A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults
Phase: PHASE3
Conditions: COVID-19
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and 
Efficacy of Investigational Therapeutics for the Treatment of COVID-19  
in Hospitalized Adults  
 
 
Short Title: Adaptive COVID-19 Treatment Trial (ACTT) 
 
 
 
DMID Protocol Number: 20-0006 
 
Sponsor:  
Division of Microbiology and Infectious Diseases (DMID), 
National Institute of Allergy and Infectious Diseases,  
National Institutes of Health 
 
Version Number: 3.0 
 
2 April 2020 
 
 
 
 

Protocol 20-0006 
Version 3.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
2 April 2020 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 2 of 65 
STATEMENT OF COMPLIANCE 
Each institution engaged in this research will hold a current Federalwide Assurance (FWA) 
issued by the Office of Human Research Protection (OHRP) for federally funded research. The 
Institutional Review Board (IRB)/Independent or Institutional Ethics Committee (IEC) must be 
registered with OHRP as applicable to the research.  
 
The study will be carried out in accordance with the following as applicable: 
• All National and Local Regulations and Guidance applicable at each site 
• The International Council for Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH) E6(R2) Good Clinical Practice, and the 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects 
of Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• United States (US) Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of 
Human Subjects 
• US Food and Drug Administration (FDA) Regulations: 21 CFR Part 50 (Protection of 
Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 
CFR Part 56 (IRBs), 21 CFR Part 11, and 21 CFR Part 312 (Investigational New Drug 
Application), and/or 21 CFR 812 (Investigational Device Exemptions) 
• The policies and procedures of National Institutes of Health (NIH) Office of Extramural 
Research and Division of Microbiology and Infectious Diseases (DMID) 
 
The signature below provides the necessary assurance that this study will be conducted 
according to all stipulations of the protocol including statements regarding confidentiality, and 
according to local legal and regulatory requirements, US federal regulations, and ICH E6(R2) 
GCP guidelines. 
 
Site Investigator Signature: 
 
 
Signed: 
 
Date: 
 
 
Name and Title 
 
 
 
 

Protocol 20-0006 
Version 3.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
2 April 2020 
DMID/NIAID/NIH 
CONFIDENTIAL 
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TABLE OF CONTENTS 
 
STATEMENT OF COMPLIANCE ................................................................................................ 2 
TABLE OF CONTENTS ................................................................................................................ 3 
LIST OF TABLES .......................................................................................................................... 5 
LIST OF FIGURES ........................................................................................................................ 6 
1. 
PROTOCOL SUMMARY ...................................................................................................... 7 
1.1 
Synopsis .......................................................................................................................... 7 
1.2 
Schedule of Assessments .............................................................................................. 13 
1.3 
Study Schema................................................................................................................ 14 
2. 
INTRODUCTION ................................................................................................................ 14 
2.1 
Study Rationale ............................................................................................................. 14 
2.2 
Background ................................................................................................................... 14 
2.2.1 
Purpose of Study ................................................................................................... 14 
2.2.2 
Potential Therapeutics ........................................................................................... 15 
2.3 
Risk/Benefit Assessment .............................................................................................. 15 
2.3.1 
Known Potential Risks .......................................................................................... 15 
2.3.2 
Potential Risks of Remdesivir ............................................................................... 16 
2.3.3 
Known Potential Benefits ..................................................................................... 17 
2.3.4 
Assessment of Potential Risks and Benefits ......................................................... 17 
3. 
OBJECTIVES AND ENDPOINTS ...................................................................................... 17 
4. 
STUDY DESIGN.................................................................................................................. 20 
4.1 
Overall Design .............................................................................................................. 20 
4.2 
Scientific Rationale for Study Design........................................................................... 21 
4.3 
Justification for Dose .................................................................................................... 22 
5. 
STUDY POPULATION ....................................................................................................... 22 
5.1 
Inclusion Criteria .......................................................................................................... 22 
5.2 
Exclusion Criteria ......................................................................................................... 23 
5.2.1 
Exclusion of Specific Populations ........................................................................ 23 
5.3 
Inclusion of Vulnerable Subjects .................................................................................. 24 
5.4 
Lifestyle Considerations ............................................................................................... 24 
5.5 
Screen Failures .............................................................................................................. 24 
5.6 
Strategies for Recruitment and Retention ..................................................................... 25 
5.6.1 
Recruitment ........................................................................................................... 25 
5.6.2 
Retention ............................................................................................................... 25 
5.6.3 
Compensation Plan for Subjects ........................................................................... 25 
5.6.4 
Costs ...................................................................................................................... 25 
6. 
STUDY PRODUCT.............................................................................................................. 25 

Protocol 20-0006 
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CONFIDENTIAL 
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6.1 
Study Product(s) and Administration – GS-5734 (Remdesivir) and placebo ............... 25 
6.1.1 
Study Product Description .................................................................................... 25 
6.1.2 
Dosing and Administration ................................................................................... 26 
6.1.3 
Dose Escalation ..................................................................................................... 26 
6.1.4 
Dose Modifications ............................................................................................... 26 
6.1.5 
Overdosage ........................................................................................................... 26 
6.2 
Preparation/Handling/Storage/Accountability .............................................................. 27 
6.2.1 
Acquisition and Accountability ............................................................................ 27 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................ 27 
6.2.3 
Product Storage and Stability................................................................................ 28 
6.2.4 
Preparation ............................................................................................................ 28 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................... 29 
6.4 
Study Intervention Compliance .................................................................................... 29 
6.5 
Concomitant Therapy.................................................................................................... 29 
6.5.1 
Rescue Medicine ................................................................................................... 30 
6.5.2 
Non-Research Standard of Care............................................................................ 30 
7. 
STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL..................................................................................... 30 
7.1 
Halting Criteria and Discontinuation of Study Intervention ......................................... 30 
7.1.1 
Individual Infusion Halting ................................................................................... 30 
7.1.2 
Study Halting ........................................................................................................ 31 
7.2 
Withdrawal from the Study ........................................................................................... 31 
7.3 
Lost to Follow-Up ......................................................................................................... 31 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 31 
8.1 
Screening and Efficacy Assessments ............................................................................ 31 
8.1.1 
Screening Procedures ............................................................................................ 31 
8.1.2 
Efficacy Assessments............................................................................................ 33 
8.1.3 
Exploratory assessments ....................................................................................... 35 
8.2 
Safety and Other Assessments ...................................................................................... 36 
8.2.1 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings .................................................................................................. 38 
8.2.2 
Unscheduled Visits ............................................................................................... 38 
8.3 
Adverse Events and Serious Adverse Events ............................................................... 38 
8.3.1 
Definition of Adverse Event (AE) ........................................................................ 38 
8.3.2 
Definition of Serious Adverse Event (SAE) ......................................................... 39 
8.3.3 
Suspected Unexpected Serious Adverse Reactions (SUSAR).............................. 39 
8.3.4 
Classification of an Adverse Event ....................................................................... 39 
8.3.5 
Time Period and Frequency for Event Assessment and Follow-Up ..................... 40 
8.3.6 
Serious Adverse Event Reporting ......................................................................... 41 
8.3.7 
Reporting of Pregnancy ........................................................................................ 42 
8.4 
Unanticipated Problems ................................................................................................ 42 
8.4.1 
Definition of Unanticipated Problems .................................................................. 42 
8.4.2 
Unanticipated Problem Reporting......................................................................... 42 
9. 
STATISTICAL CONSIDERATIONS.................................................................................. 42 

Protocol 20-0006 
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2 April 2020 
DMID/NIAID/NIH 
CONFIDENTIAL 
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9.1 
Statistical Hypotheses ................................................................................................... 43 
9.2 
Sample Size Determination........................................................................................... 43 
9.3 
Populations for Analyses .............................................................................................. 47 
9.4 
Statistical Analyses ....................................................................................................... 47 
9.4.1 
General Approach ................................................................................................. 47 
9.4.2 
Analysis of the Primary Efficacy Endpoint .......................................................... 47 
9.4.3 
Analysis of the Secondary Endpoint(s)................................................................. 47 
9.4.4 
Safety Analyses ..................................................................................................... 48 
9.4.5 
Baseline Descriptive Statistics .............................................................................. 48 
9.4.6 
Planned Interim and Early Analyses ..................................................................... 48 
9.4.7 
Sub-Group Analyses ............................................................................................. 49 
9.4.8 
Exploratory Analyses ............................................................................................ 49 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ... 50 
10.1 
Regulatory, Ethical, and Study Oversight Considerations............................................ 50 
10.1.1 
Informed Consent Process .................................................................................... 50 
10.1.2 
Study Termination and Closure ............................................................................ 52 
10.1.3 
Confidentiality and Privacy .................................................................................. 52 
10.1.4 
Secondary Use of Stored Specimens and Data ..................................................... 53 
10.1.5 
Key Roles and Study Governance ........................................................................ 53 
10.1.6 
Safety Oversight.................................................................................................... 53 
10.1.7 
Clinical Monitoring ............................................................................................... 54 
10.1.8 
Data Handling and Record Keeping ..................................................................... 54 
10.1.9 
Protocol Deviations ............................................................................................... 56 
10.1.10 Publication and Data Sharing Policy .................................................................... 56 
10.1.11 Human Data Sharing Plan ..................................................................................... 56 
10.1.12 Publication ............................................................................................................ 57 
10.1.13 Conflict of Interest Policy ..................................................................................... 57 
10.2 
Additional Considerations ............................................................................................ 57 
10.2.1 
Research Related Injuries ..................................................................................... 57 
10.3 
Abbreviations ................................................................................................................ 57 
10.4 
Protocol Amendment History ....................................................................................... 59 
11. 
REFERENCES ................................................................................................................. 62 
 
LIST OF TABLES 
Table 1. Schedule of Assessments (SOA) .................................................................................... 13 
Table 2. National Early Warning Score (NEWS) ......................................................................... 34 
Table 3. Venipuncture Volumes1 .................................................................................................. 38 
Table 4 Power under different rate ratios and probabilities of recovering by 28 days. ................ 43 
Table 5. Possible scenarios for the distribution of ordinal outcomes for the control arm at Day 15.
....................................................................................................................................................... 45 
Table 6. Sample size calculations for scenarios in Table 5 for a two-arm study assuming 85% 
power, a two-sided type I error rate of 5%, and various true odds ratios. .................................... 45 
Table 7. Treatment ordinal outcome proportions under an odds ratio of 1.75 for five scenarios in
....................................................................................................................................................... 46 

Protocol 20-0006 
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2 April 2020 
DMID/NIAID/NIH 
CONFIDENTIAL 
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LIST OF FIGURES 
No table of figures entries found. 
 

Protocol 20-0006 
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2 April 2020 
DMID/NIAID/NIH 
CONFIDENTIAL 
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1. PROTOCOL SUMMARY 
1.1 Synopsis 
Rationale for Proposed Clinical Study 
In December 2019, the Wuhan Municipal Health Committee identified an outbreak of viral 
pneumonia cases of unknown cause. Coronavirus RNA was quickly identified in some of these 
patients. This novel coronavirus has been designated severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2), and the disease caused by this virus has been designated 
Coronavirus Disease 2019 (COVID-19). There were 59 confirmed cases on January 5, 2020, 278 
cases on January 20, 2020, rising to more than 318,000 confirmed cases and 13,000 deaths as of 
March 22, 2020 according to various international health reporting agencies. Currently there are 
no approved therapeutic agents available for coronaviruses.  
 
Study Design 
This study is an adaptive, randomized, double-blind, placebo-controlled trial to evaluate the 
safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. 
The study is a multicenter trial that will be conducted in up to approximately 100 sites globally. 
The study will compare different investigational therapeutic agents to a control arm. There will 
be interim monitoring to introduce new arms and allow early stopping for futility, efficacy, or 
safety. If one therapy proves to be efficacious, then this treatment may become the control arm 
for comparison(s) with new experimental treatment(s). Any such change would be accompanied 
by an updated sample size. Because background standards of supportive care may 
evolve/improve over time as more is learned about successful management of COVID-19, 
comparisons of safety and efficacy will be based on data from concurrently randomized subjects. 
An independent Data and Safety Monitoring Board (DSMB) will actively monitor interim data to 
make recommendations about early study closure or changes to study arms.  
 
The initial sample size is projected to be 572 subjects to achieve 400 subjects with a “recovered” 
status (per the primary objective). The primary analysis will be based on those subjects enrolled 
in order to 400 recoveries.  An additional analysis of the moderate severity subgroup (those with 
baseline status of “Hospitalized, requiring supplemental oxygen” or “Hospitalized, not requiring 
supplemental oxygen - requiring ongoing medical care”)  is also of public health importance. 
Hence, enrollment will be permitted until the date of April 20, 2020 to ensure 400 recoveries and 
provide additional data about this important subgroup. With recent enrollment rates, the total 
sample size may be 600 to over 800.  
 
Subjects will be assessed daily while hospitalized. If the subjects are discharged from the 
hospital, they will have a study visit at Days 15, 22, and 29 as an outpatient. For discharged 
subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory 
tests and OP swab and blood (serum only) samples for secondary research as well as clinical 
outcome data. However, infection control or other restrictions may limit the ability of the subject 
to return to the clinic. In this case, Day 15 and 29 visits may be conducted by phone, and only 
clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of 
samples and may also be conducted by phone.  
 

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All subjects will undergo a series of efficacy, safety, and laboratory assessments. Safety 
laboratory tests and blood (serum and plasma) research samples and oropharyngeal (OP) swabs 
will be obtained on Days 1 (prior to infusion) and Days 3, 5, 8, and 11 (while hospitalized). OP 
swabs and blood (serum only) plus safety laboratory tests will be collected on Day 15 and 29 (if 
the subject attends an in-person visit or are still hospitalized).  
 
The primary outcome is time to recovery by Day 29 (see table below for definition based on the 
ordinal scale). A key secondary outcome evaluates treatment-related improvements in the 8-point 
ordinal scale at Day 15. As little is known about the clinical course of COVID-19, a pilot study 
will be used for a blinded sample size reassessment (see section 9 for more details).  
 
