Visit Safety Analysis Set
Median (Q1, Q3) Chemistry Test: Creatinine Clearance
15.11.6.2.7 Safety Analysis Set
(mL/min) by Visit
15.11.6.2.8 Median (Q1, Q3) Chemistry Test: Albumin (g/dL) by Visit Safety Analysis Set

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Figure Title Analysis Set

Median (Q1, Q3) Vital Signs: Diastolic Blood Pressure (mmHg)
15.11.7.1.1 Safety Analysis Set
by Visit
Median (Q1, Q3) Vital Signs: Systolic Blood Pressure (mmHg)
15.11.7.1.2 Safety Analysis Set
by Visit
Median (Q1, Q3) Vital Signs: Pulse Rate (beats per minute) by
15.11.7.1.3 Safety Analysis Set
Visit
Median (Q1, Q3) Vital Signs: Respiratory Rate (breaths per
15.11.7.1.4 Safety Analysis Set
minute) by Visit
15.11.7.1.5 Median (Q1, Q3) Vital Signs: Temperature (Celsius) by Visit Safety Analysis Set

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12.3. Listings

Listing Title Analysis Set

16.1.6 Subjects Who Received Study Drug from Specific Batches Safety Analysis Set
16.1.7 Randomization Schema and Codes All Randomized Analysis Set
16.2.1.1 Subject Profiles All Randomized Analysis Set
16.2.1.2 Enrollment All Randomized Analysis Set
16.2.1.3 Subject Disposition All Randomized Analysis Set
Subjects Screened but Not
16.2.1.4 Reasons for Screen Failure
Enrolled
16.2.2.1 Eligibility Criteria Deviations All Randomized Analysis Set
16.2.2.2 Important Protocol Deviations All Randomized Analysis Set
Randomization Stratification Discrepancies Between IWRS
16.2.2.3 All Randomized Analysis Set
and Clinical Database
16.2.2.4 Subjects who Received Incorrect Study Drug All Randomized Analysis Set
16.2.3.1 Subjects Excluded from Any Analysis Set All Randomized Analysis Set
Subjects Who were in the Full Analysis Set but Excluded from
16.2.3.2 Full Analysis Set
the Per Protocol Analysis Set
16.2.4.1 Demographics All Randomized Analysis Set
16.2.4.2 Baseline Characteristics All Randomized Analysis Set
16.2.4.3.1 Hematopoietic Cell Transplant Medical History All Randomized Analysis Set
16.2.4.3.2 Medical History All Randomized Analysis Set
16.2.4.4.1 Prior and Concomitant Medications All Randomized Analysis Set
16.2.4.4.2 Prior and Concomitant Ribavirin All Randomized Analysis Set
16.2.5.1 Study Drug Administration All Randomized Analysis Set
16.2.5.2 Subjects Who Prematurely Discontinued Study Drug All Randomized Analysis Set
16.2.5.3 Study Drug Accountability All Randomized Analysis Set
16.2.5.4 Plasma Pharmacokinetic Sampling Details and Concentrations PK Analysis Set
16.2.6.1 Viral Load Measurements Full Analysis Set
16.2.6.2 Hospitalizations and ICU Full Analysis Set
16.2.6.3 Oxygen Saturation Full Analysis Set
16.2.6.4 Supplemental Oxygen Full Analysis Set
16.2.6.5 Supplemental Oxygen Use Prior to RSV Infection Full Analysis Set
16.2.6.6 Mechanical Ventilation Full Analysis Set
16.2.6.7 Healthcare Related Efficacy Endpoints Full Analysis Set
16.2.7.1 All Adverse Events Safety Analysis Set

