Clinical trial NCT04431453
Conditions: COVID-19
Sponsor: Gilead Sciences
Start date: 2020-07-21; Completion date: 2023-02-10
Enrollment: 59 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The goals of this clinical study are to learn more about the study drug, remdesivir, and how safe it is in participants less than 18 years old with coronavirus disease 2019 (COVID-19).

Detailed description:
Pediatric participants will be enrolled as follows:

Pediatric participants ≥ 28 days to \< 18 years old:

* Cohort 1: ≥ 12 years to \< 18 years and weight ≥ 40 kg
* Cohort 2: ≥ 28 days to \< 18 years and weight ≥ 20 kg to \< 40 kg
* Cohort 3: ≥ 28 days to \< 18 years and weight ≥ 12 kg to \< 20 kg
* Cohort 4: ≥ 28 days to \< 18 years and weight ≥ 3 kg to \< 12 kg
* Cohort 8: \< 12 years and weight ≥ 40 kg

Term neonatal participants 0 days to \< 28 days old:

* Cohort 5: ≥ 14 days to \< 28 days of age, gestational age \> 37 weeks and weight at screening ≥ 2.5 kg
* Cohort 6: 0 days to \< 14 days of age, gestational age \> 37 weeks and birth weight ≥ 2.5 kg

Preterm neonates and infants 0 days to \< 56 days old:

* Cohort 7: 0 days to \< 56 days of age, gestational age ≤ 37 weeks and birth weight ≥ 1.5 kg

Arms: arm 1: Participants will receive RDV 200 mg, intravenous (IV) infusion on Day 1 followed by RDV 100 mg, IV infusion, daily, up to 10 days. arm 2: Participants will receive RDV 5 mg/kg, IV infusion on Day 1 followed by RDV 2.5 mg/kg mg, IV infusion, daily, up to 10 days. arm 3: Participants will receive RDV 5 mg/kg, IV infusion on Day 1 followed by RDV 2.5 mg/kg mg, IV infusion, daily, up to 10 days. arm 4: Participants will receive RDV 5 mg/kg, IV infusion on Day 1 followed by RDV 2.5 mg/kg mg, IV infusion, daily, up to 10 days. arm 5: Participants will receive RDV 5 mg/kg, IV infusion on Day 1 followed by RDV 2.5 mg/kg mg, IV infusion, daily, up to 10 days. arm 6: Participants will receive RDV 2.5 mg/kg, IV infusion on Day 1 followed by RDV 1.25 mg/kg mg, IV, daily, up to 10 days. arm 7: Participants will receive RDV 2.5 mg/kg, IV infusion on Day 1 followed by RDV 1.25 mg/kg mg, IV, daily, up to 10 days. arm 8: Participants will receive RDV 200 mg, IV infusion on Day 1 followed by RDV 100 mg, IV infusion daily up to 10 days.
Interventions: intervention 1: Remdesivir
Intervention descriptions: intervention 1: Administered as an intravenous infusion

Protocol documents:
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2/3 Single-Arm, Open-Label Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics, and Efficacy of 
Remdesivir (GS-5734™) in Participants from Birth to 
<18 Years of Age with COVID-19
Name of Test Drug:
Remdesivir (RDV; GS-5734™)
Study Number:
GS-US-540-5823
Protocol Version (Date):
Amendment 4.0 (06 January 2022); 
Amendment 4.1 (10 February 2022)
Analysis Type:
Final Analysis
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
22 May 2023
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
 
 
PPD


Remdesivir (RDV; GS-5734™)
GS-US-540-5823
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................2
LIST OF APPENDICES.................................................................................................................................................3
LIST OF ABBREVIATIONS.........................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS.................................................................................................................6
1.
INTRODUCTION..................................................................................................................................................7
1.1.
Study Objectives........................................................................................................................................7
1.2.
Study Design .............................................................................................................................................8
1.3.
Sample Size and Power ...........................................................................................................................10
2.
TYPE OF PLANNED ANALYSIS......................................................................................................................12
2.1.
Interim Analyses......................................................................................................................................12
2.1.1.
DMC Analysis.......................................................................................................................12
2.2.
Final Analysis..........................................................................................................................................12
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................13
3.1.
Analysis Sets ...........................................................................................................................................13
3.1.1.
All Enrolled Analysis Set ......................................................................................................13
3.1.2.
Full Analysis Set....................................................................................................................13
3.1.3.
Safety Analysis Set................................................................................................................13
3.1.4.
Pharmacokinetic Analysis Set ...............................................................................................13
3.2.
Subject Grouping.....................................................................................................................................14
3.3.
Strata and Covariates...............................................................................................................................14
3.4.
Examination of Subject Subgroups .........................................................................................................14
3.5.
Multiple Comparisons .............................................................................................................................14
3.6.
Missing Data and Outliers.......................................................................................................................14
3.6.1.
Missing Data..........................................................................................................................14
3.6.2.
Outliers ..................................................................................................................................14
3.7.
Data Handling Conventions and Transformations ..................................................................................15
3.8.
Analysis Visit Windows..........................................................................................................................16
3.8.1.
Definition of Study Day ........................................................................................................16
3.8.2.
Analysis Visit Windows........................................................................................................16
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window .................................................................................................................................19
4.
SUBJECT DISPOSITION ...................................................................................................................................20
4.1.
Subject Enrollment and Disposition........................................................................................................20
4.2.
Extent of Study Drug Exposure and Adherence......................................................................................20
4.3.
Protocol Deviations .................................................................................................................................21
5.
BASELINE CHARACTERISTICS .....................................................................................................................22
5.1.
Demographics and Baseline Characteristics ...........................................................................................22
5.2.
Other Baseline Characteristics ................................................................................................................22
5.3.
Medical History.......................................................................................................................................23
6.
EFFICACY ANALYSES.....................................................................................................................................24
6.1.
Primary Efficacy Endpoint......................................................................................................................24
6.2.
Secondary Efficacy Endpoints ................................................................................................................24
6.2.1.
Definition of Secondary Efficacy Endpoints.........................................................................24
6.2.2.
Analysis of Secondary Endpoints..........................................................................................25


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Statistical Analysis Plan – Final Analysis
Version 1.0
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22 May 2023
6.3.
Exploratory Efficacy Endpoints ..............................................................................................................28
6.3.1.
Analysis of Exploratory Endpoints .......................................................................................28
7.
SAFETY ANALYSES.........................................................................................................................................30
7.1.
Adverse Events and Deaths.....................................................................................................................30
7.1.1.
Adverse Event Dictionary .....................................................................................................30
7.1.2.
Adverse Event Severity .........................................................................................................30
7.1.3.
Relationship of Adverse Events to Study Drug.....................................................................30
7.1.4.
Serious Adverse Events.........................................................................................................30
7.1.5.
Treatment-Emergent Adverse Events....................................................................................30
7.1.5.1.
Definition of Treatment-Emergent Adverse Events........................................30
7.1.5.2.
Incomplete Dates .............................................................................................31
7.1.6.
Summaries of Adverse Events and Deaths............................................................................31
7.1.6.1.
Summaries of AE incidence in Combined Severity Grade 
Subsets .............................................................................................................31
7.1.6.2.
Summaries of AE Incidence by Severity.........................................................32
7.2.
Laboratory Evaluations ...........................................................................................................................33
7.2.1.
Summaries of Numeric Laboratory Results ..........................................................................33
7.2.2.
Graded Laboratory Values ....................................................................................................34
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities .............................................35
7.2.2.2.
Summaries of Laboratory Abnormalities ........................................................35
7.2.3.
Liver-related Laboratory Evaluations....................................................................................36
7.3.
Body Weight and Vital Signs..................................................................................................................36
7.4.
Prior and Concomitant Medications........................................................................................................37
7.4.1.
Prior Medications ..................................................................................................................37
7.4.2.
Concomitant Medications......................................................................................................37
7.4.3.
COVID-19 Medications Other Than the Study Drug............................................................38
7.5.
Electrocardiogram Results.......................................................................................................................38
7.6.
Other Safety Measures ............................................................................................................................38
7.7.
Changes From Protocol-Specified Safety Analyses................................................................................38
8.
PHARMACOKINETIC (PK) ANALYSES.........................................................................................................39
8.1.
PK Sample Collection .............................................................................................................................39
8.2.
PK Analyses ............................................................................................................................................39
8.2.1.
Statistical Analysis Methods .................................................................................................40
9.
REFERENCES.....................................................................................................................................................41
10.
SOFTWARE.........................................................................................................................................................42
11.
SAP REVISION...................................................................................................................................................43
12.
APPENDICES......................................................................................................................................................44
LIST OF APPENDICES
Appendix 1.
Study Procedures Table...........................................................................................................44
Appendix 2.
Pediatric Early Warning Score ................................................................................................48
Appendix 3.
Programming Specifications....................................................................................................49


Remdesivir (RDV; GS-5734™)
GS-US-540-5823
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
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LIST OF IN-TEXT TABLES
Table 1-1.
Study Design..............................................................................................................................8
Table 1-2.
Remdesivir, Nucleoside Metabolite GS-441524, and GS-704277 Plasma PK 
Parameters by Dose Following 30-Minute IV Infusion(s) of Remdesivir in Healthy 
Adult Participants in GS-US-399-5505...................................................................................11
Table 3-1.
Analysis Windows for Vital Signs (Heart Rate, Temperature, Blood Pressure [MAP 
if available, Systolic and Diastolic], Respiratory Rate, and Oxygen Saturation)....................17
Table 3-2.
Analysis Windows for Hematology, Chemistry, Urinalysis, and Routine 
Coagulation Tests ....................................................................................................................17
Table 3-3.
Analysis Windows for SARS-CoV-2 RT-qPCR Viral Load Testing......................................18
Table 3-4.
Analysis Windows for Serology for SARS-CoV-2 (IgG, IgM, and IgA) ...............................18
Table 8-1.
PK Parameters for Each Analyte.............................................................................................39
Table 13-1.
Additional COVID-19 Medications ........................................................................................50
Table 13-2.
Grouping on the COVID-19 Medications other than the Study Drug.....................................50
Table 13-3.
Viral Load Sample Details ......................................................................................................55