Study Objectives  
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
Primary 
 
To evaluate the clinical efficacy, as assessed 
by time to recovery, of different 
investigational therapeutics as compared to 
the control arm. 
Day of recovery is defined as the first day on 
which the subject satisfies one of the 
following three categories from the ordinal 
scale: 
• Hospitalized, not requiring supplemental 
oxygen - no longer requires ongoing 
medical care; 
• Not hospitalized, limitation on activities 
and/or requiring home oxygen; 
• Not hospitalized, no limitations on 
activities. 
Recovery is evaluated up until Day 29. 
Key Secondary 
 
To evaluate the clinical efficacy of different 
investigational therapeutics relative to the 
control arm in adults hospitalized with 
COVID-19 according to clinical status (8-
point ordinal scale) at Day 15 
 
 
 
• Death; 
• Hospitalized, on invasive mechanical 
ventilation or ECMO; 
• Hospitalized, on non-invasive ventilation 
or high flow oxygen devices; 
• Hospitalized, requiring supplemental 
oxygen; 
• Hospitalized, not requiring supplemental 
oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 
• Hospitalized, not requiring supplemental 
oxygen - no longer requires ongoing 
medical care; 
• Not hospitalized, limitation on activities 
and/or requiring home oxygen; 
• Not hospitalized, no limitations on 
activities. 
Additional Secondary  
 

Protocol 20-0006 
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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
1. To evaluate the clinical efficacy of 
different investigational therapeutics as 
compared to the control arm as assessed by: 
• Clinical Severity 
o Ordinal scale: 
 Time to an improvement of one 
category and two categories from 
Day 1 (baseline) using an ordinal 
scale. 
 Subject clinical status using ordinal 
scale at Days 3, 5, 8, 11, 15, 22, and 
29.  
 Mean change in the ordinal scale 
from Day 1 to Days 3, 5, 8, 11, 15, 
22, and 29. 
 
 
 
 
• Clinical outcome assessed using ordinal 
scale daily while hospitalized and on Days 
15, 22, and 29. 
 
 
 
 
 
 
 
o National Early Warning Score 
(NEWS): 
 Time to discharge or to a NEWS of 
≤ 2 and maintained for 24 hours, 
whichever occurs first.  
 Change from Day 1 to Days 3, 5, 8, 
11, 15, and 29 in NEWS.  
 
 
 
• NEWS assessed daily while hospitalized 
and on Days 15 and 29. 
o Oxygenation: 
 Oxygenation use up to Day 29. 
 Incidence and duration of new 
oxygen use during the study. 
 
 
• Days of supplemental oxygen (if 
applicable) up to Day 29 
 
o Non-invasive ventilation/high flow 
oxygen: 
 Non-invasive ventilation/high flow 
oxygen use up to Day 29. 
 Incidence and duration of new non-
invasive ventilation or high flow 
oxygen use during the study. 
 
• Days of non-invasive ventilation/high 
flow oxygen (if applicable) up to Day 29 
o Invasive Mechanical Ventilation / 
extracorporeal membrane oxygenation 
(ECMO): 
 Ventilator / ECMO use up to Day 
29. 
 
• Days of invasive mechanical 
ventilation/ECMO (if applicable) up to 
Day 29. 
 

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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
 Incidence and duration of new 
mechanical ventilation or ECMO use 
during the study.  
 
• Hospitalization 
o Duration of hospitalization (days).  
 
 
• Days of hospitalization up to Day 29 
• Mortality 
o 14-day mortality 
o 29-day mortality 
 
 
• Date and cause of death (if applicable) 
 
2. To evaluate the safety of different 
investigational therapeutics as compared to 
the control arm as assessed by: 
• Cumulative incidence of SAEs through 
Day 29. 
• Cumulative incidence of Grade 3 and 4 
clinical and/or laboratory AEs through 
Day 29. 
• Discontinuation or temporary 
suspension of infusions (for any reason) 
• Changes in white blood cell (WBC) 
count with differential, hemoglobin, 
platelets, creatinine, glucose, total 
bilirubin, alanine aminotransferase 
(ALT), aspartate aminotransferase 
(AST), and prothrombin time (PT) over 
time (analysis of lab values in addition 
to AEs noted above). 
 
 
 
• SAEs 
• Grade 3 and 4 AEs  
• WBC with differential, hemoglobin, 
platelets, creatinine, glucose, total 
bilirubin, ALT, AST, and PT on Day 1; 
Days 3, 5, 8, and 11 (while hospitalized); 
and Days 15 and 29 (if attends in-person 
visit or still hospitalized). 
 
Exploratory  
 
To evaluate the virologic efficacy of different 
investigational therapeutics as compared to 
the control arm as assessed by: 
• Percent of subjects with SARS-CoV-2 
detectable in OP sample at Days 3, 5, 
8, 11, 15, and 29.  
• Quantitative SARS-CoV-2 virus in OP 
sample at Days 3, 5, 8, 11, 15, and 29. 
• Development of resistance of SARS-
CoV-2 in OP sample at Days 3, 5, 8, 
11, 15, and 29.  
• Quantitative SARS-CoV-2 virus in 
blood at Days 3, 5, 8, and 11. 
 
 
 
 
• Qualitative and quantitative polymerase 
chain reaction (PCR) for SARS-CoV-2 in 
OP swab on Day 1; Days 3, 5, 8, and 11 
(while hospitalized); and Days 15 and 29 
(if attends in-person visit or still 
hospitalized). 
• Qualitative and quantitative PCR for 
SARS-CoV-2 in blood on Day 1; Days 3, 
5, 8, and 11 (while hospitalized). 

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Inclusion Criteria 
1. Admitted to a hospital with symptoms suggestive of COVID-19 infection. 
2. Subject (or legally authorized representative) provides informed consent prior to 
initiation of any study procedures. 
3. Subject (or legally authorized representative) understands and agrees to comply with 
planned study procedures. 
4. Male or non-pregnant female adult ≥18 years of age at time of enrollment. 
5. Has laboratory-confirmed SARS-CoV-2 infection as determined by PCR or other 
commercial or public health assay in any specimen, as documented by either of the 
following:  
• PCR positive in sample collected < 72 hours prior to randomization; OR 
• PCR positive in sample collected ≥ 72 hours prior to randomization, documented 
inability to obtain a repeat sample (e.g. due to lack of testing supplies, limited 
testing capacity, results taking > 24 hours, etc.). AND progressive disease 
suggestive of ongoing SARS-CoV-2 infection. 
6. Illness of any duration, and at least one of the following: 
• Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR 
• SpO2 ≤ 94% on room air, OR 
• Requiring supplemental oxygen, OR 
• Requiring mechanical ventilation. 
7. Women of childbearing potential must agree to either abstinence or use at least one 
primary form of contraception not including hormonal contraception from the time of 
screening through Day 29.  
8. Agrees to not participate in another clinical trial for the treatment of COVID-19 or 
SARS-CoV-2 through Day 29. 
 
Exclusion Criteria 
1. ALT or AST > 5 times the upper limit of normal. 
2. Estimated glomerular filtration rate (eGFR) < 30 ml/min (including patients receiving 
hemodialysis or hemofiltration). 
3. Pregnancy or breast feeding. 
4. Anticipated discharge from the hospital or transfer to another hospital which is not a 
study site within 72 hours. 
5. Allergy to any study medication. 
 
Study Phase 
• Phase 3 
 
Study Population 
Hospitalized adults (≥18 years old) with COVID-19. 
 
Study Sites 

Protocol 20-0006 
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There will be up to approximately 100 sites globally. Site selection will be determined as 
information becomes available about the epidemiology of COVID-19. Multiple sites will be 
IRB-approved, but site activation will be dependent on the incidence of COVID-19 at the site.  
 
Study Intervention 
The study is designed to evaluate multiple interventions. Investigational therapeutics will be 
assessed for their incorporation into the trial based on in vitro and preclinical in vivo data. 
 
Initially, the trial will have two arms and subjects will be randomized to receive either active 
product or placebo as follows:  
• Remdesivir will be administered as a 200 mg intravenous (IV) loading dose on Day 1, 
followed by a 100 mg once-daily IV maintenance dose for the duration of the 
hospitalization up to a 10-day total course.  
• A placebo will be given at an equal volume at the same schedule.  
 
The study will randomize subjects 1:1 to placebo or investigational product. If additional arms 
are added to or dropped from the trial, randomization will proceed with an equal probability of 
assignment to each of the remaining arms. As new interventions are added, the protocol will be 
amended and reviewed by IRB/IEC and applicable regulatory agencies before implementation. 
The current protocol, however, does lay out the general principles of how the multi-intervention 
trial would be implemented.  
 
Study Duration 
The study will last for up to 3 years.  
 
Participant Duration 
An individual subject will complete the study in about 29 days, from screening at Day -1 or 1 to 
follow-up on Day 29 ± 3 days.  
 
Safety 
• Given the potential severity of COVID-19 and limited information about the expected 
clinical course, there are no pre-specified study stopping rules (except as noted under 
DSMB). A subset of the protocol team will review blinded pools of Grade 3 and 4 AE / 
SAE data every 2 weeks. If there is a pattern of unexpected AEs that is out of proportion 
to the current understanding of the natural history of the disease, the DSMB will be asked 
to review unblinded safety data in an ad hoc meeting. 
• The DSMB will have access to safety data electronically after every 50 subjects and will 
have formal safety/efficacy reviews after approximately 200 subjects have met recovered 
status.  Additionally, the DSMB will be available for ad hoc reviews for safety concerns 
as described above. The study will not stop enrollment awaiting these DSMB reviews, 
though the DSMB may recommend temporary or permanent cessation of enrollment 
based on their safety reviews. 
  
 
 

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1.2 Schedule of Assessments 
Table 1. Schedule of Assessments (SOA) 
  
Screen 
Baseline  Study Intervention Period 
Follow-up Visits  
Day +/- Window 
−1 or 1 
1 
Daily until hospital 
discharge 
157  
± 2 
227 
± 3 
297 
± 3 
ELIGIBILITY 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Demographics & Medical History 
X 
 
 
 
 
 
Targeted physical exam 
X 
 
 
 
 
 
Review SARS-CoV-2 results 
X 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Administration of remdesivir or 
control 
 
Daily until discharge or 10 days. No 
study product given after Day 10. 
 
 
 
 
 
 
 
 
 
STUDY PROCEDURES 
 
 
 
 
 
 
Vital signs including SpO2 
 
X4 
Daily until discharge 
X7 
 
X7 
Clinical data collection1  
 
X4 
Daily until discharge 
X7 
X7 
X7 
Adverse event evaluation 
 
X4 
Daily until discharge 
X7 
X7 
X7 
Concomitant medication review 
 
X4 
From Day -7 to Day 11 
 
 
 
 
 
 
 
 
 
 
SAFETY LABORATORY 
 
 
 
 
 
 
Safety hematology, chemistry and 
liver tests 
X2,3 
X4,5,6 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized5,6 
X7 
 
X7 
Pregnancy test for females of 
childbearing potential 
X2,3 
 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH LABORATORY  
 
 
 
 
 
 
Blood for plasma to test for PCR 
SARS-CoV-2 
 
X5 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
 
 
 
Oropharyngeal swab 8 
 
X5 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
X7 
 
X7 
Blood for serum (secondary 
research) 
 
X5 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
X7 
 
X7 
Notes: 
1 Refer to Section 8.1 of the protocol for details of clinical data to be collected including ordinal score, NEWS, oxygen requirement, mechanical ventilator 
requirement, etc. 
2 Screening laboratory tests include: ALT, AST, creatinine (and calculate an estimated glomerular filtration rate (eGFR) the formula used is determined by 
the sites, but should be consistent throughout the study), and pregnancy test.  
3 Laboratory tests performed in the 48 hours prior to enrollment will be accepted for determination of eligibility. 
4 Baseline assessments should be performed prior to first infusion. Laboratory tests performed as part of routine clinical care in the 24 hours prior to first 
dose will be accepted for the baseline safety laboratory tests. Baseline may be the same as the screening laboratory tests.  
5Safety laboratory tests include WBC with differential, hemoglobin, platelets, creatinine, glucose, total bilirubin, ALT, AST, and PT. 
6 Any laboratory tests performed as part of routine clinical care within the specified visit window can be used for safety laboratory testing. Window during 
the 10 days of dosing is ±1 day. 
7 In-person visits are preferred but recognizing quarantine and other factors may limit the subject’s ability to return to the site for the visit. In this case, the 
visit may be performed by phone. 
• 
If still hospitalized at Day 15 and 29 or returns to the site for an in-person visit: Clinical data, vital signs, safety laboratory tests, and research 
laboratory samples (OP swab and serum only) as able.  
• 
If phone call only on Days 15 and 29 and all Day 22 visits: assess adverse events, clinical status (ordinal scale), readmission to a hospital, and 
mortality only. 
8 Oropharyngeal swabs are preferred, but if these are not obtainable, nasopharyngeal swabs may be substituted.  

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1.3 Study Schema 
 
 
2. INTRODUCTION 
2.1 Study Rationale 
COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes 
substantial morbidity and mortality. There is currently no vaccine to prevent infection with 
SARS-CoV-2 or therapeutic agent to treat COVID-19. This clinical trial is designed to evaluate 
investigational therapeutics for the treatment of adults hospitalized with COVID-19. 
2.2 Background 
2.2.1 
Purpose of Study 
Coronavirus (CoVs) are positive-sense, single stranded, enveloped RNA viruses, many of which 
are commonly found in humans and cause mild symptoms. Over the past two decades, emerging 
pathogenic CoVs capable of causing life-threatening disease in humans and animals have been 
identified, namely, severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002-2003 
and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012.  
 
In December 2019, the Wuhan Municipal Health Committee (Wuhan, China) identified an 
outbreak of viral pneumonia cases of unknown cause. Coronavirus RNA was quickly identified in 
some of these patients. This novel coronavirus has been designated as SARS-COV-2 and has 89% 
nucleotide identity with bat SARS-like-CoVZXC21 and 82% with that of human SARS-CoV (1). 
The human disease caused by SARS-CoV-2 has been designated COVID-19. In most (~80%) 
cases, COVID-19 presents as a mild-to-moderately severe, self-limited acute respiratory illness 
with fever, cough, and shortness of breath. Symptoms are thought to appear 2 to 14 days after 
exposure. COVID-19 can be severe, resulting in pneumonia, severe acute respiratory syndrome, 
kidney failure, and death. The first US COVID-19 death occurred on February 29, 2020. 