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Listing Title Analysis Set

16.2.7.2.1 Deaths All Randomized Analysis Set
16.2.7.2.2 Adverse Events Leading to Death Safety Analysis Set
16.2.7.3 Serious Adverse Events Safety Analysis Set
16.2.7.4.1 Adverse Events with Severity of Grade 3 or Higher Safety Analysis Set
16.2.7.4.2 Adverse Events with Severity of Grade 2 or Higher Safety Analysis Set
Adverse Events Leading to Premature Discontinuation of Study
16.2.7.5.1 Safety Analysis Set
Drug
16.2.7.5.2 Adverse Events Leading to Premature Discontinuation of Study Safety Analysis Set
16.2.8.1.1.1 Hematology Results: Part 1 Safety Analysis Set
16.2.8.1.1.2 Hematology Results: Part 2 Safety Analysis Set
16.2.8.1.2.1 Chemistry Results: Part 1 Safety Analysis Set
16.2.8.1.2.2 Chemistry Results: Part 2 Safety Analysis Set
16.2.8.1.2.3 Creatinine Results for Hospitalized Subjects Safety Analysis Set
16.2.8.1.4 Treatment Emergent Marked Laboratory Abnormalities Safety Analysis Set
Treatment Emergent Grade 3 or Above Laboratory
16.2.8.1.5 Safety Analysis Set
Abnormalities
16.2.8.1.6 Liver-Related Laboratory Abnormalities Safety Analysis Set
16.2.8.1.7 Laboratory Tests Reference Ranges
16.2.8.1.8 Laboratory Test Troponin Results Safety Analysis Set
16.2.8.2.1 Vital Signs Safety Analysis Set
16.2.8.2.2 Body Weight, Height and BMI Safety Analysis Set
16.2.8.3 Overall ECG Assessment Safety Analysis Set
16.2.8.4 Pregnancy Report Safety Analysis Set
16.2.8.5 General Comments All Randomized Analysis Set

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13. APPENDICES

Appendix 1. Study Procedures Table

Optional Extended Viral
Monitoringk
Visit 2: Baseline Visit Visit Visit Visit Visit Visit
Assessments, 3: Visit Visit Visit Visit Visit 9: Visit 10: 11: 12: 13: 14:
Visit 1: Randomization, Day 4: 5: 6: 7: Day 8: Day Day End of Day Day Day Day
Screening and Treatment 3p Day 5 Day 7 Day 9 13 17 22 study/Day 35 42 49 56
(Day -2 Assessments (±24 (±24 (±24 (±24 (±24 (±24 (±24 28 (±48 (±48 (±48 (±48
to -1) (Day 1) hours) hours) hours) hours) hours) hours) hours) (+3 days) hours) hours) hours) hours)
Must complete
visit in the X X X X X X X X
hospital or clinic
Written Informed
X
Consent
Medical History
X
and Demographics
Chest X-ray Xa
Screening Labs Xb
Urine or Serum
X X X X X X
Pregnancy Testc
Vital Signs (inc.
X X Xm X Xm X X X X X
O 2 Saturation d)
Height X
Weight X X X X X X X X
12-lead ECG X X X

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Optional Extended Viral

Monitoringk
Visit 2: Baseline Visit Visit Visit Visit Visit Visit
Assessments, 3: Visit Visit Visit Visit Visit 9: Visit 10: 11: 12: 13: 14:
Visit 1: Randomization, Day 4: 5: 6: 7: Day 8: Day Day End of Day Day Day Day
Screening and Treatment 3p Day 5 Day 7 Day 9 13 17 22 study/Day 35 42 49 56
(Day -2 Assessments (±24 (±24 (±24 (±24 (±24 (±24 (±24 28 (±48 (±48 (±48 (±48
to -1) (Day 1) hours) hours) hours) hours) hours) hours) hours) (+3 days) hours) hours) hours) hours)
Local Troponin
X X X
Testn
Safety Labs e X X X X X X X
RSV antibody titer X X
RSV Viremia X X X X X X X
Nasal Samples f Xo X X X X X X X X X X X X X
Local RSV
Xo Xj
Testing
Randomization X
IMP
X X X X X
Administration
PK Sample Xg Xi Xg Xg Xg Xg Xg
Serum creatinine Xh Xh
Adverse Events X X Xl X Xl X X X X X Xl Xl Xl Xl
Review ICU
admissions,
hospitalizations,
standard of care
X Xm X Xm X X X X X
test results,
mechanical
ventilation, and
supplemental O 2