Remdesivir (RDV; GS-5734™)
GS-US-540-5823
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
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22 May 2023
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CI
confidence interval
CoV
coronavirus
COVID-19
coronavirus disease 2019
CRP
C-reactive protein
CSR
clinical study report
CV
coefficient of variation
DMC
data monitoring committee
ECG
electrocardiogram
ECMO
extracorporeal membrane oxygenation
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
ESR
erythrocyte sedimentation rate
ET
endotracheal tube
FAS
Full Analysis Set
FiO2
fraction of inspired oxygen
Gilead
Gilead Sciences
HIV
human immunodeficiency virus
HLT
high-level term
IAP
interim analysis plan
Ig
immunoglobulin
IL-6
Interleukin-6
INR
international normalized ratio
IV
intravenous
LPV
lopinavir
LOD
limit of detection
LOQ
limit of quantitation
MAP
mean arterial pressure
MedDRA
Medical Dictionary for Regulatory Activities
PaO2
partial pressure of oxygen
PCR
polymerase chain reaction
PCT
procalcitonin
PEWS
Pediatric Early Warning Score


Remdesivir (RDV; GS-5734™)
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Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
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PK
pharmacokinetic(s)
PS
Patient Safety
PT
preferred term
PT
prothrombin time
PTT
partial thromboplastin time
Q1, Q3
first quartile, third quartile
RDV
remdesivir (GS-5734™)
RT-qPCR
reverse transcriptase quantitative polymerase chain reaction
SAE
serious adverse event
SAP
statistical analysis plan
SARS
severe acute respiratory syndrome
SBECD
sulfobutylether β-cyclodextrin sodium
SD
standard deviation
SE
Standard error
SOC
system organ class
SpO2
peripheral oxygen saturation
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
ULN
upper limit of normal
US
United States
PHARMACOKINETIC ABBREVIATIONS
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration
AUCtau
area under the concentration versus time curve over the dosing interval
Clast
last observed quantifiable concentration of the drug 
Cmax
maximum observed concentration of drug 
Ctau
observed drug concentration at the end of the dosing interval
CLss/F
apparent oral clearance after administration of the drug:
at steady state: CLss/F = Dose/AUCtau , where “Dose” is the dose of the drug
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural log of 
2 by the terminal elimination rate constant (z)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
Vz
volume of distribution of the drug after intravenous administration
Vz/F
apparent volume of distribution of the drug
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination 
phase of the concentration of drug versus time curve


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Statistical Analysis Plan – Final Analysis
Version 1.0
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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 final analysis clinical study 
report (CSR) for Study GS-US-540-5823. This SAP is based on the study protocol amendment 
4.0 dated 06 January 2022, the country specific protocol amendment 4.1 dated 10 February 2022, 
and the electronic case report form (eCRF). The SAP will be finalized before database 
finalization. Any changes made after the finalization of the SAP will be documented in the CSR.
1.1.
Study Objectives
The primary objective of this study is as follows:
•
To evaluate the safety and tolerability of remdesivir (RDV; GS-5734™) in participants with 
laboratory-confirmed COVID-19 aged 0 days to < 18 years
•
To evaluate the pharmacokinetics (PK) of RDV in participants with laboratory-confirmed 
COVID-19 aged 0 days to < 18 years
The secondary objectives of this study are as follows:
•
To evaluate the efficacy of RDV in participants with laboratory-confirmed COVID-19 aged 
0 days to < 18 years
•
To determine the antiviral activity of RDV in participants with laboratory-confirmed 
COVID-19 aged 0 days to < 18 years
•
To evaluate the change from baseline in oxygenation use
•
To evaluate the change from baseline in the use of mechanical ventilation or extracorporeal 
membrane oxygenation (ECMO)
•
To evaluate clinical improvement using the Pediatric Early Warning Score (PEWS) scale in 
participants with laboratory-confirmed COVID-19 aged 0 days to < 18 years
•
To determine sulfobutylether β-cyclodextrin sodium (SBECD) exposures (where possible)
•
To provide data on use of medications other than RDV for treatment of COVID-19
The exploratory objectives of this study are as follows:
CCI


Remdesivir (RDV; GS-5734™)
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Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
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1.2.
Study Design
This is a Phase 2/3 single-arm, open-label study of the safety, tolerability, PK, and efficacy of 
RDV in pediatric participants from birth to < 18 years of age with laboratory-confirmed infection 
with COVID-19 (refer to the protocol for complete inclusion and exclusion criteria). 
At least 52 participants aged 0 days to < 18 years will be enrolled as described in the table below.
Table 1-1.
Study Design
Cohort
Description
Dose
Number of 
participants
Pediatric participants ≥ 28 days to < 18 years old
1
≥ 12 years to < 18 years and weight ≥ 40 kg
IV RDV 200 mg on Day 1 
followed by IV RDV 100 mg 
daily up to 10 days
12
2
≥ 28 days to < 18 years and weight ≥ 20 kg 
to < 40 kg
12
3
≥ 28 days to < 18 years and weight ≥ 12 kg 
to < 20 kg
12
4
≥ 28 days to < 18 years and weight ≥ 3 kg to 
< 12 kg
IV RDV 5 mg/kg on Day 1 
followed by IV RDV 2.5 mg/kg 
daily up to 10 days
12
Term neonatal participants 0 days to < 28 days old
5
≥14 days to < 28 days of age, gestational age 
> 37 weeks and weight at screening ≥ 2.5 kg
IV RDV 5 mg/kg on Day 1 
followed by IV RDV 2.5 mg/kg 
daily up to 10 days
≥ 4
6
0 days to < 14 days of age, gestational age > 
37 weeks and birth weight ≥ 2.5 kg
IV RDV 2.5 mg/kg on Day 1 
followed by IV RDV 1.25 mg/kg 
daily up to 10 days
All available
Preterm neonates and infants 0 days to < 56 days old
7
0 days to < 56 days of age, gestational age ≤ 
37 weeks and birth weight ≥ 1.5 kg
IV RDV 2.5 mg/kg on Day 1 
followed by IV RDV 1.25 mg/kg 
daily up to 10 days
All available
RDV = remdesivir (GS-5734™)
CCI
CCI




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Day 30 Follow-up visit, as outpatient or inpatient depending on clinical status, will include vital 
signs, complete or symptom-directed physical examination and chemistry laboratory evaluation.
Adverse events and concomitant medications will be assessed from Screening through the 
Day 30 Follow-up visit.
As many of the specified sparse PK assessments should be obtained from each participant as is 
feasible.
1.3.
Sample Size and Power
The total sample size will be at least 52 participants.
Twelve (12) participants for each cohort (Cohorts 1-4) will be enrolled in this study. 
Pharmacokinetic data from these participants will provide >99% power for each cohort to 
conclude exposure equivalence of RDV AUCtau in adolescents and children vs. 25 healthy adult 
participants in GS-US-399-5505 study (see Table 1-2) using two one-sided tests with each 
performed at an alpha level of 0.05. In this power analysis, it is assumed that the expected 
geometric mean ratio of AUCtau between the adolescents and children group vs. the adult group is 
equal to 1, the inter-participant standard deviation (SD) (natural log scale) of AUCtau is 0.18, and 
the equivalency boundary is 70% to 143%.
Meanwhile, twelve (12) participants from each cohort (Cohorts 1-4) will also provide >99% 
power to conclude exposure equivalence of RDV Cmax in adolescents and children, compared to 
26 healthy adult participants in GS-US-399-5505 study (see Table 1-2), assuming the expected 
geometric mean ratio of Cmax between the adolescents and children group and the adult group is 
equal to 1, the inter-participant SD (natural log scale) of Cmax is 0.19, and the equivalency 
boundary is 70% to 143%.
Sample size and power calculations were made using the software package nQuery Advisor(R) 
Version 8.5.