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During this COVID-19 outbreak, the incidence of cases has rapidly increased such that on January 
5, 2020 there were 59 confirmed cases, 278 cases on January 20, 2020, and more than 318,000 
cases and 13,000 deaths as of March 22, 2020 according to various international health reporting 
agencies. As a result, on January 30, 2020, the International Health Regulations Emergency 
Committee of the World Health Organization (WHO) declared the COVID-19 outbreak a Public 
Health Emergency of International Concern. On January 31, 2020, the US Department of Health 
and Human Services declared a public health emergency in the United States. On March 11, 2020, 
the WHO declared the COVID-19 outbreak a pandemic.  Outbreak forecasting and modeling 
suggest that these numbers will continue to rise (2).  
 
Global efforts to evaluate novel antivirals and therapeutic interventions to treat COVID-19 have 
intensified. There is currently no vaccine to prevent SARS-CoV-2 infection or therapeutic agent 
to treat COVID-19. Therefore, there is an urgent public health need for rapid development of 
novel interventions.  
 
2.2.2 
Potential Therapeutics 
Remdesivir (GS-5734) is a broad-spectrum nucleotide prodrug that inhibits RNA-dependent 
RNA polymerase activity among a diverse group of RNA viruses including filoviruses (e.g. 
Ebola, Sudan, Marburg), paramyxoviruses (e.g., RSV, Nipah, Hendra) and pathogenic 
coronaviruses (3-5). Multiple nonhuman primate studies demonstrated the therapeutic efficacy of 
remdesivir against Ebola virus (4, 5). Remdesivir was used in a randomized clinical trial for 
Ebola (the PALM study) (6). While remdesivir was demonstrated to be inferior to investigational 
treatment with monoclonal antibodies MAb114 and REGN-EB3 in the PALM study, the lack of 
a control arm limits interpretation of the clinical efficacy of remdesivir. Studies in human airway 
epithelial cell assays demonstrated that remdesivir inhibits replication of coronaviruses, 
including MERS-CoV (7). In mouse infection models, remdesivir had therapeutic efficacy 
against SARS-CoV and MERS-CoV (7,8). In vitro studies with mouse hepatitis virus (a murine 
coronavirus) found that remdesivir inhibits coronavirus replication through interference with the 
viral polymerase, despite the presence of a viral proofreading exoribonuclease (9). In that study, 
coronaviruses that were partially resistant to inhibition by remdesivir were still sensitive to 
higher concentrations of remdesivir, and fitness was impaired in the resistant viruses as 
compared to wild-type MERS-CoV. In a recent non-human primate study, therapeutic remdesivir 
treatment initiated 12 hours post inoculation with MERS-CoV provided clinical benefit with a 
reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and 
severity of lung lesions (10,11). These nonclinical data suggest that remdesivir might be useful 
for the treatment of COVID-19 for which no medical countermeasures are currently approved, 
and support testing the efficacy of remdesivir treatment in hospitalized adults with COVID-19 
(12). 
2.3 Risk/Benefit Assessment 
2.3.1 
Known Potential Risks 
Potential risks of participating in this trial are those associated with having blood drawn, the IV 
catheterization, possible reactions to remdesivir (as noted in Section 2.3.2), and breach of 
confidentiality. 

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Drawing blood may cause transient discomfort and fainting. Fainting is usually transient and 
managed by having the subject lie down and elevate his/her legs. Bruising at the blood collection 
sites may occur but can be prevented or lessened by applying pressure to the blood draw site for 
a few minutes after the blood is taken. IV catheterization may cause insertion site pain, phlebitis, 
hematoma formation, and infusate extravasation; less frequent but significant complications 
include bloodstream and local infections. The use of aseptic (sterile) technique will make 
infection at the site where blood will be drawn or at catheter site less likely. 
 
Risks to Privacy 
Subjects will be asked to provide personal health information (PHI). All attempts will be made to 
keep this PHI confidential within the limits of the law. However, there is a chance that 
unauthorized persons will see the subject’s PHI. All study records will be kept in a locked file 
cabinet or maintained in a locked room at the participating clinical site. Electronic files will be 
password protected. Only people who are involved in the conduct, oversight, monitoring, or 
auditing of this trial will be allowed access to the PHI that is collected. Any publication from this 
trial will not use information that will identify subjects. Organizations that may inspect and/or 
copy research records maintained at the participating site for quality assurance and data analysis 
include groups such as the IRB, NIAID and applicable regulatory agencies (e.g., FDA). For more 
information about confidentiality and privacy see Section 10.1.3. 
 
For each new therapeutic agent under investigation, findings from the preclinical and clinical 
studies will be briefly described in this section and a summary of the findings described in the 
Investigator Brochure (IB) will be in an appendix.  
 
2.3.2 
Potential Risks of Remdesivir 
Remdesivir is an investigational therapeutic agent. As of February 14, 2020, 138 healthy adults 
have been dosed with remdesivir in four Phase 1 clinical trials. Few subjects to date experienced 
constipation, heartburn, itching, unusual feelings in the ear, dizziness, loss of appetite, nausea, 
vomiting, shaking of the leg and arm, headache, loose stool, or upset stomach. These AEs were 
temporary, lasting only a few days, and none were serious. In clinical studies, transient 
elevations in ALT and AST have been observed with single doses of remdesivir up to 225 mg 
and multiple once daily doses of remdesivir 150 mg for up to 14 days. Mild (Grade 1) reversible 
PT prolongation was also noted in some subjects but without any clinically significant change in 
INR or other evidence of hepatic effects. The mechanism of these elevations is currently 
unknown. Based on these clinical observations, patients with ALT or AST >5 times the upper 
limit of normal will not be eligible for study enrollment. Regular laboratory assessments will be 
performed in order to monitor hepatic function and PT. Any observed liver function-related 
laboratory abnormalities or possibly related AEs will be treated appropriately and followed to 
resolution.  
 
In nonclinical animal studies, toxicity studies found dose-dependent and reversible kidney injury 
and dysfunction. In clinical studies, no evidence of nephrotoxicity has been observed with single 
doses of remdesivir up to 225 mg or multiple once daily doses of remdesivir 150 mg for up to 14 
days. A 150-mg dose of the solution and lyophilized formulations of remdesivir contains 9 g and 
4.5 g, respectively, of sulfobutylether-beta-cyclodextrin (SBECD), for which the maximum daily 

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recommended daily dose (based on a European Medicines Agency (EMA) safety review) is 
approximately 250 mg/kg. Because SBECD is renally cleared, subjects with moderate or severe 
renal impairment may have SBECD exposures greater than those with less severe renal 
impairment or normal renal function. Based on this information, patients with an estimated 
glomerular filtration rate (eGFR) of less than 30 ml/min (including subjects requiring 
hemodialysis or hemofiltration) will not be eligible for study enrollment. 
 
Remdesivir is a substrate for CYP2C8, CYP2D6, and CYP3A4. However, coadministration with 
inhibitors of these CYP isoforms is unlikely to markedly increase remdesivir levels, as its 
metabolism is likely to be predominantly mediated by hydrolase activity. See IB for full 
discussion of clinical experience and risks.  
 
There is the potential of the SARS-CoV-2 developing resistance to remdesivir, which could 
result in decreased efficacy. The clinical impact of the development of resistance is not clear at 
this time.  
 
In vitro induction studies have demonstrated that a clinically relevant interaction with 
contraceptive steroids is considered to be of limited clinical significance. Therefore, the use of 
hormonal contraception with remdesivir is not recommended as the sole method for preventing 
pregnancy. 
 
2.3.3 
Known Potential Benefits 
Remdesivir may or may not improve the clinical outcome of an individual subject with COVID-
19 who participates in this trial. However, there is potential benefit to society from their 
participation in this study resulting from insights gained about the therapeutic agent under study 
as well as the natural history of the disease. While there may not be benefits for an individual 
subject, there may be benefits to society if a safe, efficacious therapeutic agent can be identified 
during this global COVID-19 outbreak.  
 
2.3.4 
Assessment of Potential Risks and Benefits 
Remdesivir is generally a well-tolerated medication. There are liver toxicities that have been 
observed in prior studies. These have been self-limited and resolved after cessation of the 
medication. There is the potential for renal toxicities as observed in pre-clinical data. By excluding 
those with elevated liver transaminases and decreased kidney function (eGFR < 30 ml/min or 
requires hemodialysis or hemofiltration), and appropriate monitoring during the study, we can 
minimize the risk to subjects. While there may not be benefits for an individual subject, there may 
be benefits to society if a safe, efficacious therapeutic agent can be identified during this global 
COVID-19 outbreak. The potential risks therefore are thought to be acceptable given the potential 
benefits.  
3. OBJECTIVES AND ENDPOINTS 
The overall objective of the study is to evaluate the clinical efficacy and safety of different 
investigational therapeutics relative to the control arm among hospitalized adults who have 
COVID-19. 
 

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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
Primary 
 
To evaluate the clinical efficacy, as assessed 
by time to recovery, of different 
investigational therapeutics as compared to 
the control arm. 
Day of recovery is defined as the first day on 
which the subject satisfies one of the 
following three categories from the ordinal 
scale: 
• Hospitalized, not requiring supplemental 
oxygen - no longer requires ongoing 
medical care; 
• Not hospitalized, limitation on activities 
and/or requiring home oxygen; 
• Not hospitalized, no limitations on 
activities. 
Recovery is evaluated up until Day 29. 
Key Secondary 
 
To evaluate the clinical efficacy of different 
investigational therapeutics relative to the 
control arm in adults hospitalized with 
COVID-19 according to clinical status (8-
point ordinal scale) at Day 15 
 
 
 
• Death; 
• Hospitalized, on invasive mechanical 
ventilation or ECMO; 
• Hospitalized, on non-invasive ventilation 
or high flow oxygen devices; 
• Hospitalized, requiring supplemental 
oxygen; 
• Hospitalized, not requiring supplemental 
oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 
• Hospitalized, not requiring supplemental 
oxygen - no longer requires ongoing 
medical care; 
• Not hospitalized, limitation on activities 
and/or requiring home oxygen; 
• Not hospitalized, no limitations on 
activities. 
Additional Secondary  
 
1. To evaluate the clinical efficacy of 
different investigational therapeutics as 
compared to the control arm as assessed by: 
• Clinical Severity 
o Ordinal scale: 
 Time to an improvement of one 
category and two categories from 
Day 1 (baseline) using an ordinal 
scale. 
 
 
 
• Clinical outcome assessed using ordinal 
scale daily while hospitalized and on Days 
15, 22, and 29. 
 
 
 
 
 

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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
 Subject clinical status using ordinal 
scale at Days 3, 5, 8, 11, 15, 22, and 
29.  
 Mean change in the ordinal scale 
from Day 1 to Days 3, 5, 8, 11, 15, 
22, and 29. 
 
 
 
o National Early Warning Score 
(NEWS): 
 Time to discharge or to a NEWS of 
≤ 2 and maintained for 24 hours, 
whichever occurs first.  
 Change from Day 1 to Days 3, 5, 8, 
11, 15, and 29 in NEWS.  
 
 
 
• NEWS assessed daily while hospitalized 
and on Days 15 and 29. 
o Oxygenation: 
 Oxygenation use up to Day 29. 
 Incidence and duration of new 
oxygen use during the study. 
 
 
• Days of supplemental oxygen (if 
applicable) up to Day 29 
 
o Non-invasive ventilation/high flow 
oxygen: 
 Non-invasive ventilation/high flow 
oxygen use up to Day 29. 
 Incidence and duration of new non-
invasive ventilation or high flow 
oxygen use during the study. 
 
• Days of non-invasive ventilation/high 
flow oxygen (if applicable) up to Day 29 
o Invasive Mechanical Ventilation / 
extracorporeal membrane oxygenation 
(ECMO): 
 Ventilator / ECMO use up to Day 
29. 
 Incidence and duration of new 
mechanical ventilation or ECMO use 
during the study.  
 
 
• Days of invasive mechanical 
ventilation/ECMO(if applicable) up to 
Day 29. 
 
• Hospitalization 
o Duration of hospitalization (days).  
 
 
• Days of hospitalization up to Day 29 
• Mortality 
o 14-day mortality 
o 29-day mortality 
 
 
• Date and cause of death (if applicable) 
 

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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
2. To evaluate the safety of different 
investigational therapeutics as compared to 
the control arm as assessed by: 
• Cumulative incidence of SAEs through 
Day 29. 
• Cumulative incidence of Grade 3 and 4 
clinical and/or laboratory AEs through 
Day 29. 
• Discontinuation or temporary 
suspension of infusions (for any reason) 
• Changes in white blood cell (WBC) 
count with differential, hemoglobin, 
platelets, creatinine, glucose, total 
bilirubin, alanine aminotransferase 
(ALT), aspartate aminotransferase 
(AST), and prothrombin time (PT) over 
time (analysis of lab values in addition 
to AEs noted above). 
 
 
 
• SAEs 
• Grade 3 and 4 AEs  
• WBC with differential, hemoglobin, 
platelets, creatinine, glucose, total 
bilirubin, ALT, AST, and PT on Day 1; 
Days 3, 5, 8, and 11 (while hospitalized); 
and Days 15 and 29 (if attends in-person 
visit or still hospitalized). 
 
Exploratory  
 
To evaluate the virologic efficacy of different 
investigational therapeutics as compared to 
the control arm as assessed by: 
• Percent of subjects with SARS-CoV-2 
detectable in OP sample at Days 3, 5, 
8, 11, 15, and 29.  
• Quantitative SARS-CoV-2 virus in OP 
sample at Days 3, 5, 8, 11, 15, and 29. 
• Development of resistance of SARS-
CoV-2 in OP sample at Days 3, 5, 8, 
11, 15, and 29.  
• Quantitative SARS-CoV-2 virus in 
blood at Days 3, 5, 8, and 11. 
 
 
 
 
• Qualitative and quantitative polymerase 
chain reaction (PCR) for SARS-CoV-2 in 
OP swab on Day 1; Days 3, 5, 8, and 11 
(while hospitalized); and Days 15 and 29 
(if attends in-person visit or still 
hospitalized). 
• Qualitative and quantitative PCR for 
SARS-CoV-2 in blood on Day 1; Days 3, 
5, 8, and 11 (while hospitalized). 
  