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Optional Extended Viral

Monitoringk
Visit 2: Baseline Visit Visit Visit Visit Visit Visit
Assessments, 3: Visit Visit Visit Visit Visit 9: Visit 10: 11: 12: 13: 14:
Visit 1: Randomization, Day 4: 5: 6: 7: Day 8: Day Day End of Day Day Day Day
Screening and Treatment 3p Day 5 Day 7 Day 9 13 17 22 study/Day 35 42 49 56
(Day -2 Assessments (±24 (±24 (±24 (±24 (±24 (±24 (±24 28 (±48 (±48 (±48 (±48
to -1) (Day 1) hours) hours) hours) hours) hours) hours) hours) (+3 days) hours) hours) hours) hours)
Concomitant
X X Xm X Xm X X X X X
Medications
a Chest X-ray obtained < 48 hours prior to Screening may be used
b Existing values collected ≤ 6 days prior to Screening may be used
c Required for women unable to confirm menopause, hysterectomy and/or bilateral oophorectomy
d On room air
e Central laboratory testing: hematology and serum chemistry to include WBC with differential, Hgb, platelets, BUN, creatinine, serum albumin, AST, ALT, ALP, and total
bilirubin
f 2 samples total, 1 from each nostril – collected prior to dosing on dosing days
g PK samples collected for all subjects 4 hours (± 30 mins) post-dose Day 1; pre-dose on Days 5, 9, 13, and 17; and anytime on Day 22
h For hospitalized subjects only: blood will be drawn for serum creatinine at 4 hours (± 30 mins) post-dose at Visit 2 (Day 1) and at any time on Days 2, 3 and 4
(approximately 24, 48 and 72 hours post-first presatovir dose if they remain hospitalized at those times.
i For hospitalized subjects only: PK sample collected at Visit 3 (48 hours [±3 hours] post-first presatovir dose)
j Only for subjects who agree to the Optional Extended Viral Monitoring at the time of consent
k Only for subjects who agree to the Optional Extended Viral Monitoring at the time of consent and test positive (or inconclusive) for RSV at Visit 9 (Day 22)
l Assessment of procedure-related AEs only, if home visit.
m Not required if home visit.
n Local troponin testing will be done pre-dose in accordance with the standard assay available and used at the site. Point-of-care “rapid” troponin tests are not acceptable for
protocol-mandated troponin testing.
o If only the upper or lower respiratory tract was assessed prior to consent, a separate local RSV test in the tract not previously assessed must be performed. Subjects who were
not tested for RSV as standard of care may consent to the study and be tested for RSV during the Screening visit.
p Visit 3 Day 3 is an optional study visit for subjects who are not hospitalized.

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Appendix 2. Cardiac Adverse Events of Interest

The following search criteria are used to identify cardiac adverse events:

• All PTs from Cardiac disorders SOC

• Narrow scope PTs from the below SMQs, and associated sub-SMQs:

 Cardiac arrhythmias (SMQ)

 Cardiac failure (SMQ)

 Cardiomyopathy (SMQ)

 Ischaemic heart disease (SMQ)

 Torsade de pointes/QT prolongation (SMQ)

• Select PTs from HLTs:

 Cardiac histopathology procedures,

 Skeletal and cardiac muscle analyses,

 Arterial therapeutic procedures (excl aortic),

 ECG investigations, Cardiac function diagnostic procedures,

 Heart rate and pulse investigations

Duplicate PTs were removed where necessary.

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Appendix 3. Sample SAS Code for MMRM Model

The following model statement may be used for the analyses of viral load and FLU-PRO as
described in Sections 6.3.2:

proc mixed data=change;

class trt visit subjid strata;
model change = baseline strata trt visit trt*visit / s ddfm=kr;
repeated visit / type=un subject=subjid(trt);
lsmeans trt*visit / cl;
run;

Note that since the response variable is change from baseline, the Visit 2 (baseline) value will
always be 0 and should not be included in the above model.

An unstructured covariance will be assumed (type=un); if there are convergence or model fitting
issues, then the alternative covariance structure of Toeplitz will be assumed (type=toep).

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Appendix 4. Sample SAS Code for Negative Binomial Model

The following model statement may be used for the analyses of number of hospital-free day,
ICU-free day, and ventilator-free day described in Section 6.3.2:

proc genmod data=dataset;

class trt strata;
model count = trt strata / offset=logt dist=NB;
run;

where logt is the offset parameter defined as the natural logarithm of study duration for each
subject to account for potential differential study durations due to early discontinuations.

In the event that the negative binomial model fails to converge, a zero-inflated negative binomial
model may be fit (dist=ZINB).

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