Remdesivir (RDV; GS-5734™)
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Version 1.0
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Table 1-2.
Remdesivir, Nucleoside Metabolite GS-441524, and GS-704277 
Plasma PK Parameters by Dose Following 30-Minute IV Infusion(s) 
of Remdesivir in Healthy Adult Participants in GS-US-399-5505
Study 
GS-US-399-5505
PK Parametera
Multiple RDV Dose (100mg)
Day 5 and 10
N = 26b
Plasma RDV
Remdesivir
GS-441524 Metabolite
GS-704277 Metabolite
Cmax (ng/mL)
2228.8 (19.2)
145.0 (19.3)
245.5 (33.9)
Ctau (ng/mL)
--
69.2 (18.2)
--
Clast (ng/mL)
8.1 (46.9)
12.2 (50.0)
3.9 (27.5)
Tmax (h)
0.68 (0.25, 0.75)
1.51 (1.50, 2.00)
0.75 (0.75, 0.78)
Tlast (h)
4.00 (4.00, 4.02)
96.00 (96.00, 96.00)
8.00 (8.00, 8.00)
t1/2 (h)d
0.96 (0.86, 1.08)
27.36 (25.29, 30.32)
1.23 (1.15, 1.38)
AUClast (h∙ng/mL)
1562.8 (17.0)
4189.3 (17.7)
454.4 (31.8)
AUCtau (h∙ng/mL)
1585.3 (16.6)
2229.2 (18.4)
461.5 (31.4)
CLss (mL/h)
65068.7 (19.8)
--
--
Vz (mL)
92557.2 (29.5)
--
--
% CV = percentage coefficient of variation; IV = intravenous; PK = pharmacokinetic; Q1 = first quartile; Q3 = third quartile;
RDV = remdesivir (GS-5734™)
Certain parameters are missing since Lambda_z is not reliably estimable.
a
Data are presented as mean (%CV), except for Tmax, Tlast, and t1/2, which are presented as median (Q1, Q3).
b
N = 25 for AUCtau, t1/2, CLss, and Vz
c
N = 25 for Ctau and N = 20 for t1/2
Source: GS-US-399-5505 Final CSR Table 15.10.1.1.6.1, 15.10.1.1.6.3, 15.10.1.1.6.2, 15.10.1.1.6.4.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analyses
Prior to the final analysis, an interim analysis was conducted to support the submission of 
applications to extend the indication for RDV to include pediatric participants 28 days of age and 
older weighing at least 3kg. The interim analysis was performed after (i) all participants in 
Cohorts 1-4 had been enrolled and had completed the study or prematurely discontinued from the 
study, (ii) participants in Cohort 8 as of the last date of enrolment into Cohorts 1-4 had 
completed the study or prematurely discontinued from the study, (iii) outstanding data queries 
had been resolved or adjudicated as unresolvable, and (iv) the data had been cleaned and 
finalized. 
The Interim Analysis Plan (IAP) describes the analysis plan for the Cohorts 1-4 and 8 interim 
analysis.
2.1.1.
DMC Analysis
An external multidisciplinary Data Monitoring Committee (DMC) reviewed safety, PK, and 
efficacy data after the first 27 enrolled participants in Cohorts 1-4 had completed the study or 
prematurely discontinued from the study.
The DMC reviewed the safety, PK, and efficacy data and determined that the study could 
continue according to the protocol without modification. More details are documented in the 
DMC charter. 
2.2.
Final Analysis
The final analysis will be performed after all participants have completed the study, outstanding 
data queries have been resolved or adjudicated as unresolvable, and the data have been cleaned 
and finalized.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of participants in each category will be presented; for continuous 
variables, the number of participants (n), mean, SD or standard error (SE), median, first quartile 
(Q1), third quartile (Q3), minimum, and maximum will be presented. For PK analyses, the 
geometric mean, 95% confidence interval (CI) of the geometric mean, and the mean and SD of 
the natural log-transformed values will also be provided, if appropriate.
By-participant listings will be presented for all participants in the All Enrolled Analysis Set and 
sorted by subject identifier (ID) number, visit date, and time (if applicable). Data collected on log 
forms, such as adverse events (AEs), will be presented in chronological order within the 
participant. The cohort group to which participants were initially assigned 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 participants to be included in an analysis. Analysis sets and their 
definitions are provided in this section. Participants included in each analysis set will be 
determined before database finalization for final analysis. The analysis set will be identified and 
included as a subtitle of each table, figure, and listing.
A summary of the number and percentage of participants in each analysis set will be provided by 
cohort and overall total.
3.1.1.
All Enrolled Analysis Set
The All Enrolled Analysis Set includes all participants who are enrolled into the study. This is 
the primary analysis set for by-participant listings.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all enrolled participants who received at least 1 dose of 
study drug. This is the primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all enrolled participants who received at least 1 dose of study 
drug. This is the primary analysis set for safety analyses.
3.1.4.
Pharmacokinetic Analysis Set
The RDV PK analysis set includes all enrolled participants who received at least 1 dose of RDV 
and for whom PK concentrations of RDV are available.


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The Metabolites (GS-441524 and GS-704277) PK analysis set includes all enrolled participants 
who received at least 1 dose of RDV and for whom PK concentrations of metabolite(s) (analytes) 
are available.
The SBECD PK analysis set includes all enrolled participants who received at least 1 dose of 
RDV and for whom PK concentrations of SBECD are available.
3.2.
Subject Grouping
Participants will be analyzed based on the cohort group to which they were initially assigned as 
well as overall.
3.3.
Strata and Covariates
This study does not use a stratified randomization schedule when enrolling participants. 
No covariates will be included in efficacy and safety analyses.
3.4.
Examination of Subject Subgroups
There are no prespecified subject subgroupings for efficacy and safety analyses.
3.5.
Multiple Comparisons
Adjustments for multiplicity will not be made, because no formal statistical testing will be 
performed in this study.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
Missing pre-treatment laboratory results will be treated as normal (ie, no toxicity grade) for the 
laboratory abnormality summary. 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.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis, unless 
specified otherwise.


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3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:
•
If only month and year of birth is collected, then “15” will be imputed as the day of birth
•
If only year of birth is collected, then “01 July” will be imputed as the day and month of birth
•
If year of birth is missing, then date of birth will not be imputed.
In general, age collected at Day 1 (in years) will be used for analyses and presented in listings. If 
age at Day 1 is not available for a participant, then age derived based on date of birth and the 
Day 1 visit date will be used instead. If an enrolled participant was not dosed with any study 
drug, the enrollment date will be used instead of the Day 1 visit date. For screen failures, the date 
the first informed consent was signed will be used for the age derivation. Age required for 
longitudinal and temporal calculations and analyses (e.g., estimates of creatinine clearance, age 
at date of AE) will be based on age derived from date of birth and the date of the measurement or 
event, unless otherwise specified.
Laboratory 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 lower LOQ will be used to calculate descriptive statistics if 
the datum is reported in the form of “< x” (where x is considered the lower 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 upper LOQ will be used to calculate descriptive statistics if 
the datum is reported in the form of “> x” (where x is considered the upper LOQ). Values 
with decimal points will follow the same logic as above.
•
The lower or upper 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 lower or upper LOQ, 
respectively).
SARS-CoV-2 viral load results that are below LOQ but have a positive signal will be reported as 
“< LOQ SARS-CoV-2 detected” and those negative results will be reported as “No 
SARS-CoV-2 detected”. The data will be imputed as follows:
•
A value of half of the LOQ will be used to calculate descriptive statistics if the datum is 
reported as “< LOQ SARS-CoV-2 detected”. 


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•
A value of half of the limit of detection (LOD) will be used to calculate descriptive statistics 
if the datum is reported as “No SARS-CoV-2 detected”.
Refer to Table 13-3 for more details on the viral load samples LOQ and LOD. Participants with 
negative viral load at baseline are not included in the viral load analysis. 
Any SARS-CoV-2 viral load samples collected on or after the participants are receiving 
additional COVID-19 treatments (see Table 13-1) will be excluded from the viral load analysis.
For participants who had received IV RDV prior to the enrollment of this study, their viral loads 
will be excluded from the analysis. 
Base 10 logarithm transformation will be used for analyzing SARS-CoV-2 viral load.
3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the first dosing date of study drug and derived as follows:
•
For postdose Study days: Assessment Date - First Dosing Date + 1
•
For days prior to the first dose: Assessment Date - First Dosing Date
Therefore, Study Day 1/ First Dose Date is the day of first dose of study drug administration, as 
recorded on the Study Drug Administration eCRF.
Last Dose Date is defined as the maximum, nonmissing, nonzero dose end date of treatment 
recorded on the Study Drug Administration eCRF form with “Study Drug Permanently 
Withdrawn” box checked for participants who prematurely discontinued or completed study drug 
according to the Study Drug Completion eCRF. Refer to Section 12 for missing date imputation, 
if necessary.
Last Study Date is the latest of the study drug start dates and end dates, the clinic visit dates, and 
the laboratory visit dates, including the 30-day follow-up visit date, for participants who 
prematurely discontinued study according to the Study Completion eCRF. 
Baseline value is defined as the last nonmissing value obtained on or prior to the first dose date 
(and time, if available) unless otherwise specified.
3.8.2.
Analysis Visit Windows
Participant visits might not occur on protocol-specified days. Therefore, for the purpose of 
analysis, observations will be assigned to analysis windows.
The analysis windows for vital signs, respiratory, hematology and chemistry laboratory 
parameters are presented in Table 3-1 and Table 3-2.


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Table 3-1.
Analysis Windows for Vital Signs (Heart Rate, Temperature, Blood 
Pressure [MAP if available, Systolic and Diastolic], Respiratory Rate, 
and Oxygen Saturation)
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline/Day 1
1
1
Day 2
2
2
2
Day 3
3
3
3
Day 4
4
4
4
Day 5
5
5
5
Day 6
6
6
6
Day 7
7
7
7
Day 8
8
8
8
Day 9
9
9
9
Day 10
10
10
10
Day 30
30
25
35
Table 3-2.
Analysis Windows for Hematology, Chemistry, Urinalysis, and 
Routine Coagulation Tests 
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline/Day 1
1
1 (pre dose)*
Day 2
2
1 (post dose)*
3
Day 5
5
4
6
Day 8
8
7
8
Day 10
10
9
11
Day 30 **
30
25
35
* For Baseline, the upper limit includes values collected at or prior to the first dose date/time. For Day 2, the lower limit includes 
values collected after the first dose date/time on Day 1.
** Only the comprehensive metabolic panel will be collected on Day 30
Nasopharyngeal and oropharyngeal samples (combined) OR nasal and oropharyngeal samples 
(combined), and rectal or fecal swab will be collected on Days 1, 3, 5, 7, and 10 (if feasible) for 
SARS-CoV-2 reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) viral load 
testing and possible viral resistance testing. Endotracheal tube aspirates will also be collected if 
the particpant is intubated. If the participant is discharged prior to Day 10, the samples for 
SARS-CoV-2 RTqPCR viral load testing and possible viral resistance testing can be collected by 
assigned study staff at the participant’s home or as an outpatient on the assigned days noted 
above, if feasible. 