4. STUDY DESIGN 
4.1 Overall Design 
This study is an adaptive, randomized, double-blind, placebo-controlled trial to evaluate the 
safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. 
The study is a multicenter trial that will be conducted in up to approximately 100 sites globally. 
The study will compare different investigational therapeutic agents to a control arm. There will 
be interim monitoring to allow early stopping for futility, efficacy, or safety. If one therapy 

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proves to be efficacious, then this treatment may become the control arm for comparison(s) with 
new experimental treatment(s). Any such change would be accompanied by an updated sample 
size. Because background standards of supportive care may evolve/improve over time as more is 
learned about successful management of COVID-19, comparisons of safety and efficacy will be 
based on data from concurrently randomized subjects. An independent Data and Safety 
Monitoring Board (DSMB) will actively monitor interim data to make recommendations about 
early study closure or changes to study arms.  
 
The initial sample size is projected to be 572 subjects to achieve 400 subjects with a “recovered” 
status (per the primary objective). The primary analysis will be based on those subjects enrolled 
in order to 400 recoveries.  An additional analysis of the moderate severity subgroup (those with 
baseline status of “Hospitalized, requiring supplemental oxygen” or “Hospitalized, not requiring 
supplemental oxygen - requiring ongoing medical care”)  is also of public health importance. 
Hence, enrollment will be permitted until the date of April 20, 2020 to ensure 400 recoveries and 
provide additional data about this important subgroup. With recent enrollment rates, the total 
sample size may be 600 to over 800.  
 
If any additional therapeutic arms are added, the sample size will be recalculated.  
 
Subjects will be assessed daily while hospitalized. If the subjects are discharged from the 
hospital, they will have a study visit at Days 15, 22, and 29. For discharged subjects, it is 
preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests and OP 
swab and blood (serum only) samples for secondary research as well as clinical outcome data. 
However, infection control or other restrictions may limit the ability of the subject to return to 
the clinic. In this case, these visits may be conducted by phone, and only clinical data will be 
obtained. The Day 22 visit does not have laboratory tests or collection of samples and may also 
be conducted by phone.  
 
The primary outcome is time to recovery by Day 29 (see table below for definition based on the 
ordinal scale). A key secondary outcome evaluates treatment-related improvements in the 8-point 
ordinal scale at Day 15. As little is known about the clinical course of COVID-19, an evaluation 
of the pooled (i.e., blinded to treatment assignment) proportion recovered will be used to gauge 
whether the targeted total number of subjects in the recovered categories of the ordinal scale will 
be achieved with a planned sample size of 572.  The primary analysis will include data from both 
severity groups using a stratified log-rank test. The analysis of the pilot data will be blinded, 
allowing for the pilot data to be included in subsequent analyses.  
 
The study will randomize subjects 1:1 to placebo or investigational product. In the absence of an 
established treatment, the use of placebo is justified. If additional arms are added to or dropped 
from the trial, randomization will proceed with an equal probability of assignment to each of the 
remaining arms. Randomization will be stratified by site and severity (severe versus mild-
moderate). See Section 6.3 for more information on randomization and stratification. 
4.2 Scientific Rationale for Study Design 
At present, there is no specific antiviral therapy for coronavirus infections. Few treatment studies 
have been conducted because most human coronavirus strains cause self-limited disease and care 

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is supportive. After the SARS-CoV was identified in 2002-2003 and caused a large global 
outbreak, there was an increased interest in the development of specific therapeutic agents. 
SARS-CoV patients were treated with corticosteroids, type 1 IFN agents, convalescent plasma, 
ribavirin, and lopinavir or ritonavir, and except for ribavirin, many of these agents have in vitro 
pre-clinical data that support their efficacy (13-28). Since the SARS-CoV outbreak in 2002-
2003, new therapeutic agents targeting viral entry proteins, proteases, polymerases, and 
methyltransferases have been tested; however, none of them has been shown to be efficacious in 
clinical trials (29-31).  
 
This study utilizes an adaptive design that increases efficiency to identify safe and efficacious 
therapeutic agents for patients with COVID-19 during the current outbreak. Some investigational 
products may be in limited supply and this study design enables continuation of the study even if 
a product becomes unavailable. In addition, the adaptive design allows for the evaluation of new 
therapeutic agents as they are identified and ready for testing in clinical trials. As the study is a 
multicenter, multinational randomized controlled study, we will be able to acquire rigorous data 
about the safety and efficacy of investigational therapeutic agents for COVID-19 that will lead to 
generalizable evidence. Randomization is essential for establishing efficacy of these new 
therapeutic agents. Last, collecting clinical and virologic data on enrolled subjects using a 
standardized timeline and collection instruments should provide valuable information about the 
clinical course of and morbidities associated with COVID-19 in a diverse group of hospitalized 
adults. 
 
4.3 Justification for Dose 
The dose of remdesivir used in this study will be the same dose that was used in the Ebola 
clinical trials.  
 
5. STUDY POPULATION 
Approximately 572 male and non-pregnant female adults ≥18 years of age or older with COVID-
19 and who meet all eligibility criteria will be enrolled at up to approximately 100 clinical trial 
sites globally. The target population should reflect the community at large. The estimated time 
from screening (Day -1 or Day 1) to end of study for an individual subject is approximately 29 
days.  
 
Subject Inclusion and Exclusion Criteria must be confirmed by any clinician named on the 
delegation log. If there is any uncertainty, the PI should make the decision on whether a potential 
subject is eligible for study enrollment. There is no exclusion for receipt of SARS-CoV-2 
vaccine (experimental or licensed). 
 
5.1 Inclusion Criteria 
In order to be eligible to participate in this study, a patient must meet all of the following criteria: 
1. Admitted to a hospital with symptoms suggestive of COVID-19 infection. 
2. Subject (or legally authorized representative) provides informed consent prior to 
initiation of any study procedures. 

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3. Subject (or legally authorized representative) understands and agrees to comply with 
planned study procedures. 
4. Male or non-pregnant female adult ≥18 years of age at time of enrollment. 
5. Has laboratory-confirmed SARS-CoV-2 infection as determined by PCR or other 
commercial or public health assay in any specimen, as documented by either of the 
following:  
• PCR positive in sample collected < 72 hours prior to randomization; OR 
• PCR positive in sample collected ≥ 72 hours prior to randomization, documented 
inability to obtain a repeat sample (e.g. due to lack of testing supplies, limited 
testing capacity, results taking > 24 hours, etc.). AND progressive disease 
suggestive of ongoing SARS-CoV-2 infection. 
6. Illness of any duration, and at least one of the following: 
• Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR 
• SpO2 ≤ 94% on room air, OR 
• Requiring supplemental oxygen, OR 
• Requiring mechanical ventilation. 
7. Women of childbearing potential must agree to either abstinence or use at least one 
primary form of contraception not including hormonal contraception from the time of 
screening through Day 29.  
8. Agrees to not participate in another clinical trial for the treatment of COVID-19 or 
SARS-CoV-2 through Day 29. 
 
5.2 Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. ALT or AST > 5 times the upper limit of normal. 
2. Estimated glomerular filtration rate (eGFR) < 30 ml/min (including patients receiving 
hemodialysis or hemofiltration). 
3. Pregnancy or breast feeding. 
4. Anticipated discharge from the hospital or transfer to another hospital which is not a 
study site within 72 hours. 
5. Allergy to any study medication. 
 
5.2.1 
Exclusion of Specific Populations 
Children and adolescents will not be included in this trial. Remdesivir has only been used in a 
small number of pediatric patients. Initial information about the epidemiology of COVID-19 
indicates that the overwhelming burden of severe disease occurs among older adults, especially 
those with comorbidities. Given significant gaps in knowledge in this population, and a low 
incidence of severe morbidity/mortality in children, the risk/benefits do not warrant inclusion of 
this population into this trial at this time.  
 
In nonclinical reproductive toxicity studies, remdesivir demonstrated no adverse effect on 
embryo-fetal development when administered to pregnant animals. Embryonic toxicity was seen 

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when remdesivir was initiated in female animals prior to mating and conception, but only at a 
systemically toxic dose. Remdesivir has not been studied in pregnant women. Because the 
effects on the fetus and the pregnant woman are not fully known, pregnant women will not be 
eligible for the trial.  
 
In animal studies, remdesivir metabolites have been detected in the nursing pups of mothers 
given remdesivir. It is not known whether remdesivir is secreted in human milk. Because the 
effects of remdesivir on the breastfeeding infant is not known, women who are breast feeding 
will not be eligible for the trial. 
 
5.3 Inclusion of Vulnerable Subjects 
Certain human subjects are categorized as vulnerable populations and require special treatment 
with respect to safeguards of their well-being. For this clinical trial, examples include cognitively 
impaired or mentally disabled persons and intubated individuals who are sedated. When it is 
determined that a potential research subject is cognitively impaired, federal and institutional 
regulations permit researchers to obtain consent from a legally authorized representative (LAR). 
The study team will obtain consent from these vulnerable subjects using an IRB-approved 
protocol- specific process for consent using a LAR. 
 
For subjects for whom a LAR gave consent, during the course of the study, if the subject regains 
the capacity to consent, informed consent must be obtained from the subject and the subject 
offered the ability to leave the study if desired. 
5.4 Lifestyle Considerations 
During this study, subjects are asked to: 
• Refrain from drinking alcohol through Day 15.  
• Avoid taking paracetamol (acetaminophen) through Day 15. (Other non-steroidal anti-
inflammatory drugs or antipyretic drugs are acceptable). 
• Avoid getting pregnant during the study from Day 1 through Day 29. 
• Avoid participation in another clinical trial for the treatment of COVID-19 or SARS-
CoV-2. Co-enrollment for natural history studies of COVID-19 or SARS-CoV-2 is 
permitted; however, participation in both ACTT and natural history studies can only 
occur if the recommended blood collection volumes are not exceeded.  
5.5 Screen Failures 
Following consent, after the screening evaluations have been completed, the investigator or 
designee is to review the inclusion/exclusion criteria and determine the subject’s eligibility for 
the study. If there is any uncertainty, the PI should make the decision on whether a potential 
subject is eligible for study enrollment.  
 
Only basic demographic information and the reason(s) for ineligibility will be collected on 
screen failures. Subjects who are found to be ineligible will be told the reason(s) for ineligibility. 
 

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Individuals who do not meet the criteria for participation in this study (screen failure) because of 
an abnormal laboratory finding may be rescreened once. 
5.6 Strategies for Recruitment and Retention 
5.6.1 
Recruitment 
It is anticipated that patients with COVID-19 will present to participating hospitals, and that no 
external recruitment efforts towards potential subjects are needed. Recruitment efforts may also 
include dissemination of information about this trial to other medical professionals / hospitals.  
 
The IRB will approve the recruitment process and all materials provided prior to any recruitment 
to prospective subjects directly. 
 
Screening will begin with a brief discussion with study staff. Some will be excluded based on 
demographic data and medical history (i.e., pregnant, < 18 years of age, renal failure, etc.). 
Information about the study will be presented to potential subjects (or legally authorized 
representative) and questions will be asked to determine potential eligibility. Screening 
procedures can begin only after informed consent is obtained. 
 
5.6.2 
Retention 
Retention of subjects in this trial is very important for determining the primary endpoint. As 
such, after hospital discharge, participating subjects will be reminded of subsequent study visits 
and every effort will be made to accommodate the subject’s schedule to facilitate follow-up 
within the specified visit window. Additionally, there are many circumstances that influence the 
ability to obtain outcome information after discharge. Follow-up visits may be conducted by 
phone if in-person visits are not feasible.  
5.6.3 
Compensation Plan for Subjects  
Compensation, if any, will be determined locally and in accordance with local IRB requirements, 
and subject to local IRB approval.  
 
5.6.4 
Costs 
There is no cost to subjects for the research tests, procedures/evaluations and study product while 
taking part in this trial. Procedures and treatment for clinical care including costs associated with 
hospital stay may be billed to the subject, subject’s insurance or third party. 
 
6. STUDY PRODUCT 
6.1 Study Product(s) and Administration – GS-5734 (Remdesivir) and 
placebo 
6.1.1 
Study Product Description  
Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular 
delivery of a modified adenine nucleoside analog GS-441524. In addition to the active 

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ingredient, the lyophilized formulation of remdesivir contains the following inactive ingredients: 
water for injection, SBECD, and hydrochloric acid and/or sodium hydroxide. 
 
The supplied matching placebo lyophilized formulation is identical in physical appearance to the 
active lyophilized formulation and contains the same inactive ingredients. Alternatively, due to 
limitations on placebo supplies, normal saline may be given at an equal volume as a placebo in 
place of the lyophilized formulation. 
 
6.1.2 
Dosing and Administration 
Subjects will be randomized 1:1 to receive either active product or placebo. Initially, the trial 
will have 2 arms:  
• Remdesivir will be administered as a 200 mg IV loading dose on Day 1, followed by a 
100 mg once-daily IV maintenance dose while hospitalized for up to a 10 day total 
course. If a subject is no longer hospitalized, then infusions will no longer be given.  
o The total course should not exceed 10 calendar days even if an infusion was 
missed.  
• A matching placebo will be given at an equal volume at the same schedule.  
 
The dose should be given the same time each day (+/- 2 hours for medication scheduling). 
 
Any dose that is delayed may be given later that calendar day. Any dose that is missed (not given 
that calendar day) is not made up. The treatment course continues as described above even if the 
subject becomes PCR negative.  
 
6.1.3 
Dose Escalation 
Not Applicable 
 
6.1.4 Dose Modifications 
There are no clinical safety or pharmacokinetic data available for remdesivir in patients with 
renal and/or hepatic impairment. Given the benefit-to-risk ratio in patients with COVID-19, these 
subjects are excluded from the study.  
 
If the eGFR decreases to an eGFR < 25 ml/min, the study infusion should not be given on that 
day. The infusion may be resumed on the next day if the eGFR returns to ≥ 30 ml/min. If the 
subject’s renal function worsens to the point that they require hemodialysis or hemofiltration, 
study product will be discontinued. 
 
If the ALT and/or AST increases to > 5 times upper limits of normal, the dose of remdesivir 
should be held and not be restarted until the ALT and AST ≤ 5 times upper limits of normal. 
 
6.1.5 
Overdosage 
There is no known antidote for remdesivir. In the case of overdose, the subject should receive 
supportive therapy based on the subject´s signs and symptoms. 
 

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6.2 Preparation/Handling/Storage/Accountability 
6.2.1 
Acquisition and Accountability 
Investigational products (IP) will be shipped to the site either directly from participating 
companies, from the Sponsor, or from other regional or local drug repositories. All other supplies 
should be provided by the site. Multiple lots of each IP may be supplied. 
 
Study products received at the sites will be open label and not kit specific, unless specified in the 
protocol-specific Manual of Procedures (MOP). Drug preparation will be performed by the 
participating site’s research pharmacist on the same day of administration to the subject. See the 
MOP Appendices for detailed information on the preparation, labeling, storage, and 
administration of remdesivir and placebo.  
 
Accountability: 
The site PI is responsible for study product distribution and disposition and has ultimate 
responsibility for study product accountability. The site PI may delegate to the participating 
site’s research pharmacist responsibility for study product accountability. The participating site’s 
research pharmacist will be responsible for maintaining complete records and documentation of 
study product receipt, accountability, dispensation, storage conditions, and final disposition of 
the study product(s). Time of study drug administration to the subject will be recorded on the 
appropriate data collection form (CRF). All study product(s), whether administered or not, must 
be documented on the appropriate study product accountability record or dispensing log. The 
Sponsor’s monitoring staff will verify the participating site’s study product accountability 
records and dispensing logs per the site monitoring plan. Refer to the protocol-specific MOP for 
details on storing study medications.  
Destruction: 
After the study treatment period has ended or as appropriate over the course of the study after 
study product accountability has been performed, used active and placebo vials can be destroyed 
on-site following applicable site procedures with a second staff member observing and verifying 
the destruction.  
Unused vials at the end of the study should be saved until instructed by the Sponsor. 
 
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
Product: Remdesivir 
The lyophilized formulation of remdesivir is a preservative-free, white to off-white or yellow, 
lyophilized solid containing 150 mg or 100 mg of remdesivir to be reconstituted with 29 mL or 
19 mL (respectively) of sterile water for injection respectively and diluted into IV infusion fluids 
prior to IV infusion. Following reconstitution, each vial contains a 5 mg/mL remdesivir 
concentrated solution with sufficient volume to allow withdrawal of 30 mL (150 mg of 
remdesivir) or 20 mL (100 mg of remdesivir).  
 
It is supplied as a sterile product in a single-use, Type 1 clear glass vial. In addition to the active 
ingredient, the lyophilized formulation of remdesivir contains the following inactive ingredients: 

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water for injection, SBECD, hydrochloric acid, and/or sodium hydroxide. For more information, 
refer to the MOP. 
 
Placebo:  
The supplied matching placebo lyophilized formulation, 150 mg or 100 mg equivalent, is 
identical in physical appearance to the active lyophilized formulation and contains the same 
inactive ingredients. The lyophilized formulation of matching placebo is filled in a Type 1 clear 
glass vial closed with a rubber stopper and aluminum seal with a plastic flip-off cap. Each single-
use vial contains sufficient volume to allow withdrawal of 30 mL or 20 mL of placebo following 
reconstitution. 
 
Alternatively, due to limitations on placebo supplies, a matching placebo of normal saline may 
be given at an equal volume at the same schedule. In this case, IV bags of study treatment (both 
the Active and the Placebo) will be covered to mask the slight color difference between the 
remdesivir solution and placebo to maintain the study blind.  
 
Each of the study products will be labeled according to manufacturer specifications and include 
the statement “Caution: New Drug Limited by Federal Law to Investigational Use.” 
 
6.2.3 
Product Storage and Stability 
Product: Remdesivir 
Ambient vials of the lyophilized formulation of remdesivir should be stored below 30°C. The 
lyophilized formulation needs to be reconstituted and then diluted into IV infusion fluids before 
use. After reconstitution, the total storage time before completion of administration (including 
any time before or after dilution) should not exceed 4 hours at room temperature (20°C to 25°C) 
or 24 hours at refrigerated temperature (2°C to 8°C). See MOP for additional information.  
 
Placebo:  
Vials of the lyophilized formulation of matching placebo should be stored below 30°C. The 
lyophilized formulation needs to be reconstituted and then diluted into IV infusion fluids before 
use. After reconstitution, the total storage time before completion of administration (including 
any time before or after dilution) should not exceed 4 hours at room temperature (20°C to 25°C) 
or 24 hours at refrigerated temperature (2°C to 8°C). 
 
If used, the saline placebo should be kept under the same conditions as the matching lyophilized 
placebo, in order to maintain the blind. 
 
6.2.4 
Preparation 
Refer to the protocol-specific MOP for details about preparation.  
 
Remdesivir does not meet the criteria for a hazardous compound as defined by NISOH and 
ASHP hazard classification systems. The study products may be prepared in a clean room but do 
not need to be prepared or handled in a fume hood. 
 

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Measures that minimize drug contact with the body should always be considered during 
handling, preparation, and disposal procedures as indicated in the IB.  
6.3 Measures to Minimize Bias: Randomization and Blinding 
The study will randomize subjects 1:1 to placebo or investigational product. If additional arms 
are added to or dropped from the trial, randomization will proceed with an equal probability of 
assignment to each of the remaining arms. Randomization will be stratified by: 
• Site 
• Severity of illness at enrollment: 
o Severe disease: requiring mechanical ventilation, requiring oxygen, a SpO2 ≤ 94% 
on room air, or tachypnea (respiratory rate ≥ 24 breaths/min). 
o Mild-moderate disease: SpO2 > 94% and respiratory rate < 24 breaths/min without 
supplemental oxygen.  
 
The randomization procedure will be described in the MOP.  
6.4 Study Intervention Compliance 
Each dose of study product will be administered by a member of the clinical research team who 
is qualified and licensed to administer the study product. Administration and date, and time, will 
be entered into the case report form (CRF). 
 
6.5 Concomitant Therapy 
Therapy prior to enrollment with any other experimental treatment or off-label use of marketed 
medications that are intended as specific treatment for COVID-19 or the SARS-CoV-2 infection 
(i.e., post-exposure prophylaxis [PEP]) are permitted but must be discontinued on enrollment. 
There is no waiting period between discontinuation of these treatments and infusion of study 
product. However, these prior treatments and their end date should be documented on the 
Concomitant Medication (CCM) form.  
 
Subjects who are taking another antiviral for a concurrent infection (e.g. oseltamivir for an 
influenza virus, lopinavir/ritonavir for HIV, etc.) or immunosuppressive drugs for other medical 
conditions (tocilizumab for rheumatoid arthritis, hydroxychloroquine for lupus, etc.) may 
continue with the treatment.  
 
A subject cannot participate in another clinical trial for the treatment of COVID-19 until after Day 
29 (see exclusion criteria).  
 
If the local standard of care per written policies or guidelines for treatment for COVID-19 or 
SARS-CoV-2 infection (i.e., not just an individual clinician decision) includes lopinavir/ritonavir 
(Kaletra), hydroxychloroquine or other agents (e.g. those targeting the host immune response), 
then continuing these during the study is permitted, but may require additional safety monitoring 
as determined by the treating clinician. Additionally, there should be plans on how the 
concomitant drugs are stopped for additive toxicities (Section 6.1.4). If there are NO written 
policies or guidelines for local standard of care, concomitant use of any other experimental 

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treatment or off-label use of marketed medications intended as specific treatment for COVID-19 
or SARS-CoV-2 infection are prohibited. This includes medications that target the host immune 
response. 
 
No clinical drug-drug interaction (DDI) studies have been conducted with remdesivir. Final 
guidance about the drug and possible DDI should come from the IB and the protocol. Site PIs 
should review the prescription drugs that the subject is getting for pre-existing comorbidities and 
determine if these agents may lead to antagonism or synergy with remdesivir and modify safety 
monitoring accordingly. 
 
There is no available data on potential interactions between remdesivir and other anti-SARS-
CoV investigational agents. Administering remdesivir concurrently with other agents may lead to 
antagonism or synergy or may have no effect.  
 
Concomitant medications will be assessed only from 7 days prior to enrollment to Day 11 or 
upon discharge, whichever comes first. Concomitant medications should be reported on the 
designated CRF. Report all prescription medications taken during this time period. Do not report 
vitamins, herbal supplements, or topical medications. Do not report over-the-counter cold 
medicines and antipyretics that the subject reportedly took at home prior to hospitalization. 
Record all antipyretics and other medications given for symptomatic care, if they are 
administered while an inpatient. However, record these medications only once, even if given 
multiple times, as needed during hospital course.  
 
Of note, acetaminophen is prohibited during the study through Day 15, even if clinically 
indicated for a subject. Acetaminophen should not be used because of the concerns of additive 
hepatotoxicity with active product. Other antipyretics and/or analgesics that are not hepatotoxic 
may be used, such as NSAIDS. 
 
6.5.1 
Rescue Medicine 
Not Applicable 
 
6.5.2 
Non-Research Standard of Care 
Not Applicable 
 
7. STUDY INTERVENTION DISCONTINUATION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Halting Criteria and Discontinuation of Study Intervention 
7.1.1 
Individual Infusion Halting 
See Section 6.1.4. for information about dosing modifications due to laboratory abnormalities. 
For an individual subject, an individual infusion must be stopped if they have a suspected drug-
related event of hypersensitivity (Grade 2 or higher) during the infusion. While there are no criteria 

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for grading “hypersensitivity” in the Division of AIDS (DAIDS) Table for Grading the Severity 
of Adverse Events, sites should use acute allergic reaction from that toxicity table. Subjects who 
have an IV infusion stopped for a safety related issues will not continue with dosing.  
The treatment of any given subject may be stopped for SAEs, clinically significant adverse events, 
severe laboratory abnormalities, or any other medical conditions that indicate to the Investigator 
that continued dosing is not in the best interest of the patient. 
In addition, a subject in this clinical study may discontinue study drug at their request for any 
reason. Every effort should be made to encourage subjects to remain in the study for the duration 
of their planned outcome assessments. Subjects should be educated on the continued scientific 
importance of their data, even if they discontinue study drug.  
Unless the subject withdraws consent, those who discontinue study drug early will remain in the 
study. The reason for subject discontinuation of study drug should be documented in the case 
report form. 
7.1.2 
Study Halting 
Given the potential severity of COVID-19, there are no pre-specified study stopping rules. 
Instead there will be close oversight by the protocol team and frequent DSMB reviews of the 
safety data.  
 
7.2 
Withdrawal from the Study 
Subjects are free to withdraw from participation in the study at any time upon request, without 
any consequence. Subjects should be listed as having withdrawn consent only when they no 
longer wish to participate in the study and no longer authorize the Investigators to make efforts 
to continue to obtain their outcome data.  
 
Subjects who withdraw from this study or are lost to follow-up after signing the informed 
consent form (ICF) and administration of the study product, will not be replaced. The reason for 
subject withdrawal from the study will be recorded on the appropriate CRF. 
7.3 
Lost to Follow-Up 
A subject will be considered lost to follow-up if he or she fails to appear for all follow-up 
assessments. In lost to follow-up cases, attempts to contact the subject should be made and these 
efforts should be documented in the subject’s records.  
8. STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Screening and Efficacy Assessments 
8.1.1 
Screening Procedures 
Screening procedures may be done over one to two calendar days (from Day -1 to Day 1). 
However, in many cases all the screening assessments can be done in less than 24 hours. If that is 
the case, Day 1 pre-infusion baseline assessments, specimen collection and the initial infusion 
can occur on the same calendar day as the screening procedures.  

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After the informed consent, the following assessments are performed to determine eligibility and 
obtain baseline data: 
• 
Confirm the positive SARS-CoV-2 test result (per inclusion criteria).  
• 
Take a focused medical history, including the following information:  
• Day of onset of COVID-19 signs and symptoms. 
• History of chronic medical conditions including chronic oxygen requirement prior to 
onset of COVID-19. 
• History of medication allergies. 
• Medications and therapies for this current illness taken in the 7 days prior to Day 1. 
• Ask if they are participating in another clinical trial or plan to enroll in another 
clinical trial in the next 30 days. 
• 
Women of childbearing potential should be counseled to either practice abstinence or use at 
least one primary form of contraception not including hormonal contraception from the time 
of screening through Day 29. Women should be confirmed to not be breastfeeding. 
• 
Note: If a woman is either postmenopausal (i.e., has had ≥12 months of spontaneous 
amenorrhea) or surgically sterile (i.e., has had a hysterectomy, bilateral ovariectomy 
(oophorectomy), or bilateral tubal ligation), she is not considered to be of 
childbearing potential.  
• 
Height and weight (height can be self-reported). 
• 
Results of recent radiographic imaging (x-ray or CT scan). 
• 
SpO2. 
• 
Blood for screening laboratory evaluations if not done as part of routine clinical care in the 
preceding 48 hours: 
 ALT. 
 AST. 
 Creatinine (and calculate eGFR).  
• Any automated calculation by the clinical laboratory or published formula for this 
calculation is acceptable. The site should select a formula to be used for all 
subjects enrolled at the site for the duration of the study. 
• 
Urine or serum pregnancy test (in women of childbearing potential). 
 
Clinical screening laboratory evaluations will be performed locally by the site laboratory. The 
volume of venous blood to be collected is presented in Table 3. 
 
The overall eligibility of the subject to participate in the study will be assessed once all screening 
values are available. Complete the Eligibility Checklist on day of enrollment as this form 
includes data needed to register all potential subjects in the Advantage eClinical system. The 

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screening process can be suspended prior to complete assessment at any time if exclusions are 
identified by the study team. 
 
Study subjects who qualify will be randomized in the Advantage eClinical system, and all others 
will be registered as screen failures. The study team has 24 hours to complete Day 1 baseline 
assessments prior to the first infusion including the collection of OP swab and blood, assessment 
of the ordinal scale and NEWS and completing or recording a baseline physical examination that 
was done. 
8.1.2 Efficacy Assessments 
For all baseline assessments and follow-up visits, refer to the Schedule of Assessments (SOA) 
for procedure to be done, and details below for each assessment. 
 
8.1.2.1 Measures of clinical support, limitations and infection control 
The subject’s clinical status will be captured on each study day while hospitalized and on Day 15 
and 29 if hospitalized or the subject returns for an in-person clinic visit. It will also be captured on 
Day 22 during a phone visit. Clinical status is largely measured by the ordinal scale and the NEWS. 
Unlike the NEWS, the ordinal scale can also be evaluated over the phone if the discharged subject 
is unable to return for visits on Day 15 and 29 as well as on Day 22.  
 