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Serum for SARS-CoV-2 IgG, IgM, and IgA serology will be collected at Screening, Day 5, 
Day 10 (if feasible), and the Day 30 Follow-up visit for participants with weight ≥ 12 kg. 
The analysis windows for SARS-CoV-2 RT-qPCR viral load and serology for SARS-CoV-2 are 
presented in Table 3-3 and Table 3-4.
Table 3-3.
Analysis Windows for SARS-CoV-2 RT-qPCR Viral Load Testing
Visit ID
Testing
Nominal 
Day
Lower 
Limit
Upper 
Limit
Baseline/Day 1
SARS-CoV-2 RT-qPCR viral load
1
1 (pre 
dose)
Day 3
SARS-CoV-2 RT-qPCR viral load
3
2
3
Day 5
SARS-CoV-2 RT-qPCR viral load
5
4
5
Day 7
SARS-CoV-2 RT-qPCR viral load
7
6
8
Day 10 
SARS-CoV-2 RT-qPCR viral load
10
9
11
Discharge*
SARS-CoV-2 RT-qPCR viral load
Day of 
discharge
* If the participant is discharged prior to Day 10, the SARS-CoV-2 samples/swabs will be collected on the day of discharge. 
Thereafter, these samples can be collected by assigned study staff at the participant’s home or as an outpatient on the assigned 
days noted above.
Table 3-4.
Analysis Windows for Serology for SARS-CoV-2 (IgG, IgM, and IgA) 
Visit ID
Testing
Nominal 
Day
Lower 
Limit
Upper Limit
Baseline/Day 1
Serology for SARS-CoV-2 (IgG, IgM, and IgA)
1
1 (pre-dose)
Day 5
Serology for SARS-CoV-2 (IgG, IgM, and IgA)
5
4
6
Day 10 
Serology for SARS-CoV-2 (IgG, IgM, and IgA) 
10
9
11
Discharge*
Serology for SARS-CoV-2 (IgG, IgM, and IgA)
Day of 
discharge
Day 30
Serology for SARS-CoV-2 (IgG, IgM, and IgA)
30
25
35
 Includes the serum for SARS-CoV-2 IgG, IgM, and IgA serology collected at Screening.
* If the participant is discharged prior to Day 10, the serology for SARS-CoV-2 will be collected on the day of discharge. 
Thereafter, these samples can be collected by assigned study staff at the participant’s home or as an outpatient on the assigned 
days noted above.
Clinical scoring using the PEWS (0 to 3 on each of 3 categories) will be recorded at Screening 
and daily through the duration of dosing. Results will be summarized for each Study Day without 
windows.
The 7-point Ordinal Scale is an assessment of the clinical status of a given Study day. Each day, 
the worst (ie, lowest ordinal) score from the previous day will be recorded (ie, on Day 3, the 


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lowest ordinal score from Day 2 is obtained and recorded for Day 2). Results will be summarized 
for each Study Day without windows.
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each Study Day 
or analysis window. For example, change from baseline by visit usually requires a single value, 
whereas a time-to-event analysis does not require 1 value per Study Day or analysis window.
If multiple valid, nonmissing measurements exist for a Study Day/analysis window, records will 
be chosen based on the following rules if a single value is needed:
•
For baseline, the last nonmissing value on or prior to the first dosing date (and time, if 
available) of study drug will be selected, unless specified differently. If there are multiple 
records with the same time or no time recorded on the same day, the baseline value will be 
the average of the measurements for continuous data, or the measurement with the lowest 
severity for categorical data.
•
For postbaseline values (other than PCR negative confirmation):
The record collected on the day closest to the nominal day will be selected.
If there are 2 days equidistant from the nominal day, the later day will be selected. 
If there is more than 1 record on the selected day, values will be selected for analysis as 
follows:
■
For PCR, if there is more than 1 record on the selected day, the latest value will be 
selected. If there are multiple records with the same time or no time recorded on the 
same day, the geometric mean value (copies/mL) will be taken.
■
For other parameters, if there is more than 1 record on the selected day, the average 
will be taken for continuous data and the worst severity will be taken for categorical 
data, unless otherwise specified.
•
For postbaseline values of PCR negative confirmation:
Use all available data to derive negative confirmation except if there are multiple records 
on the same day in which case the worst value will be used for negative confirmation for 
that day.
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.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
Key study dates (i.e., first participant screened, first paticipant enrolled, last participant enrolled, 
and last participant last visit for the CSR) will be provided.
A summary of participant enrollment will be provided by cohort for each country, investigator 
and overall total. The summary will present the number and percentage of participants enrolled. 
For each column, the denominator for the percentage calculation will be the total number of 
participants analyzed for that column.
A summary of participant disposition will be provided by cohort and overall total for all screened 
participants. This summary will present the number of participants screened, the number of 
participants who met all eligibility criteria but were not enrolled along with the reasons the 
participants were not enrolled, the number of participants enrolled, the number of participants 
enrolled but never treated, the number of participants in the Safety Analysis Set, and the number 
of participants in the FAS.
For the status of study drug and study completion and reasons for premature discontinuation, the 
number and percentage of participants in each category will be provided. The denominator for 
the percentage calculation will be the total number of participants in the Safety Analysis Set 
corresponding to that column. In addition, a flowchart will be provided to depict the disposition.
The following by-participant listings will be provided by subject 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 summarizing the number of doses received 
by cohort and overall total for the Safety Analysis Set.
A by-participant listing of study drug administration will be provided by subject ID number (in 
ascending order) and visit (in chronological order).


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4.3.
Protocol Deviations 
A by-participant listing will be provided for those participants who did not meet at least 1 
eligibility (inclusion or exclusion) criterion, or took prohibited medications from Screening to 
the Day 30 Follow-up visit, including:
•
Investigational agents for COVID-19 with direct antiviral effect including approved HIV 
protease inhibitors such as lopinavir (LPV)/ ritonavir (RTV), chloroquine, interferon, etc.
•
Strong inducers of P-glycoprotein (e.g. rifampin, rifabutin, carbamazepine, phenytoin or 
herbal medications)
Protocol deviations occurring after participants entered the study are documented during routine 
monitoring. The number and percentage of participants with important protocol deviations, and 
the total number of important protocol deviations by deviation category (e.g., eligibility criteria, 
informed consent) will be summarized by cohort and overall total for the Safety Analysis Set. A 
by-participant listing will be provided for those participants with important protocol deviations.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Participant demographic variables (i.e., age, sex, race, and ethnicity) and baseline characteristics 
(i.e., body weight [in kg], body weight-for-age z-scores, height [in cm], height-for-age z-scores, 
body mass index [BMI; in kg/m2], BMI-for-age percentiles, BMI-for-age z-scores) will be 
summarized by cohort and overall total using descriptive statistics for continuous variables and 
using number and percentage of participants for categorical variables. The summary of 
demographic data will be provided for the Safety Analysis Set. No formal statistical testing is 
planned.
A by-participant demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order. Note: If information on Apgar score for participants 
< 24 hours of life and/or gestational age and birth weight for participants < 56 days of age has 
been collected this information will be listed.
5.2.
Other Baseline Characteristics
The following other baseline characteristics will be summarized by cohort and overall total using 
descriptive statistics for continuous variables and number and percentage of participants for 
categorical variables.
•
Oxygen support status at baseline based on the 7-point ordinal scale: (a) invasive mechanical 
ventilation, (b) non-invasive ventilation or high flow oxygen, (c) low flow oxygen, and (d) 
room air
•
Clinical status (7-point ordinal scale)
•
COVID-19 symptoms (respiratory, gastrointestinal, neurological, circulatory, systemic 
inflammatory response)
•
Duration of hospitalization prior to first dose of RDV (days)
•
Duration of symptoms prior to first dose of RDV (days)
•
SARS-Cov-2 viral load (log10 copies)
•
Aspartate aminotransferase (AST) (U/L)
•
Alanine aminotransferase (ALT) (U/L)
•
Electrocardiogram (ECG) (normal, abnormal [not clinically significant, clinically 
significant])


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•
Creatinine (mg/dL)
•
Estimated glomerular filtration rate (eGFR) using the Bedside IDMS-traceable Schwartz 
formula (mL/min/1.73 m2)
The summary of these baseline characteristics will be provided for the Safety Analysis Set. No 
formal statistical testing is planned.
A by-participant listing of other baseline characteristics will be provided by subject ID number in 
ascending order. 
5.3.
Medical History
Medical history will be collected at screening for general conditions (i.e., conditions not specific 
to the disease being studied). It will be coded using the current version of Medical Dictionary for 
Regulatory Activities (MedDRA).
A summary table will present the number and percentage of participants reporting each medical 
history preferred term, sorted first in alphabetical order by system organ class (SOC) and then by 
preferred term (PT) in descending order of total frequency within SOC for each cohort and 
overall total for the Safety Analysis Set. No formal statistical testing is planned.


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
There is no primary efficacy endpoint in this study.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
Clinical improvement based on scoring using the 7-point Ordinal Scale
Clinical improvement improvement based on scoring using the 7-point Ordinal Scale will be 
derived as follows:
•
If a participant dies while hospitalized (as recorded on the Death Report eCRF and 
Hospitalization Information eCRF), the endpoint on the day of death and all subsequent days 
through Day 10 will be set to Death (=1).
•
If the participant is discharged alive, the endpoint on the day of discharge alive and all 
subsequent days through Day 10 will be set to Not hospitalized (=7).
•
If the participant is discharged alive and dies on the same day or a later day (as recorded on 
the Death Report eCRF and Hospitalization Information eCRF), the endpoint on the day of 
discharge alive and all subsequent days until the day of death will be set to Not hospitalized 
(=7). On the day of death and all subsequent days through Day 10, the endpoint will be set to 
Death (=1).
Every effort will be made to obtain clinical status data for all participants prior to discharge 
alive. The last known clinical status will be used for days with missing clinical status (eg, where 
the reason for Hospital Discharge is not “Discharged Alive” and the participant has not died). All 
postbaseline days with missing ordinal scale score, from Day 2 to Day 10, will use the previous 
last known clinical status.
Clinical improvement is investigated in two settings:
•
≥ 1 point improvement from baseline clinical status or discharged alive
•
≥ 2-point improvement from baseline clinical status or discharged alive on the 7-point 
ordinal scale
Recovery is defined as an improvement from a baseline score of 2 through 5 to a score of 6 or 7, 
or an improvement from a baseline score of 6 to a score of 7. 


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Clinical improvement based on scoring using the PEWS Improvement Scale
Clinical improvement is investigated in two settings:
•
≥ 1 point improvement from baseline clinical status or discharged alive
•
≥ 2-point improvement from baseline clinical status or discharged alive on the 7-point 
ordinal scale
Recovery is defined as an improvement from a baseline score of 1-3 to a score of 0, or being 
discharged alive, whichever comes first.
Time (days) to discharge from hospital
•
Duration of hospitalization from Day 1 = number of days from first dose to date discharged 
alive.
•
Total duration of hospitalization = number of days from hospital admission to date 
discharged alive.
Oxygen usage and ventilation modality and settings
Oxygen support status is defined based on the 7-point ordinal scale.
Days to the first confirmed negative PCR result
•
Confirmed negative PCR result is defined as 2 consecutive negative PCR results or a 
negative PCR result at the last available sample for participants who completed or 
discontinued from this study. 
6.2.2.
Analysis of Secondary Endpoints
The FAS will be the primary analysis set for secondary efficacy endpoints. No formal statistical 
testing is planned.
Clinical improvement based on scoring using the 7-point Ordinal Scale 
For each cohort and overall total, clinical status and change from Baseline in clinical status by 
Study Day as well as last available assessment will be summarized by the number and 
percentage of participants for each category. It should be noted that the main timepoint of 
interest for this endpoint is Day 10. In addition, a stacked bar chart will also be provided for each 
cohort and overall total depicting the percentage of participants for each category by Study Day. 
Furthermore, descriptive statistics for change from Baseline in clinical status by Study Day and 
last available assessment will also be provided for each cohort and overall total. 