Ideally, complete the ordinal scale concurrently with the NEW Score just prior to infusion, as time 
permits. The following measures are recorded for the ordinal scale: 
• Hospitalization. 
• Oxygen requirement. 
• Non-invasive mechanical ventilation (via mask) requirement. 
• High flow oxygen requirement. 
• Invasive mechanical ventilation (via endotracheal tube or tracheostomy tube) 
requirement. 
• ECMO requirement. 
• Ongoing medical care preventing hospital discharge (COVID-19 related or other medical 
conditions). 
• Limitations of physical activity (self-assessed). 
• Isolated for infection control purposes. 
 
8.1.2.2 Ordinal Scale 
 
The ordinal scale is the primary measure of clinical outcome.  
 
The scale used in this study is as follows (from worst to best): 
• Death; 
• Hospitalized, on invasive mechanical ventilation or ECMO; 
• Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
• Hospitalized, requiring supplemental oxygen; 

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• Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 
• Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical 
care; 
o This would include those kept in hospital for quarantine/infection control, awaiting 
bed in rehabilitation facility or homecare, etc. 
• Not hospitalized, limitation on activities and/or requiring home oxygen; 
• Not hospitalized, no limitations on activities 
 
To determine a subject’s clinical status using  the ordinal scale: On Day 1, report their clinical 
status at randomization. On Day 2, report the period from randomization to midnight on Day 1. 
On Day 3 through Day 11, or until discharged, and on Days 15, 22 and 29, provide the worst 
clinical assessment for the previous day (i.e., midnight to midnight; 00:00 – 23:59 (24-hr clock)). 
For example, on study Day 3 when completing the form, the worse clinical outcome measure of 
Day 2 is captured with the worst being death followed by ECMO, mechanical ventilation, etc. 
The Day 2 measurement is assessed as occurring anytime in that 24-hour period (00:00 to 23:59). 
 
8.1.2.3 National Early Warning Score (NEWS) 
NEWS has demonstrated an ability to discriminate subjects at risk of poor outcomes. (Smith, 
2016). This score is based on 7 clinical parameters (see Table 2). The NEWS is being used as an 
efficacy measure. The NEW Score should be evaluated daily while hospitalized and on Days 15 
and 29. It can be performed concurrently with the Ordinal Scale. This should be evaluated at a 
consistent time for each study day and prior to administration of study product. The 7 parameters 
can be obtained from the hospital chart or electronic medical record (EMR) using the last 
measurement prior to the time of assessment and a numeric score is given for each parameter 
(e.g., a RR of 9 is one point, oxygen saturation of 92 is two points). This is recorded for the day 
obtained (i.e., on Day 3, the vital signs and other parameters from Day 3 are used to obtain NEW 
Score for Day 3). 
 
Table 2. National Early Warning Score (NEWS) 

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  Level of consciousness = alert (A), and arousable only to voice (V) or pain (P), and 
unresponsive (U).  
 
8.1.3 
 Exploratory assessments 
8.1.3.1 Viral Load and/or Shedding 
As outlined on the SOA, OP swabs and plasma and serum will be collected on Day 1; and Days 
3, 5, 8, and 11 (while hospitalized); and OP swabs and serum on Day 15 and 29 (if attends an in- 
person visit or still hospitalized). Samples are stored as outlined in the MOP. These assays are 
not developed yet, and the ability to test samples at one central lab is not clear. Therefore, while 
viral load/shedding is thought to be an important endpoint, considering the limitations above, it is 
listed as an exploratory endpoint.  
 
OP swabs are preferred, but if these are not obtainable, nasopharyngeal (NP) swabs may be 
substituted. Due to limited lack of swabs and other supplies at some sites and limitations on 
personal protective equipment (PPE), the inability to obtain these samples are not considered 
protocol deviations and should be documented in the subject’s record.  
 
If virology assays can be set up with enough numbers of specimens tested, these data will be 
submitted as part of the Clinical Study Report (CSR). This may be submitted separately, as a 
supplemental CSR.  
 
Samples collected for viral assessment may be probed for the emergence of antiviral resistance at 
a future date. These data, if available, may be submitted as a supplement report. 
 
The schedule of assessments (SOA, Section 1.2) lists several research laboratory samples. It is 
preferred that these samples are collected and sent to the NIAID repository to be tested in one 
central laboratory. Current US Centers for Disease Control and Prevention (CDC) guidance is 
these samples can be processed in a Biosafety Laboratory (BSL) 2 environment. However, 
institutions may impose restrictions on processing the samples (i.e., they may require BSL-3) or 
there may be restrictions on sending samples. In these circumstances, the following apply: 

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Blood for PCR SARS-CoV-2 
• If the samples can be processed but cannot be sent to the repository, the samples may be 
stored locally.  
• The sponsor may elect to have some or all of these samples run locally, pending 
confirmation of the assays to be used and the qualifications of the local laboratory. The 
sponsor will work with the site to determine when this could occur and how these data can 
be imported into the study database.  
• If a BSL-3 environment is needed for processing these samples, these samples may be 
omitted.  
 
Oropharyngeal swab 
• If the samples can be processed but cannot be sent to the repository, the samples may be 
stored locally.  
• The sponsor may elect to have some or all of these samples run locally, pending 
confirmation of the assays to be used and the qualifications of the local laboratory. The 
sponsor will work with the site to determine when this could occur and how these data can 
be imported into the study database.  
• If a BSL-3 environment is needed for processing these samples, these samples may be 
omitted.  
 
Blood for serum (for secondary research) 
• If the samples can be processed and but not sent to the repository, the samples may be 
stored locally.  
• If a BSL-3 environment is needed for processing these samples, these samples may be 
omitted.  
 
8.1.3.2 Alternative Ordinal Scales 
Given the limited clinical data available for COVID-19, the best construct of ordinal scale is not 
known. Additional data may be used to construct different ordinal scales to test their utility in a 
treatment study. These are hypothesis generating and will not be submitted as part of a final 
CSR. 
 
8.2 
Safety and Other Assessments 
Study procedures are specified in the SOA. A study physician licensed to make medical 
diagnoses and listed on the 1572 will be responsible for all trial-related medical decisions. 
 
Physical examination:  
A targeted physical examination will be performed at baseline prior to initial infusion on Day 1. 
The baseline physical examination can be one that is conducted from screening to Day 1. Post-
baseline physical examinations will be done only when needed to evaluate possible adverse 
event(s) (i.e. any new signs or symptoms). No routine physical exam is needed for study visits 
after Day 1.  
 

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Study staff at some sites are not allowed into the subject’s rooms due to a limited supply of PPE 
and the need for strict respiratory isolation measures for COVID-19 patients. Because of limited 
access to subjects, physical exams can be performed by any licensed provider at the study 
hospital even if they are not study staff listed on the 1572. The study team can extract 
information from the hospital chart or EMR.  
 
Clinical laboratory evaluations: 
• Fasting is not required before collection of laboratory samples. 
• Blood will be collected at the time points indicated in the SOA.  
• Clinical safety laboratory tests include WBC, differential, Hgb, PLT, creatinine, 
glucose, total bilirubin, AST, ALT, and PT.  Sites that do not have access to a test 
for PT will be allowed to report an international normalized ratio (INR). 
• Day 1 clinical laboratory evaluations are drawn prior to initial infusion as a 
baseline and results do not need to be reviewed to determine if initial infusion 
should be given. 
• Clinical laboratory testing will be performed at each clinical trial site in real time.  
 
 
 

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Table 3. Venipuncture Volumes1 
 
Screen 
Baseline 
 
 
 
 
 
 
Day +/- Window 
−1 to 1 
1 ± 1 
3 ± 1 
5 ±1 
8 ± 1 
11 ± 1 
15 ± 2 
29 ± 3 
Safety hematology, 
chemistry and liver 
tests 
 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
 X3 
10mL2 
X3 
10mL2 
Blood for Serum 
 
 
X 
24mL 
X 
24mL 
X 
24mL 
X 
24mL 
X 
24mL 
X 
24mL 
X 
24mL 
Plasma  
(includes PCR) 
 
X 
8mL 
X 
8mL 
X 
8mL 
X 
8mL 
X 
8mL 
 
 
Total volume 
10mL 
42ml 
42mL 
42ml 
42ml 
42ml 
34mL 
34mL 
Total all study days 
 
 
 
 
 
 
 
268~288 
mL 
1. See SOA in Section 1.2 for specific tests to be performed. 
2. Total volume calculated assumes there are no routine clinical laboratory were done within 48 hours of screening 
that can be used for determining eligibility and no routine clinical laboratory tests were done within the window for 
that visitor 24 hours of Day 1, 3, 5, 8 and 11 and 48 hours for Day 15 and 72 hours for Day 29 if still hospitalized.  
3. Safety laboratory tests will be collected on Day 15 and 29 if the subject is still hospitalized at these time points or 
if they return for an in-person outpatient visit and the site has the capacity to collect blood in the outpatient setting. 
8.2.1 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
If a physiologic parameter (e.g., vital signs, or laboratory value) is outside of the protocol-
specified range, then the measurement may be repeated once if, in the judgment of the 
investigator, the abnormality is the result of an acute, short-term, rapidly reversible condition or 
was an error. A physiologic parameter may also be repeated if there is a technical problem with 
the measurement caused by malfunctioning or an inappropriate measuring device (i.e., 
inappropriate-sized BP cuff). 
 
8.2.2 
Unscheduled Visits 
If clinical considerations require the subject to be contacted or seen prior to the next schedule 
assessment to assure the subject’s well-being, it is permissible in this protocol.  However, no 
research data is collected at this visit.   
8.3 
Adverse Events and Serious Adverse Events 
8.3.1 
Definition of Adverse Event (AE) 
AE means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of medicinal (investigational) product. 
 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE. However, if the severity of any pre-existing medical 
condition increases to severity level 3 or 4, it should be recorded as an AE. 
 
Given the nature of severity of the underlying illness, subjects will have many symptoms and 
abnormalities in vital signs and laboratory values. All Grade 3 and 4 AEs will be captured as 

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AEs in this trial. In addition, any Grade 2 or higher, suspected drug-related hypersensitivity 
reaction will be reported as an AE in this trial (see Section 7.1.1). 
 
8.3.2 
Definition of Serious Adverse Event (SAE) 
An AE or suspected adverse reaction is considered serious (i.e., is an SAE) if, in the view of 
either the investigator or the Sponsor, it results in any of the following outcomes: 
• Death; 
• A life-threatening AE; 
• Inpatient hospitalization or prolongation of existing hospitalization; 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; or 
• A congenital anomaly/birth defect. 
 
Important medical events that may not meet the above criteria may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias, convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
“Life-threatening” refers to an AE that at occurrence represents an immediate risk of death to a 
subject. An event that may cause death if it occurs in a more severe form is not considered life-
threatening. Similarly, a hospital admission for an elective procedure is not considered a SAE. 
 
All SAEs, as with any AE, will be assessed for severity and relationship to study intervention. 
 
All SAEs will be recorded on the SAE CRF. 
 
All SAEs will be followed through resolution or stabilization by a licensed study physician (for 
IND studies, a physician listed on the Form FDA 1572 as the site PI or Sub-Investigator). 
 
All SAEs will be reviewed and evaluated by DMID and will be sent to the DSMB (for periodic 
review), and the IRB/IEC. 
8.3.3 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A SUSAR is any SAE where a causal relationship with the study product is at least reasonably 
possible but is not listed in the IIB, Package Insert, and/or Summary of Product Characteristics. 
8.3.4 
Classification of an Adverse Event 
The determination of seriousness, severity, and causality will be made by an on-site investigator 
who is qualified (licensed) to diagnose AE information, provide a medical evaluation of AEs, 
and classify AEs based upon medical judgment. This includes but is not limited to physicians, 
physician assistants, and nurse practitioners. 

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8.3.4.1 Severity of Adverse Events 
All AEs and SAEs will be assessed for severity using the DAIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events, version 2.1 (July 2017).  
 
For AEs not included in the Table, the following guidelines will be used to describe severity. In 
addition, all deaths related to an AE are to be classified as grade 5 according to the DAIDS Table.   
 
 
• Moderate (Grade 2): Events that are usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living and 
causes discomfort, but poses no significant or permanent risk of harm to the research 
subject. 
 
• Severe (Grade 3): Events that interrupt usual activities of daily living, or significantly 
affect clinical status, or may require intensive therapeutic intervention. Severe events are 
usually incapacitating. 
 
• Severe (Grade 4): Events that are potentially life threatening. 
 
• Deaths (Grade 5): All deaths related to an AE are to be classified as grade 5. (per DAIDS 
Table). 
 
AEs characterized as intermittent require documentation of onset and duration of each episode. 
The start and stop dates (duration) of each reported AE will be recorded on the appropriate CRF. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of intensity. 
8.3.4.2 Relationship to Study Intervention 
For each reported adverse reaction, the PI or designee must assess the relationship of the event to 
the study product using the following guideline: 
 
• Related – There is a temporal relationship between the study intervention and event, and 
the AE is known to occur with the study intervention or there is a reasonable possibility 
that the study intervention caused the AE. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study intervention and the AE. 
 
• Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
8.3.5 
Time Period and Frequency for Event Assessment and Follow-Up 
For this study, all Grade 3 and 4 AEs, all SAEs occurring from the time the informed consent is 
signed through the Day 29 visit will be documented, recorded, and reported. In addition, any 
Grade 2 or higher suspected drug-related hypersensitivity reactions associated with study product 
infusions will be reported as an AE.  
 

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8.3.5.1 Investigators Reporting of AEs 
Information on all AEs will be recorded on the appropriate CRF. All clearly related signs, 
symptoms, and results of diagnostic procedures performed because of an AE should be grouped 
together and recorded as a single diagnosis. If the AE is a laboratory abnormality that is part of 
a clinical condition or syndrome, it should be recorded as the syndrome or diagnosis rather than 
the individual laboratory abnormality. Each AE will also be described in terms of duration (start 
and stop date), severity, association with the study product, action(s) taken, and outcome. 
8.3.6 
Serious Adverse Event Reporting 
8.3.6.1 Investigators Reporting of SAEs 
Any AE that meets a protocol-defined criterion as a SAE must be submitted within 24 hours of 
site awareness on an SAE form to the DMID Pharmacovigilance Group, at the following 
address:  
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
 
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible. The DMID Medical Monitor will review and 
assess the SAE for regulatory reporting and potential impact on study subject safety and protocol 
conduct. 
 
At any time after completion of the study, if the site PI or appropriate sub-investigator becomes 
aware of an SAE that occurred during the subject’s participation in the study, the site PI or 
appropriate sub-investigator will report the event to the DMID Pharmacovigilance Group. 
8.3.6.2 Regulatory Reporting of SAEs 
Following notification from the site PI or appropriate sub-investigator, DMID, as the IND 
Sponsor, will report any SUSAR in an IND safety report to the FDA and will notify all 
participating site PIs as soon as possible. DMID will report to the FDA any unexpected fatal or 
life-threatening suspected adverse reaction as soon as possible, but in no case later than 7 
calendar days after the Sponsor’s initial receipt of the information. If the event is not fatal or life-
threatening, the IND safety report will be submitted within 15 calendar days after the Sponsor 
determines that the information qualifies for reporting as specified in 21 CFR Part 312.32. 
Relevant follow up information to an IND safety report will be submitted as soon as the 
information is available. Upon request from the FDA, DMID will submit to the FDA any 
additional data or information that the agency deems necessary, as soon as possible, but in no 
case later than 15 calendar days after receiving the request. 
 
SAEs that are not SUSARs will be reported to the FDA at least annually in a summary format 
which includes all SAEs. 

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Sites may have additional local reporting requirements (to the IRB and/or national regulatory 
authority).  
8.3.7 
Reporting of Pregnancy 
Pregnancy is not an AE. However, any pregnancy that occurs during study participation should 
be reported to the Sponsor on the appropriate CRF. Pregnancy should be followed to outcome.  
8.4 
Unanticipated Problems 
8.4.1 
Definition of Unanticipated Problems 
An Unanticipated Problem (UP) is any event, incident, experience, or outcome that meets the 
following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied; 
 Related to participation in the research (meaning there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures involved in the 
research); and 
 Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
8.4.2 
Unanticipated Problem Reporting 
To satisfy the requirement for prompt reporting, all UPs will be reported using the following 
timeline: 
 UPs that are SAEs will be reported to the IRB and to the Statistical and Data 
Coordinating Center (SDCC)/study Sponsor within 24 hours of the investigator becoming 
aware of the event per the above describe SAE reporting process. 
 Any other UP will be reported to the IRB and to the SDCC/study Sponsor within 3 days 
of the investigator becoming aware of the problem. 
9. STATISTICAL CONSIDERATIONS 
This study is intended to allow for two types of adaptations: 1) sample size re-estimation and 2) 
addition of new experimental arm(s). A brief summary is provided here. Details will be 
described in the statistical analysis plan (SAP).  
 
Sample size re-estimation: The target of 400 recoveries corresponds to a total sample size that 
depends on the proportion of subjects who recover by Day 29. This proportion will be evaluated 
on pooled (i.e., blinded) data to evaluate the total sample size required. A preliminary estimate 
based on a 70% recovery probability is 572 patients.  
 

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Addition of new experimental therapies: If additional data become available to add an 
experimental therapy, the sample size will be updated accordingly. Analyses of newly added 
arm(s) will be performed comparing concurrently enrolled control subjects. This approach was 
used in the recent PALM study in patients with Ebola virus disease [Mulangu 2019]. Principles 
of adding arms and addressing questions of “when, what and how” to add them will be 
developed to guide the study team in their decision-making and will be outlined in a document 
on interim monitoring.  
9.1 Statistical Hypotheses 
 
The primary null hypothesis being tested is that time-to-recovery does not differ between the 
experimental and control arms.  
 
A key secondary endpoint is the distribution of the 8-point ordinal scale at Day 15. For this, the 
parameter of interest is the “common odds ratio,” which quantifies the shift in the severity 
distribution resulting from treatment. For an efficacious treatment, an odds ratio greater than 1 
quantifies an improvement in disease severity; a value of 2 indicates a bigger improvement than 
a value of 1.25. The null hypothesis to be tested is that the odds of improvement on the ordinal 
scale is the same for the placebo and experimental treatment arms (i.e., the common odds ratio is 
1). It is worth noting that, for large sample sizes, the test based on the proportional odds model is 
nearly the same as the Wilcoxon rank sum test. 
 
9.2 Sample Size Determination 
 
Primary endpoint: The log-rank test will be used to compare treatment arms with respect to time 
to recovery. For the log-rank test, the two key determinants of power are the total number of 
events (i.e., recoveries) E and the treatment-to-control ratio of the rate of recovery, R. The 
number of events required for power 1 −𝛽𝛽 to detect a recovery rate ratio of θ using a two-tailed 
test at alpha=0.05 is approximately 
𝐸𝐸=
4൫1.96 + 𝑧𝑧𝛽𝛽൯
2
{ln(𝜃𝜃)}2
, 
where 𝑧𝑧𝛽𝛽 is the 100(1 −𝛽𝛽)th percentile of the standard normal distribution. 
For 85% power, approximately 320 recoveries are required to detect a 40% increase in the rate of 
recovery (𝜃𝜃= 1.40) from remdesivir. A recovery rate ratio of 1.40 is similar to, but slightly 
higher than the figure of 1.31 reported in Cao, Wang, Wen et al. (2020) for a lopinavir/ritonavir 
trial that used time to improvement by 2 categories as primary endpoint. A total of 400 
recoveries is needed for a recovery ratio of 1.35 with 85% power. Table 4 provides power for 
various recovery rate ratios. 
 
Table 4 Number of recoveries needed for 85% power assuming a type I error rate of 5% 
for various recovery ratios. 
 

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Recovery ratio 
(θ) 
Number of recoveries 
needed for 85% 
power 
1.25 
723 
1.30 
523 
1.35 
400 
1.40 
318 
 
Key secondary: A sample size can be computed using an (assumed) ordinal scale distribution for 
the placebo and the odds ratio representing clinical improvement. The odds ratio represents the 
odds of improvement in the ordinal scale for treatment relative to placebo [Whitehead, 1993]. 
The sample size to detect a given odds ratio for 1:1 randomization using a 2-tailed test at level α 
is given by 
12൫𝑧𝑧α/2 + 𝑧𝑧β൯
2
λ2(1 −∑
𝑝𝑝𝑖𝑖
3
𝐾𝐾
𝑖𝑖=1
), 
 
where λ is the log odds ratio, 𝑝𝑝𝑖𝑖 is the overall probability (combined over both arms) of being in 
the ith category of the K ordinal outcomes, and 𝑧𝑧α/2 and 𝑧𝑧𝛽𝛽 are the 1 −α/2 and 1 −β quantiles 
of the standard normal distribution.  
 
Table 5 displays five scenarios considered for outcome probabilities in the placebo arm for 
sample size determination. There is significant uncertainty with these assumptions given the 
limited data available. Table 5 shows a range of sample sizes for odds ratios ranging from 1.25 to 
2.5 for 85% power. For 90% power, increase the sample size by 17%. Table 6 displays the 
probabilities of being in different categories of the ordinal scale under an odds ratio of 1.75. A 
total sample size of 396 gives approximately 85% power to detect an odds ratio of 1.75 using a 
2-tailed test at level α = 0.05. The categories of the 8-point ordinal scale are: 
 
• Death; 
• Hospitalized, on invasive mechanical ventilation or ECMO; 
• Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
• Hospitalized, requiring supplemental oxygen; 
• Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 
• Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical 
care; 
• Not hospitalized, limitation on activities and/or requiring home oxygen; 
• Not hospitalized, no limitations on activities. 
 
Note that the data elements contributing to this scale will be captured separately, in order to 
facilitate different orderings or groupings, as might arise if external data provide information 
about the clinical course of disease.  
 
 

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Table 5. Possible scenarios for the distribution of ordinal outcomes for the control arm at 
Day 15. 
 
Anticipated 
Different scenarios for control arm 
  
Scenario 1 
Scenario 2 
Scenario 3 
Scenario 4 
Scenario 5 
 
 
more mild disease                       more severe disease 
Severity Outcome 
outcome (%) outcome (%) 
outcome (%) outcome (%) outcome (%) 
Death 
2 
1 
1 
2 
3 
Hospitalized, on mechanical 
ventilation or ECMO 
1 
1 
1 
1 
3 
Hospitalized, on non-
invasive ventilation or high 
flow oxygen devices 
2 
1 
1 
2 
4 
Hospitalized, requiring 
supplemental oxygen 
7 
2 
5 
5 
9 
Hospitalized, not requiring 
supplemental oxygen - 
requiring ongoing medical 
care (COVID-19 related or 
otherwise) 
8 
5 
7 
17 
23 
Hospitalized, not requiring 
supplemental oxygen - no 
longer requires ongoing 
medical care 
10 
9 
10 
20 
25 
Not hospitalized, limitation 
on activities and/or requiring 
home oxygen 
30 
36 
35 
25 
18 
Not hospitalized, no 
limitations on activities 
40 
45 
40 
28 
15 
 
 
Table 6. Sample size calculations for scenarios in Table 5 for a two-arm study assuming 
85% power, a two-sided type I error rate of 5%, and various true odds ratios.  
True odds 
ratio 
Total sample size 
 
Scenario 1 
Scenario 2 
Scenario 3 
Scenario 4 
Scenario 5 
1.25 
2420 
2554 
2459 
2293 
2252 
1.5  
744 
786 
755 
700 
684 
1.75 
396 
419 
401 
370 
360 
2.0 
262 
277 
265 
243 
236 
2.25 
194 
206 
196 
179 
173 
2.5 
154 
163 
155 
141 
136 
 
 
 

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Table 7. Treatment ordinal outcome proportions under an odds ratio of 1.75 for five 
scenarios in Table 6 at Day 15. 
  
Scenario 
1 
Scenario 
2 
Scenario 
3 
Scenario 
4 
Scenario 
5 
 
Anticipated more mild disease                more severe disease 
Severity Outcome 
Control % 
Treatment % 
Control % 
Treatment % 
Control % 
Treatment % 
Control % 
Treatment % 
Control % 
Treatment % 
Death 
2 
1.2 
1 
0.6 
1 
0.6 
2 
1.2 
3 
1.7 
Hospitalized, on mechanical 
ventilation or ECMO 
1 
0.6 
1 
0.6 
1 
0.6 
1 
0.6 
3 
1.8 
Hospitalized, on non-invasive 
ventilation or high flow 
oxygen devices 
2 
1.2 
1 
0.6 
1 
0.6 
2 
1.2 
4 
2.5 
Hospitalized, requiring 
supplemental oxygen 
7 
4.3 
2 
1.2 
5 
3.0 
5 
3.1 
9 
5.8 
Hospitalized, not requiring 
supplemental oxygen - 
requiring ongoing medical 
care (COVID-19 related or 
otherwise) 
8 
5.3 
5 
3.1 
7 
4.4 
17 
11.5 
23 
17.4 
Hospitalized, not requiring 
supplemental oxygen - no 
longer requires ongoing 
medical care; 
10 
7.2 
9 
5.9 
10 
6.8 
20 
16.2 
25 
24.4 
Not hospitalized, limitation 
on activities and/or requiring 
home oxygen 
30 
26.5 
36 
29.3 
35 
30.2 
25 
25.9 
18 
22.7 
Not hospitalized, no 
limitations on activities 
40 
53.8 
45 
58.9 
40 
53.8 
28 
40.5 
15 
23.6 
Note that columns may not sum to exactly 100 due to rounding errors. 
 
 

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9.3 Populations for Analyses 
The primary analysis will be based on an intention-to-treat population, including all subjects 
randomized. Similarly, safety analyses will be based a modified intent-to-treat population 
consisting of all subjects who received at least one infusion. The primary analysis will be based 
on those subjects enrolled in order to 400 recoveries. Subsequent analysis will be performed on 
all enrolled subjects.   
 
9.4 Statistical Analyses 
9.4.1 
General Approach 
This is a double-blind placebo controlled randomized trial testing a superiority hypothesis with a 
two-sided type I error rate of 5%. Secondary hypotheses have been ordered according to relative 
importance, with one key secondary hypothesis highlighted. These will be described according to 
the appropriate summary statistics (e.g., proportions for categorical data, means with 95% 
confidence intervals for continuous data, median for time-to-event data).  
 
A statistical analysis plan will be developed and filed with the study sponsor prior to unblinding 
of study and database lock.  
 
Unblinding of the study will occur after all subjects enrolled for 400 recoveries have reached the 
end of study, and these visits are monitored and data is cleaned.     
 
9.4.2 
Analysis of the Primary Efficacy Endpoint 
The primary efficacy analysis is a stratified log-rank test, where stratification is according to 
baseline disease severity (i.e. protocol defined mild/moderate vs severe disease). Deaths will be 
considered censored at Day 29. 
 
9.4.3 
Analysis of the Secondary Endpoint(s) 
 
1) The ordinal scale will be used to estimate a proportional odds model by disease strata. 
The hypothesis test will perform a stratified test to evaluate whether the common odds 
ratio for treatment is equal to one. The distribution of severity results will be summarized 
by treatment arm as percentages. Efforts to minimize loss-to-follow-up will be 
considerable. However, small amounts of missing data may occur. In such cases, subjects 
without final outcome data will be excluded from the analysis. Sensitivity analyses will 
evaluate the impact of making different assumptions about missing observations. These 
analyses will be defined in the SAP.  
 
2) Differences in time-to-event endpoints (e.g., time to at least a one category improvement 
in ordinal scale) by treatment will be summarized with Kaplan-Meier curves and 95% 
confidence bounds. The same procedure will be used to compare time to at least a two 
category improvement. 

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3) Change in ordinal scale at specific time points will be summarized by proportions (e.g., 
proportion who have a 1-, 2-, 3-, or 4-point improvement or 1-, 2-, 3-, 4-point 
worsening). 
4) Duration of event (e.g., duration of mechanical ventilation) will be summarized according 
to median days with quartiles. 
5) Binary data (e.g., incidence of new oxygen use) will be summarized as a percent with 
95% confidence intervals. Comparisons between arms will be presented as differences in 
proportions with 95% confidence intervals. 
6) Categorical data (e.g., 28-day mortality or ordinal scale by day) may be summarized 
according to proportions by category and/or odds ratios with confidence intervals.  
 