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Time to clinical improvement (days) will be modelled using a competing risk analysis. The 
competing event is death. Participants not achieving clinical improvement at the last assessment 
will be censored on the day of the last clinical assessment. In addition, the cumulative incidence 
from the competing risk analysis will also be graphically presented. The number and percentage 
of participants with clinical improvement will also be summarized by cohort and overall total.
Time to ≥ 1-point improvement from baseline clinical status or discharged alive on the 7-point 
ordinal scale will be modelled using a competing risk analysis. The competing event is death. 
Participants not achieving ≥ 1-point improvement at the last assessment will be censored on the 
day of the last clinical assessment. In addition, the cumulative incidence from the competing risk 
analysis will also be graphically presented. Furthermore, the number and percentage of 
participants with a ≥ 1-point improvement or discharged alive based on the 7-point ordinal scale 
on Day 2 through Day 10 as well as last available assessment will be summarized by cohort and 
overall total.
Time to recovery based on the 7-point ordinal scale will be modelled using a competing risk 
analysis. The competing event is death. Participants not achieving recovery at the last assessment 
will be censored on the day of the last clinical assessment. In addition, the cumulative incidence 
from the competing risk analysis will also be graphically presented. Furthermore, the number 
and percentage of participants with recovery based on the 7-point ordinal scale on Day 2 through 
Day 10 as well as last available assessment will be summarized by cohort and overall total.
Clinical improvement based on scoring using the PEWS Improvement Scale
For each cohort and overall total, clinical status and change from Baseline in clinical status by 
Study day will be summarized for the number and percentage of participants for each PEWS 
improvement scale category (behavior, cardiovascular, respiratory) as well as total score. It 
should be noted that the main timepoint of interest for this endpoint is Day 10. A stacked bar 
chart will also be provided for each cohort and overall total for each PEWS improvement scale 
category (behavior, cardiovascular, respiratory) depicting the percentage of participants for each 
category by Study Day.
Time to ≥ 2-point improvement or discharged alive will be modelled using a competing risk 
analysis for each PEWS improvement scale category (behavior, cardiovascular, respiratory). The 
competing event is death. Participants not achieving ≥ 2-point improvement at the last 
assessment will be censored on the day of the last clinical assessment. In addition, the 
cumulative incidence from the competing risk analysis for each PEWS improvement scale 
category (behavior, cardiovascular, respiratory) will also be graphically presented. The number 
and percentage of participants with a ≥ 2-point improvement or discharged alive on Day 2 
through Day 10 or discharged alive for each PEWS improvement scale category (behavior, 
cardiovascular, respiratory) will also be summarized by cohort and overall total.
Time to ≥ 1-point improvement or discharged alive will be modelled using a competing risk 
analysis for each PEWS improvement scale category (behavior, cardiovascular, respiratory). The 
competing event is death. Participants not achieving ≥ 1-point improvement at the last 
assessment will be censored on the day of the last clinical assessment. In addition, the 


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cumulative incidence from the competing risk analysis for each PEWS improvement scale 
category (behavior, cardiovascular, respiratory) will also be graphically presented. Furthermore, 
the number and percentage of participants with a ≥ 1-point improvement or discharged alive on 
Day 2 through Day 10 or discharged alive for each PEWS improvement scale category 
(behavior, cardiovascular, respiratory) will be summarized by cohort and overall total.
Time to recovery based on the PEWS scale on Day 2 through Day 10, and last available 
assessment will be modelled using a competing risk analysis for each PEWS improvement scale 
category (behavior, cardiovascular, respiratory). The competing event is death. Participants not 
achieving a score of 0 at the last assessment will be censored on the day of the last clinical 
assessment. In addition, the cumulative incidence from the competing risk analysis for each 
PEWS improvement scale category (behavior, cardiovascular, respiratory) will also be 
graphically presented. Furthermore, the number and percentage of paricipants with recovery 
based on the PEWS scale on Day 2 through Day 10, and last available assessment for each 
PEWS improvement scale category (behavior, cardiovascular, respiratory) will be summarized 
by cohort and overall total.
Time (days) to discharge from hospital
Time to discharge from hospital will be modelled using a competing risk analysis. The 
competing event is death. Participants not discharged from hospital will be censored on the day 
of the last clinical assessment. In addition, the cumulative incidence from the competing risk 
analysis will also be graphically presented.
Descriptive statistics for duration of hospitalization from Day 1 and total duration of 
hospitalization will also be provided for each cohort and overall total. In addition, information on 
hospitalization status will be summarized for each cohort and overall total. Only participants who 
are discharged alive on or prior to Day 30 will be included in the duration of hospitalization 
through Day 30 follow-up visit analysis.
Oxygen usage and ventilation modality and settings
Descriptive statistics will be provided by cohort and overall total for the number of days of 
oxygen support through discharge alive, death or Day 10 based on the 7-point ordinal scale 
reported values, including:
•
Days on invasive mechanical ventilation 
•
Days on high flow oxygen devices 
•
Days requiring low flow supplemental oxygen 
As oxygen support status will be collected only while the participant is in the hospital, if a 
participant is discharged alive and dies afterwards, the participant will be included only in the 
summary for participants discharged alive. 






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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 MedDRA. System organ 
class, high-level group term (HLGT), high-level term (HLT), PT, and lower-level term (LLT) 
will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
The severity of AEs will be graded using the Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017. For each episode, 
the highest grade attained should be reported as defined in the grading scale. The DAIDS scale is 
available at the following location:
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to toxicity 
criteria specified in the protocol. The severity grade of events for which the investigator did not 
record severity will be categorized as “missing” for tabular summaries and data listings. The 
missing category will be listed last in summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE 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 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-participant data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious AEs (SAEs) will be identified and captured as SAEs if the AEs met the definitions of 
SAEs that were specified in the study protocol. SAEs captured and stored in the clinical database 
will be reconciled with the SAE database from the Gilead Patient Safety (PS) Department before 
data finalization.
7.1.5.
Treatment-Emergent Adverse Events 
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent AEs (TEAEs) are defined as 1 or both of the following:


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Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug
•
Any AEs leading to premature discontinuation of study drug.
7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:
•
The AE onset is the same as or after the month and year (or year) of the first dosing date of 
study drug, and
•
The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
7.1.6.1.
Summaries of AE incidence in Combined Severity Grade Subsets 
A brief, high-level summary of the number and percentage of participants who experienced at 
least 1 treatment-emergent AE (TEAE) in the categories described below will be provided by 
treatment group. All deaths observed in the study will also be included in this summary.
One of the primary endpoints of the study is the proportion of participants with TEAEs. 
Therefore, the number and percentage of participants who experienced at least 1 TEAE will be 
provided and summarized by SOC, HLT (if applicable), PT, and cohort: 
•
TEAEs
For the AE categories described below, summaries will be provided by SOC, PT, and cohort:
•
TEAEs with Grade 3 or higher 
•
TE treatment-related AEs
•
TE treatment-related AEs with Grade 3 or higher 


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•
TE SAEs
•
TE treatment-related SAEs 
•
TEAEs leading to premature discontinuation of study drug
•
TE AEs leading to death (i.e., outcome of death)
Multiple events will be counted only once per participant in each summary. Adverse events will 
be summarized and listed first in alphabetical 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 participant during the study. 
In addition to the above summary tables, all TEAEs, TE SAEs, TE treatment-related AEs, and 
TE treatment-related SAEs 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 TE treatment-related AEs
•
All AEs with severity of Grade 3 or higher
•
All SAEs
•
All TE treatment-related SAEs
•
All Deaths
•
All AEs leading to premature discontinuation of study drug
7.1.6.2.
Summaries of AE Incidence by Severity 
A brief, high-level summary of the number of percentage of participants who experienced at 
least 1 TEAE in the categories described below will be provided by treatment group. All deaths 
observed in the study will also be included in this summary.
The number and percentage of participants who experienced at least 1 TEAE will be provided 
and summarized by SOC, HLT (if applicable), PT, and treatment group. 
For the AE categories described below, summaries will be provided by SOC, PT, and treatment 
group:
•
TEAEs by maximum severity 


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•
TE treatment-related AEs by maximum severity 
Multiple events will be counted only once per participant 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, the most severe severity will be used for those AEs that occurred more 
than once in a given participant during the study. 
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days 
for participants who have permanently discontinued study drug. The analysis will be based on 
values reported in conventional units. When values are below the LOQ, they will be listed as 
such, and the closest imputed value will be used for the purpose of calculating summary statistics 
as specified in Section 3.7. 
A by-participant listing for laboratory test results will be provided by subject ID number and 
visit in chronological order for hematology, coagulation, inflammatory markers, serum 
chemistry, and urinalysis separately. It should be noted that the routine coagulation test will only 
be done for cohorts 5-7 at Screening and Day 10 or Discharge). Values falling outside of the 
relevant reference range and/or having a severity grade of 1 or higher on the DAIDS grading 
scale will be flagged in the data listings, as appropriate.
No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by cohort for each of the following laboratory categories 
and tests 
•
Hematology (Hemoglobin [g/dL]; Hematocrit [%]; Platelet Count [x10^9/L]; WBC 
[x10^9/L])
•
Chemistry (ALT [U/L]; AST [U/L]; Glucose [mg/dL]; Serum Creatinine [mg/dL]; eGFR, 
Bedside Schwartz [mL/min/1.73m2])
•
Coagulation (Prothrombin Time [PT] [sec]; Activated Partial Thromboplastin Time [aPTT] 
[sec]; Prothrombin International Normalized Ratio [INR])
as follows:
•
Baseline values 
•
Values at each postbaseline time point


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•
Change from baseline at each postbaseline time point
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
values will be displayed to the reported number of digits; SD values will be displayed to the 
reported number of digits plus 1.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.2.
One of the secondary endpoints is descriptive statistics of bilirubin concentrations in < 14 days 
old participants. If there are sufficient participants who are < 14 days old in the Safety Analysis 
Set then descriptive statistics for bilirubin will be repeated for the subset of participants who are 
< 14 days old when enrolled into their respective cohorts. In addition descriptive statistics for 
bilirubin will also be provided for the subset of participants who are ≥ 14 days old when enrolled 
into their respective cohorts. A by-participant listing of bilirubin concentrations will be provided 
by subject ID number and visit in chronological order for the subset of participants who are 
< 14 days old as well the subset of participants who are ≥ 14 days old when enrolled into their 
respective cohorts.
In addition, line plots showing the median (Q1, Q3) change from baseline at each postbaseline 
time point will also be provided for the following laboratory parameters:
•
ALT (U/L)
•
AST (U/L)
•
Serum creatinine (mg/dL)
•
eGFR, using the Bedside IDMS-traceable Schwartz formula (mL/min/1.73 m2)
•
Total bilirubin (mg/dL)
Note: This will be produced only for participants who are ≥ 14 days old.
7.2.2.
Graded Laboratory Values
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Event, Version 2.1 
(July 2017) will be used to assign 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. The DAIDS scale is available at 
the following location:
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf


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7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days for participants who permanently discontinued study drug, or the 
last available date in the database snapshot for participants who were still on treatment at the 
time of an interim analysis. If the relevant baseline laboratory value is missing, any abnormality 
of at least Grade 1 observed within the time frame specified above will be considered treatment 
emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
participants in the study with the given response at baseline and each scheduled postbaseline 
time point.
The following summaries (number and percentage of participants) for treatment-emergent 
laboratory abnormalities will be provided by lab test and treatment group; participants will be 
categorized according to the most severe postbaseline abnormality grade for a given lab test:
•
laboratory abnormalities
•
Grade 3 or 4 laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of participants 
with nonmissing postbaseline values up to 30 days after last dosing date.
A by-participant listing of 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.
Abnormalities in coagulation parameters will be graded for INR, PT, and aPTT.
For the INR of prothrombin time and aPTT, protocol specified toxicity grading scale depends on 
the upper limit of normal range (ULN). While the ULN of INR and aPTT depends on whether 
the participant is taking anticoagulant medication or not (ie, Not taking oral anticoagulant: 
0.8 – 1.2; Taking oral anticoagulant: 2.0 – 3.0), this information is not collected by the reference 
laboratory. As a result, INR and aPTT will be graded by assuming participant is not taking an 
oral anticoagulant, which is a conservative approach that may lead to over-reporting of 
abnormalities for INR and aPTT.


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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 particpants who were reported to have the following 
laboratory test values for postbaseline measurements:
•
AST > 3 x upper limit of reference range (ULN)
•
ALT > 3 x ULN
•
AST or ALT > 3 x ULN
•
Total bilirubin > 2 x ULN
•
Alkaline phosphatase (ALP) > 1.5 x ULN
•
AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
The summary will include data from all postbaseline visits up to 30 days after the last dose of 
study drug. For individual laboratory tests, particpants will be counted once based on the most 
severe postbaseline values. For both the composite endpoint of AST or ALT and total bilirubin, 
particpants will be counted once when the criteria are met at the same postbaseline visit date. 
The denominator is the number of particpants in the Safety Analysis Set who have nonmissing 
postbaseline values of all relevant tests at the same postbaseline visit date. A listing of 
particpants 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 analysis visit
•
Change from baseline at each postbaseline analysis 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 postbaseline visit will be defined as the 
postbaseline value minus the baseline value. Body weight and vital signs measured at 
unscheduled visits will be included for the baseline value selection. It should be noted that 
temperature will not be summarized due to different methods of measuring temperature. Oxygen 
saturation (SpO2 and PaO2) will also not be summarized due to collection under different oxygen 
support statuses. 


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In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.2. No formal statistical testing is planned.
A by-participant listing of vital signs will be provided by subject ID number and analysis visit in 
chronological order. Body weight, height, and BMI 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 Gilead-modified World Health Organization (WHO) Drug dictionary.
7.4.1.
Prior Medications
Prior medications are defined as any medications taken before a participant took the first dose of 
study drug.
A summary of prior medications will not be provided. 
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a participant took study drug. 
Use of concomitant medications will be summarized by preferred name using the number and 
percentage of participants for each cohort. A participant reporting the same medication more 
than once will be counted only once when calculating the number and percentage of participants 
who received that medication. The summary will be ordered by preferred term in descending 
overall frequency. For drugs with the same frequency, sorting will be done alphabetically.
For the purposes of analysis, any medications with a start date prior to or on the first dosing date 
of study drug and continued to be taken 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 
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.


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All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-participant listing sorted by subject ID number and administration date in chronological 
order.
7.4.3.
COVID-19 Medications Other Than the Study Drug
COVID-19 medications from the first day of first dose of study drug administration until the end 
of the study will be categorized into the following categories: 
•
Experimental antiviral
•
Immune modulator
•
Anti-inflammatory
•
Antiviral antibody therapy
•
Other medication
Refer to Table 13-1 for the list of COVID-19 medications and the associated categories. It should 
be noted that a COVID-19 medication may belong to more than one category. 
One of the secondary endpoints is the proportion of participants with concomitant use of 
medications other than RDV for treatment of COVID-19. Therefore, a summary table will 
present the number and percentages of participants with concomitant use of COVID-19 
medications by cohort and overall for the Safety Analysis Set, sorted first by categories and then 
by PT in descending order of total frequency. 
7.5.
Electrocardiogram Results
A by-participant listing of ECG results will be provided by subject ID number (in ascending 
order).
7.6.
Other Safety Measures
A by-participant listing will be provided for those participants experiencing pregnancy during the 
study.
A by-participant listing of chest imaging reslts will also be provided by subject ID number (in 
ascending order).
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC (PK) ANALYSES
8.1.
PK Sample Collection
Sparse PK assessments will be conducted in all participants at participating sites. A single PK 
blood sample is planned to be collected at the following times and visits:
•
Cohorts 1-4 and Cohort 8:
Day 2: end of infusion (± 15 minutes) and 4 hours (±30 minutes) post end of infusion
Day 3: pre-infusion (≤ 60 minutes) and 2 hours (± 15 minutes) post end of infusion

•
Cohorts 5, 6 and 7, Day 2 OR Day 3:
Day 2: end of infusion (± 15 minutes) and 4 hours (±30 minutes) post end of infusion
Day 3: pre-infusion (≤ 60 minutes) and 2 hours (± 15 minutes) post end of infusion
As many of the specified PK time points should be obtained from each participant as is feasible.
8.2.
PK Analyses
Concentrations of RDV, the metabolites (GS-441524 and GS-704277), and SBECD in plasma 
will be determined using validated bioanalytical assays.
The analytes and parameters presented in Table 8-1 will be used to evaluate the PK objectives of 
the study.
Table 8-1.
PK Parameters for Each Analyte
Analytes
Sample Matrix
Parameters
RDV
Plasma
AUC0-24 loading dose (h*ng/mL), Cmax loading dose (ng/mL), AUCtau 
steady state (h*ng/mL), Cmax steady state (ng/mL), t1/2 steady state (h), CLss 
(L/h), Vss (L)
GS-441524
Plasma
AUC0-24 loading dose (h*ng/mL), Cmax loading dose (ng/mL), AUCtau 
steady state (h*ng/mL), Cmax steady state (ng/mL), Ctau steady state 
(ng/mL), t1/2 steady state (h)
GS-704277
Plasma
AUC0-24 loading dose (h*ng/mL), Cmax loading dose (ng/mL), AUCtau 
steady state (h*ng/mL), Cmax steady state (ng/mL), t1/2 steady state (h)
CCI


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8.2.1.
Statistical Analysis Methods
Individual participant concentration data for RDV, the metabolites (GS-441524 and GS-704277), 
and SBECD 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 presented by 
time point. In addition, the geometric mean, 95% CI of the geometric mean, and the mean and 
SD of the natural log-transformed values will be presented for individual participant PK 
parameter data.
Individual concentration data listings and summaries will include all participants with 
concentration data. The sample size for each time point will be based on the number of 
participants with nonmissing concentration data at that time point. The number of participants 
with concentration below the limit of quantitation (BLQ) will be presented for each time point. 
For summary statistics, BLQ values will be treated as 0 at predose and one-half of the lower 
LOQ for postdose time points. 
The following tables will be provided for each analyte by cohort and overall total:
•
Individual participant concentration data and summary statistics
•
Individual participant PK parameters and summary statistics
The following figures will be provided for each analyte by cohort and overall total:
•
Boxplots of selected PK parameters
RDV: AUCtau steady state (h*ng/mL), Cmax steady state (ng/mL), t1/2 steady state (h), CLss 
(L/h), Vss (L)
GS-441524: AUCtau steady state (h*ng/mL), Cmax steady state (ng/mL), Ctau steady state 
(ng/mL), t1/2 steady state (h)
GS-704277: AUCtau steady state (h*ng/mL), Cmax steady state (ng/mL), t1/2 steady state 
(h)
•
PK sampling details by participant, including procedures, differences in scheduled and actual 
draw times, and sample age will be provided in listings.


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9.
REFERENCES
GS-US-399-5505 Final Clinical Study Report. A Phase 1, Blinded, Randomized, Placebo-
Controlled, Multiple-Dose Study Evaluating the Safety, Tolerability, and 
Pharmacokinetics of Intravenous Remdesivir in Healthy Volunteers. 09 April 
2020. Page 63 – 69.
GS-US-540-5823 Data Monitoring Committee (DMC) Charter. A Phase 2/3 Single-Arm, Open-
Label Study to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetics 
of Remdesivir (GS 5734™) in Participants from Birth to < 18 Years of Age with 
COVID-19. 22 June 2020. Page 1 – 35.
GS-US-540-5823 Interim Study Report. A Phase 2/3 Single-Arm, Open-Label Study to Evaluate 
the Safety, Tolerability, Efficacy, and Pharmacokinetics of Remdesivir (GS 
5734™) in Participants from Birth to < 18 Years of Age with COVID-19. 
04 October 2021.


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.
nQuery Advisor(R) Version 8.5. Statistical Solutions, Cork, Ireland.


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


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12.
APPENDICES
Appendix 1.
Study Procedures Table
Administration Periodb
Follow-up 
Period
Screening
Baseline/
Day 1a
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 30
(± 5 days)
Assent/Parent or Legal 
Guardian consent
X
Inclusion/Exclusion criteria
X
Focused medical history 
X
Documentation of 
SARS-CoV-2 confirmation by 
PCR
X
ECG 
X
Complete or symptom-directed 
physical examination
X
X
X
X
X
X
X
X
X
X
X
X
Body weightc 
X
X
X
X
X
X
X
X
X
X
X
X
Height/Length
X
Xd
Head circumference and last 
recorded Apgar score if 
< 24 hours of age
X
Xd
Birth weight and gestational 
age if < 56 days
X
Vital signs (heart rate, 
temperature, blood pressure 
[MAP if available, systolic and 
diastolic], respiratory rate, 
oxygen saturation)
X
X
X
X
X
X
X
X
X
X
X
X
Documented respiratory status
X
X
X
X
X
X
X
X
X
X
X
X


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Administration Periodb
Follow-up 
Period
Screening
Baseline/
Day 1a
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 30
(± 5 days)
If available, record chest 
radiographic impression (or 
other imaging) but not 
mandatory to perform 
otherwise
X
X
X
X
X
X
X
X
X
X
X
Tanner Stage assessment if 
≥ 6 years of age
X
Hematology, chemistry, 
urinalysis 
X
X
X
X
X
Xe
Routine coagulation test 
(Days 5 and 10 only for 
Cohorts 5-6 and Day 10 only 
for Cohort 7)
X
X
X
X
X
Inflammatory Markers 
(D-dimer, Ferritin, qCRP, 
Procalcitonin, and IL-6) 
X
X
X
X
X
ESR 
If ≥4 kg (Cohorts 1-4 only)
X
X
X
X
X
Neonatal bilirubin panel for all 
neonates < 14 days, and any 
neonate presenting with 
jaundice
X
X
Serology for SARS-CoV-2 if 
≥ 12 kg (IgG, IgM, and IgA)f
X
X
X
X
Pregnancy test (urine/blood)
X


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Administration Periodb
Follow-up 
Period
Screening
Baseline/
Day 1a
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 30
(± 5 days)
Nasopharyngeal and 
oropharyngeal samples 
(combined), rectal or fecal 
swab, and ET aspirates (if 
intubated) for SARS-CoV-2 
PCR testing and possible viral 
sequencingf
X
X
X
X
X
Pediatric Early Warning Score 
Improvement Scaleg
X
X
X
X
X
X
X
X
X
X
X
Ordinal Scale
X
X
X
X
X
X
X
X
X
X
X
Plasma PK assessmentsh
X
X
X
IV RDV administration
Xi
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
Adverse eventsk
X
X
X
X
X
X
X
X
X
X
X
X
CoV = coronavirus; CRP = C-reactive protein; ECG = electrocardiogram; ET = endotracheal tube; Ig = immunoglobulin; IV = intravenous; MAP = mean arterial pressure; 
PK =pharmacokinetic; RDV = remdesivir (GS-5734™); SARS = severe acute respiratory syndrome; TBD = to be determined
a
If the Screening and Day 1 visits occur within 24 hours, only the following procedures need to be completed: Tanner Stage assessment and samples for SARS-CoV-2 PCR 
testing and viral sequencing
b
The following evaluations are to be completed on Days 2-10 or until discharge, whichever comes earlier. 
c
d
Record length and head circumference if < 28 days at enrollment.
e
Comprehensive metabolic panel (Chemistry 14) only.
f
If the subject is discharged prior to Day 10, the Serology for SARS-CoV-2 and SARS-CoV-2 samples/swabs will be collected on the day of discharge. Thereafter, these 
samples can be collected by assigned study staff at the subject’s home or as an outpatient on the assigned days noted above. 
g
If a subject is on a ventilator, a score of 3 should be given in the respiratory category.
h
i
IV administration on Day 1 with either IV RDV 200 mg (Cohort 1), IV RDV 5 mg/kg (Cohorts 2-5), or RDV dose TBD (Cohorts 6-7).
j
IV administration daily up to Day 10 with either IV RDV 100 mg (Cohort 1), IV RDV 2.5 mg/kg (Cohorts 2-5), or RDV dose TBD (Cohorts 6-7).
CCI
CCI
CCI


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k
All subjects presenting with multisystem inflammatory syndrome in children (MIS-C; https://emergency.cdc.gov/han/2020/han00432.asp) should be monitored and treated as 
clinically indicated.
l
 
CCI


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Appendix 2.
Pediatric Early Warning Score
0
1
2
3
Behavior
Playing
Appropriate
Sleeping
Irritable
Lethargic and/or
Confused and/or
Reduced response to 
pain
Cardiovascular
Within normal 
parameters for 
age
Pink and/or
Capillary refill 
1-2 seconds
Tachycardia < 20 
above normal for age 
and/or
Pale and/or
Capillary refill 
3 seconds
Tachycardia 20-29 
above normal for 
age
Gray and/or
Capillary refill 
4 seconds
Tachycardia ≥ 30 above 
or bradycardia ≥ 10 
below normal for age 
or
Gray
Capillary refill 
≥ 5 seconds
Respiratory
Within normal 
parameters
No retractions
Respiratory rate > 10 
above normal 
parameters using 
accessory muscles 
and/or
30+ %FiO2 or 3+ L/min
Respiratory rate > 
20 above normal 
parameters and 
retractions and/or
40+ %FiO2 or 
6+ L/min
Respiratory rate ≥ 5 
below normal 
parameters with 
retractions and grunting 
and/or
50% FiO2 or 8+ L/min


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Appendix 3.
Programming Specifications
1) If the age from the Day 1 eCRF is not available, age will be calculated as follows:
Only year is provided for the date of birth (DOB). Use July 1 for the month and day.
a) AGE (years) is calculated from the number of days between the DOB and Study Day 1,
b) Use the SAS INTCK function to determine the number of “1st-of-month days” 
(eg, January 1st, February 1st, March 1st) between DOB and Day 1 (inclusive),
c) Divide the result in (b) by 12,
AGE = the integer of the result in (c),
Age for laboratory test reference range will be based on the age at the sample collection 
date.
2) All screened participants refer to all participants who are screened (ie, with non-missing 
screening date) and have a screening number. For summaries the same participant is counted 
only once.
3) Screen failure participants are the participants who were screened and answered “No” for any 
inclusion criteria or “Yes” for any exclusion criteria regardless of which version of protocol 
the participant was consented to.
4) Participants in the All Enrolled Analysis Set are defined as participants enrolled into the 
study. IXRSRAND is the source to determine whether the participants is enrolled (ie, 
participant with non-missing ENRDTN in the IXRSRAND dataset), and confirmed by the 
eCRF ENROLL dataset (ie, ENROLLYN = “Yes” in ENROLL dataset).
5) Enrolled treatment (ie, TRT01P in ADSL) is derived from IXRSRAND, while actual 
treatment received (ie, TRT01A in ADSL) is assigned as the enrolled treatment if the 
participant took at least 1 dose of study drug and assigned as blank if the participant was 
never dosed.
6) In the disposition table, the reasons for premature discontinuation are displayed in the order 
as they appear on the eCRF.
7) Body mass index (BMI) 
BMI will be calculated only at baseline as follows:
BMI = (weight [kg]) / (height [meters]2)
Baseline height and weight will be used for this calculation if available.


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8) Details of additional COVID-19 medications are provided in table below. 
Table 13-1.
Additional COVID-19 Medications
Drug name
ATC Code
WHODRUG Preferred Term
Chloroquine
P01BA
CHLOROQUINE
Hydroxychloroquine
P01BA
HYDROXYCHLOROQUINE
Lopinavir/ritonavir
J05AR
LOPINAVIR/RITONAVIR
Ribavirin
J05AP
RIBAVIRIN
Bamlanivimab/Etesevimab
--
BAMLANIVIMAB/ETESEVIMAB
Casirivimab/Imdevimab
--
CASIRIVIMAB/IMDEVIMAB
Molnupiravir
--
MOLNUPIRAVIR
ATC = anatomical therapeutic chemical
Additional medications may be included during final review of concomitant medications 
prior to data finalization.
9) Grouping on COVID-19 medications other than the study drug
Table 13-2.
Grouping on the COVID-19 Medications other than the Study Drug
Standardized Medication 
Name
Experimental 
antiviral
Immune 
modulator
Anti-
inflammatory
AntiViral 
antibody 
therapy
Other 
medication
ANAKINRA
N
Y
Y
N
N
AZITHROMYCIN
Y
Y
Y
N
N
BETAMETHASONE
N
Y
Y
N
N
CLARITHROMYCIN
N
N
Y
N
N
CYCLOBENZAPRINE
N
N
N
N
Y
DEXAMETHASONE
N
Y
Y
N
N
DEXAMETHASONE 
SODIUM PHOSPHATE
N
Y
Y
N
N
DIPHENHYDRAMINE; 
ZINC ACETATE
N
N
N
N
Y
ENOXAPARIN
N
N
N
N
Y
ENOXAPARIN SODIUM
N
N
N
N
Y
GANCICLOVIR
Y
N
N
N
N
HYDROCORTISONE
N
Y
Y
N
N
HYDROCORTISONE 
SODIUM SUCCINATE
N
Y
Y
N
N


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Standardized Medication 
Name
Experimental 
antiviral
Immune 
modulator
Anti-
inflammatory
AntiViral 
antibody 
therapy
Other 
medication
HYDROXYCHLOROQUIN
E
Y
N
N
N
N
IMMUNOGLOBULIN G 
HUMAN
N
Y
N
N
N
IMMUNOGLOBULIN 
HUMAN NORMAL
N
Y
N
N
N
IMMUNOGLOBULINS 
NOS
N
Y
N
N
N
LEVOFLOXACIN
N
N
N
N
Y
METHYLPREDNISOLONE
N
Y
Y
N
N
ONDANSETRON
N
N
N
N
Y
PLASMA
N
N
N
Y
N
POTASSIUM PHOSPHATE 
DIBASIC
Y
Y
Y
N
N
POTASSIUM PHOSPHATE 
DIBASIC;SODIUM 
PHOSPHATE
Y
Y
Y
N
N
PREDNISOLONE
N
Y
Y
N
N
PREDNISOLONE SODIUM 
PHOSPHATE
N
Y
Y
N
N
PREDNISONE
N
Y
Y
N
N
REMDESIVIR
N
N
N
N
Y
RITUXIMAB
N
Y
N
N
N
TOCILIZUMAB
N
Y
Y
N
N
ZINC
N
N
N
N
Y
Additional medications may be included during final review of COVID-19 medications other 
than the study drug prior to data finalization.
10) Graded Laboratory Abnormalities Summary
The following labels will be used for laboratory abnormalities and Grade 3 or 4 
laboratory abnormalities summary tables and listings:


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Battery
Lab Test Label
Used in l-labtox Listing
Toxicity 
Direction
Lab Test Label
Used in t-labtox Table
Basophils
Increase
Basophils (Increased)
Eosinophils
Increase
Eosinophils (Increased)
Hemoglobin
Decrease
Hemoglobin (Decreased)
Lymphocytes
Decrease
Lymphocytes (Decreased)
Monocytes
Increase
Monocytes (Increased)
Neutrophils
Decrease
Neutrophils (Decreased)
Platelets
Decrease
Platelets (Decreased)
Hematology
WBC
Decrease
WBC (Decreased)
Albumin
Decrease
Albumin (Decreased)
Alkaline Phosphatase
Increase
Alkaline Phosphatase (Increased)
ALT
Increase
ALT (Increased)
AST
Increase
AST (Increased)
Calcium
Decrease
Calcium (Decreased)
Calcium, Ionized 
Decrease
Calcium, Ionized (Decreased)
Creatine Kinase
Increase
Creatine Kinase (Increased)
Creatinine
Increase
Creatinine (Increased)
Direct Bilirubin
Increase
Direct Bilirubin (Increased)
eGFR, Bedside Schwartz
Decrease
eGFR, Bedside Schwartz 
(Decreased)
GGT
Increase
GGT (Increased)
Magnesium
Decrease
Magnesium (Hypomagnesemia)
Serum Carbon Dioxide
Decrease
Serum Carbon Dioxide (Decreased)
Serum Glucose
Increase
Serum Glucose (Hyperglycemia)
Serum Glucose
Decrease
Serum Glucose (Hypoglycemia)
Serum Potassium
Increase
Serum Potassium (Hyperkalemia)
Serum Potassium
Decrease
Serum Potassium (Hypokalemia)
Serum Sodium
Increase
Serum Sodium (Hypernatremia)
Serum Sodium
Decrease
Serum Sodium (Hyponatremia)
Total Bilirubin
Increase
Total Bilirubin (Hyperbilirubinemia)
Chemistry
Urea Nitrogen (BUN)
Increase
Urea Nitrogen (Increased)
Coagulation
Prothrombin Time
Increase
Prothrombin Time (Increased)


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Battery
Lab Test Label
Used in l-labtox Listing
Toxicity 
Direction
Lab Test Label
Used in t-labtox Table
Activated Partial 
Thromboplastin Time
Increase
Activated Partial Thromboplastin 
Time (Increased)
Prothrombin Intl. 
Normalized Ratio
Increase
Prothrombin Intl. Normalized Ratio 
(Increased)
Urine Glucose
Increase
Urine Glucose (Glycosuria)
Urinalysis
Urine Protein
Increase
Urine Protein (Proteinuria)
11) Lab and blood pressure evaluation
Test
Evaluation
globulin
globulin in g/dL = Total Protein in g/dL – Albumin in g/dL
albumin: globulin (A:G) ratio
A:G (%) = Albumin in g/dL / (Total Protein in g/dL – Albumin in g/dL)
BUN to Creatinine ratio (%)
BUN: SCr (%) = BUN/ SCr,
where BUN is Blood Urea Nitrogen (mg/dL); Cr is Creatinine (mg/dL)
eGFR (Bedside IDMS-traceable 
Schwartz GFR Calculator for 
Children) 
GFR (mL/min/1.73 m²) = (0.413 × Height in cm) / Creatinine in mg/dL
mean arterial pressure (MAP)
mean arterial pressure = diastolic pressure + (1/3) × pulse pressure, 
where pulse pressure = systolic pressure – diastolic pressure.
12) Confidence Interval (CI) for Single Proportion
•
The 95% CI for percentage estimate is calculated based on the Clopper-Pearson exact 
method.
proc freq;
 by cohort;
 tables event/ binomial alpha=0.05;
 exact binomial;
 output out=_ci95 binomial;
run;
13) TEAE
Events with Missing Onset Day and/or Month
An event is considered treatment emergent if the following 3 criteria are met:
a) The month and year (or year) of onset date is the same as or after the month and year 
(or year) of the first dose of study drug, and


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b) The month and year (or year) of the onset date is the same as or before the month and 
year (or year) of the 30th day after the date of the last dose of study drug, and
c) End date is as follows: 
The (complete) end date is on or after the first dose date, or
The month and year (or year) of end date is the same or after the month and year (or year) 
of the first dose of study drug, or
End date is completely missing 
Events with Completely Missing Onset Date
•
An AE with a completely missing onset date is defined as TEAE if end date meets any of 
the 3 criteria specified above.
14) The precision in reporting numerical values should be as follows:
•
Raw measurements will be reported the same as the data captured electronically or on the 
eCRF.
•
Standard deviation and standard error will be reported to one more significant decimal 
place than the raw measurement.
•
Mean, median, minimum, Q1, Q3, maximum, 95% CIs will be reported to the same 
number of decimal places of the raw measurements. 
•
Exceptions may be considered; for example, if more than 4 significant digits are provided 
for the measurement.
15) Last dose date is not expected to be missing. However, if last dose date is missing due to data 
issues, it will be imputed using the maximum of non-missing, non-zero dose, study drug start 
and stop dates.
16) Ordinal scale and oxygen support status
•
The Ordinal Scale is an assessment of the clinical status of a given study day. Each day, 
the worst (ie, lowest ordinal) score from the previous day will be recorded (ie, on Day 3, 
the lowest ordinal score from Day 2 is obtained and recorded for Day 2). The original 
Ordinal Scale (A to G) has been converted to a 7-point scale with the associated oxygen 
support status defined in the following table:


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Ordinal Scale
Oxygen Support Status
1
Death
Death
2
Hospitalized, on invasive mechanical ventilation or ECMO
Invasive Mechanical Ventilation 
3
Hospitalized, on non-invasive ventilation or high flow oxygen 
devices
High Flow Oxygen
4
Hospitalized, requiring low flow supplemental oxygen
Low Flow Oxygen
5
Hospitalized, not requiring supplemental oxygen - requiring 
ongoing medical care (COVID-19 related or otherwise)
Room Air
6
Hospitalized, not requiring supplemental oxygen - no longer 
requires ongoing medical care (other than per protocol RDV 
administration)
Room Air
7
Not hospitalized
Discharge
17) Censoring rules for competing risk analysis
•
Time to ≥ 2 point improvement and time to ≥ 1 point improvement: if a participant did 
not experience the event of interest and did not die, the participant was censored at the 
last non-missing assessment date. Participants who died were considered to have 
experienced a competing event.
•
Time to recovery: Participants not achieving recovery at the last assessment were 
censored on the day of the last assessment. Participants who died were considered to have 
experienced a competing event.
•
Time to discharge from hospital: Participants not discharge at the last assessment were 
censored on the day of the last clinical assessment. Participants who died were considered 
to have experienced a competing event.
18) Details on the LOQ and LOD for the viral load samples are provided below.
Table 13-3.
Viral Load Sample Details
Sample type
Limit of quantitation 
(copies/mL)
Limit of detection 
(copies/mL)
Nasal/oropharyngeal samples
Nasopharyngeal/oropharyngeal samples
ET aspirates
1018
925
Rectal or fecal swabs
488
306


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19) Quantitative and categorical summary on SARS-CoV2 results and change from baseline in 
SARS-CoV-2 viral load up to Day 10 or up to the first confirmed negative PCR result 
(whichever comes first)
•
For quantitative summary (e.g., mean viral load, change from baseline etc.), 
“Inconclusive” SARS-CoV2 result is set to missing
•
For categorical SARS-CoV2 summary, 3 categories will be included, i.e. Positive, 
Inconclusive, Negative
Positive = Any numeric result or “< 1018cp/mL SARS-CoV-2 detected” (for 
Nasal/oropharyngeal samples, Nasopharyngeal/oropharyngeal samples, or ET 
aspirates) or “< 488cp/mL SARS-CoV-2 detected” (for rectal or fecal swabs)
Negative = “No SARS-CoV2 detected”
Inconclusive = “Inconclusive”
20) Days to the first confirmed negative PCR result 
•
Categorical SARS-CoV2 and SARS-CoV2 negative summary will be separated out by 
sample type. There will be no combined positive or negative category using 2 or 3 sample 
types.
•
Confirmed negative PCR result is defined as 2 consecutive negative results, or negative at 
last available sample for participants who completed or discontinued from study. Notice 
2 negative results from the same day do not equal confirmation.
•
For a negative SARS-CoV2 confirmation, “Inconclusive” SARS-CoV2 result will not be 
considered as missing thus a “Negative” followed by a “Inconclusive” is NOT a 
confirmed negative PCR result.
•
All participants without a confirmed SARS-CoV2 negative result will be censored on the 
last day with available PCR test results. 


GS-US-540-5823_SAP_v1.0_Final_Cohorts_1_to_8
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
22-May-2023
11:23:50
Global Development
Lead (GDL) eSigned
22-May-2023
18:13:26
Clinical Pharmacology
eSigned
24-May-2023
14:33:01
PPD
PPD
PPD