Procedures for handling missing data, including informative censoring (e.g., a missing 
duration of oxygen use endpoint due to a death), will be described in the SAP. 
 
9.4.4 
Safety Analyses 
Safety endpoints include death through Day 29, SAEs and Grade 3 and 4 AEs. These events will 
be analyzed univariately and as a composite endpoint. Time-to-event methods will be used for 
death and the composite endpoint. Each AE will be counted once for a given subject and graded 
by severity and relationship to COVID-19 or study intervention. AEs will be coded using the 
current version of the Medical Dictionary for Regulatory Activities (MedDRA). AEs will be 
presented by system organ class, duration (in days), start- and stop-date. Adverse events leading 
to premature discontinuation from the study intervention and serious treatment-emergent AEs 
will be presented either in a table or a listing.  
 
9.4.5 
Baseline Descriptive Statistics 
Baseline characteristics will be summarized by treatment arm. For continuous measures the 
mean and standard deviation will be summarized. Categorical variables will be described by the 
proportion in each category (with the corresponding sample size numbers).  
 
9.4.6 
Planned Interim and Early Analyses  
Early analyses: 
A blinded sample size re-estimation will be conducted after approximately 115 patients to 
evaluate the proportion of subjects who have recovered by Day 29, which will provide important 
information about the number of patients needed to achieve 400 recoveries. Additionally, the 
number of deaths will be evaluated. 
 
Additional early analyses include monitoring enrollment, baseline characteristics, and follow-up 
rates throughout the course of the study by the study team. Analyses will be conducted blinded to 
treatment assignment.  
 
Interim analyses: 
A DSMB will monitor ongoing results to ensure subject well-being and safety as well as study 
integrity. The DSMB will be asked to recommend early termination or modification only when 
there is clear and substantial evidence of a treatment difference. More details about the interim 

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analyses are described in section 9.4.6.1 and 9.4.6.2 below as well as a separate guidance 
document for the DSMB.  
 
9.4.6.1 Interim Safety Analyses 
Safety analyses will evaluate Grade 3 and 4 AE and SAEs by treatment arm.  Safety monitoring 
will be ongoing (see section 10.1.6) and evaluate safety results weekly. This approach is less 
conservative than what will be used to test for early efficacy results because proving definitive 
harm of the experimental agents is not the focus of this study. Pocock stopping boundaries at the 
looks described correspond to z-scores of (2.28, 2.29, 2.30). This contrasts with the z-score 
stopping boundaries for the Lan-DeMets spending function that mimics O’Brien-Fleming 
boundaries: (3.71, 2.51, 1.99). The unblinded statistical team will prepare these reports for 
review by the DSMB.  
 
9.4.6.2 Interim Efficacy Review 
The Lan-DeMets spending function analog of the O’Brien-Fleming boundaries will be used to 
monitor the primary endpoint as a guide for the DSMB for an overall two-sided type-I error rate 
of 0.05. Interim efficacy analyses will be conducted after the blinded sample size re-estimation 
of the primary efficacy endpoint at approximately 33%, 67%, and 100% of total information.  
 
Conditional power will be presented as an additional guide to the DSMB. Conditional power 
allows computation of the probability of obtaining a statistically significant result by the end of 
the trial given the data accumulated thus far, incorporating and assuming a hypothesized 
treatment effect (e.g., the treatment effect assumed for sample size determination) thereafter. If 
conditional power is less than 20% under the original trial assumptions, consideration should be 
given to stopping the trial.  
 
The unblinded statistical team will prepare these closed reports for DSMB review and 
recommendations. Analyses will be presented with blinded codes for treatment arms to protect 
against the possibility that the DSMB report may fall into the wrong hands. A DSMB charter 
will further describe procedures and membership. An additional document on statistical issues 
related to monitoring will be provided to the DSMB prior to interim analyses.  
 
9.4.7 
Sub-Group Analyses 
Subgroup analyses for the primary outcomes will evaluate the treatment effect across the 
following subgroups: geographic region, duration of symptoms prior to enrollment, age, sex and 
comorbidities. A forest plot will display confidence intervals across subgroups. Interaction tests 
will be conducted to determine whether the effect of treatment varies by subgroup. 
 
9.4.8 
Exploratory Analyses 
An exploratory analysis will compare treatment efficacy estimates according to the various 
scales outlined in section 8.1.3. Specifically, the probability of falling into category “i” or better 
will be compared between arms for each i.  
 
 

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Regulatory, Ethical, and Study Oversight Considerations 
This study will be conducted in conformity with the principles set forth in The Belmont Report: 
Ethical Principles and Guidelines for the Protection of Human Subjects of Research (US 
National Commission for the Protection of Human Subjects of Biomedical and Behavioral 
Research; April 18, 1979), and the federal policy for the Protection of Human Subjects codified 
in 45 CFR Part 46, 21 CFR Part 50 (Protection of Human Subjects), and the ICH E6 (R2). 
 
Each institution engaged in this research will hold an OHRP-approved FWA. OHRP-registered 
IRBs will review and approve this protocol, associated informed consent documents, recruitment 
material, and handouts or surveys intended for the subjects, prior to the recruitment, screening, 
and enrollment of subjects. The IRB review shall be in accordance with 45 CFR 46 and 21 CFR 
50, 21 CFR 56 (IRBs), and other federal, state, and local regulations and policies, as applicable. 
 
Site IRBs may have additional national and local regulations. 
 
Any amendments to the protocol or consent materials will be approved by the IRB before they 
are implemented. IRB review and approval will occur at least annually throughout the duration 
of the study. The investigator will notify the IRB of deviations from the protocol and SAEs, as 
applicable to the IRB policy. 
 
DMID must receive the documentation that verifies IRB-approval for this protocol, informed 
consent documents, and associated documents prior to the recruitment, screening, and enrollment 
of subjects, and any IRB-approvals for continuing review or amendments as required by the 
DMID. 
10.1.1 Informed Consent Process 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation. Investigators or designated 
research staff will obtain a subject’s informed consent in accordance with the requirements of 45 
CFR 46, 21 CFR 50 and 21 CFR 56 for FDA-regulated studies, state and local regulations and 
policy, and ICH E6 GCP before any study procedures or data collection are performed. 
Typically, subjects or their legally authorized representatives (LAR) receive a concise and 
focused presentation of key information about the clinical trial, verbally and with a written 
consent form. Subjects will be asked to read and review the consent form. Subjects (or LAR) 
must sign the ICF prior to starting any study procedures being done specifically for this trial. 
Once signed, a copy of the ICF will be given to the subject or the LAR for their records. 
 
For subjects for whom a LAR gave consent, during the course of the study, if the subject regains 
the capacity to consent, informed consent must be obtained from the subject and the subject 
offered the ability to leave the study if desired. 
 
 

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However, due to strict respiratory isolation policies, limited access to COVID-19 patient rooms 
and SARS-CoV-2 transmissibility via droplet-contaminated paper, verbal consent and alternative 
methods of obtaining consent (e.g., by phone) will be allowed if approved by the IRB. In 
addition, if a signed paper copy of the ICF is allowed by hospital policy, how it will be obtained 
and stored will need to be determined. Any variation from the standard the consent process due 
to isolation and infection control should be sent to the IRB for approval prior to enrollment. The 
site should document the process in their regulatory files and demonstrate that the process has 
IRB concurrence or approval. 
 
Regardless of the method for obtaining consent, the key information about the study will be 
organized and presented in lay terminology and language that facilitates understanding why one 
might or might not want to participate. The site should translate the consent into non-English 
languages consistent with the local population. Translations should be sent to the sponsor for any 
necessary back translations. New information will be communicated by the site PI to subjects 
who consent to participate in this trial in accordance with IRB requirements. The informed 
consent document will be updated, and subjects will be re-consented per IRB requirements, if 
necessary. 
 
10.1.1.1 Requirements for Permission by Parents/Guardians and Assent by Children (in 
case of a minor) 
Not Applicable 
 
10.1.1.2 Other Informed Consent Procedures 
Subjects will be asked for consent to collect additional blood, the use of residual specimens, and 
samples for secondary research. Extra blood will be drawn for secondary research during each 
visit when a study blood samples are obtained.  
 
The stored samples will be labeled with barcodes to maintain confidentiality. Research with 
identifiable samples and data may occur as needed; however, subject confidentiality will be 
maintained as described for this protocol and with IRB approval. 
 
Samples designated for secondary research use may be used for understanding the SARS-CoV-2 
infection, the immune response to this infection, and the effect of therapeutics on these factors.  
Samples will not be used to create immortal cell lines, neither sold for commercial profit. 
Although the results of any future research may be patentable or have commercial profit, 
subjects will have no legal or financial interest in any commercial development resulting from 
any future research. 
There are no direct benefits to the subject for extra specimens collected or from the secondary 
research. No results from secondary research will be entered into the subject’s medical record. 
Incidental findings will not be shared with the subject, including medically actionable incidental 
findings, unless required by law. 
Subjects may withdraw permission to use samples for secondary use at any time. They will need 
to contact the study site and the samples will be removed from the study repository after this 

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study is completed and documentation will be completed that outlines the reason for withdrawal 
of permission for secondary use of samples.  
 
10.1.2 Study Termination and Closure 
Section 7, Study Intervention Discontinuation and Subject Discontinuation/Withdrawal, 
describes the temporary halting of the study. 
 
This study may be prematurely terminated if there is sufficient reasonable cause, including but 
not limited to: 
• Determination of unexpected, significant, or unacceptable risk to subjects 
• Results of interim analysis 
• Insufficient compliance with protocol requirements 
• Data that are not sufficiently complete and/or not evaluable 
• Regulatory authorities decide that study should be terminated 
If the study is prematurely terminated, then the site PI will promptly inform study subjects and 
the IRB as applicable. The site PI will assure appropriate follow-up for the subjects, as 
necessary. 
 
The Sponsor will notify regulatory authorities as applicable. 
10.1.3 Confidentiality and Privacy 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
the Sponsor(s) and their agents. This confidentiality is extended to cover clinical information 
relating to subjects, test results of biological samples, and all other information generated by 
participation in the study. No identifiable information concerning subjects in the study will be 
released to any unauthorized third party. Subject confidentiality will be maintained when study 
results are published or discussed in conferences. 
 
The study monitor, other authorized representatives of the Sponsor, representatives of the IRB, 
and/or regulatory agencies may inspect all documents and records required to be maintained by 
the investigator, including but not limited to medical records (office, clinic, or hospital) and 
pharmacy records for the subjects in this study. The clinical study site will permit access to such 
records. 
 
All source records including electronic data will be stored in secured systems in accordance with 
institutional policies and federal regulations. 
 
All study data and research specimens that leave the site (including any electronic transmission 
of data) will be identified only by a coded number that is linked to a subject through a code key 
maintained at the clinical site. Names or readily identifying information will not be released 
unless DMID approves and it aligns with the consent form, or according to laws for required 
reporting. 

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10.1.4 Secondary Use of Stored Specimens and Data 
This section applies to those subjects who consented to storage of samples for secondary 
research. Secondary Human Subject Research is the re-use of identifiable data or identifiable 
biospecimens that were collected from some other ‘‘primary’’ or ‘‘initial’’ activity, such as the 
data and samples collected in this protocol. Any use of the sample or data for secondary research 
purposes, however, will be presented in a separate protocol and require separate IRB approval. 
 
Each sample will be labeled only with a barcode and a unique tracking number to protect subject 
confidentiality. Secondary research with coded samples and data may occur; however, subject 
confidentiality will be maintained as described for this protocol. An IRB review of the secondary 
research using coded specimens is required. 
 
The subject’s decision can be changed at any time by notifying the study doctors or nurses in 
writing. If the subject subsequently changes his/her decision, the samples will be destroyed if the 
samples have not been used for research or released for a specific research project. 
10.1.4.1 Data Sharing for Secondary Research 
Data from this study may be used for secondary research. All of the individual subject data 
collected during the trial will be made available after de-identification. The SAP and Analytic 
Code will also be made available. This data will be available immediately following publication, 
with no end date.  
 
The investigator may request removal of data on individual study subjects from NIH data 
repositories in the event that a research subject withdraws or changes his or her consent. 
However, some data that have been distributed for approved research use cannot be retrieved. 
10.1.5 Key Roles and Study Governance 
The study is sponsored by DMID. Decisions related to the study will be made by a protocol team 
that includes representatives from all countries, and separate networks within a country. 
10.1.6 Safety Oversight 
10.1.6.1 Protocol team oversight 
A subset of the protocol team will review blinded pools of AE data every 2 weeks to ensure no 
significant number of unexpected AEs (AEs that do not fit with the known course of COVID-
19). If there are a significant number of unexpected AEs, the DSMB will be asked to review 
unblinded safety data in an ad hoc meeting.  
10.1.6.2 Data Safety Monitoring Board 
Safety oversight will be conducted by a DSMB that is an independent group of experts that 
monitors subject safety and advises DMID. The DSMB members will be separate and 
independent of study personnel participating in this trial and should not have scientific, financial 
or other conflicts of interest related to this trial. The DSMB will consist of members with 
appropriate expertise to contribute to the interpretation of the data from this trial. The DSMB 
should be as broadly informed as possible regarding emerging evidence from related studies. The 
DSMB will operate under the guidelines of a DMID-approved charter that will be written at the 
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hoc during this trial. The DMID Medical Monitor will be responsible for reviewing SAEs in real 
time. The DSMB will review SAEs on a regular basis and ad hoc during this trial. 
 
The DSMB will conduct the following reviews: 
• Electronic access to safety data after every 50 subjects are dosed. If this trigger occurs 
more frequently than every 4 weeks, then the meeting can be delayed until approximately 
4 weeks after the last meeting. 
• Formal reviews of safety/efficacy after approximately 200 subjects have met recovered 
status. 
• Ad hoc meeting if the protocol team raises any concerns 
• A final review meeting after final clinical database lock, to review the cumulative 
unblinded safety data for this trial.  
 
The study will not stop enrollment awaiting these DSMB reviews, although the DSMB may 
recommend temporary or permanent cessation of enrollment based on their safety reviews. 
  
Additional data may be requested by the DSMB, and interim statistical reports may be generated 
as deemed necessary and appropriate by DMID. The DSMB may receive data in aggregate and 
presented by treatment arm. The DSMB may also be provided with expected and observed rates 
of the expected AEs in an unblinded fashion and may request the treatment assignment be 
unblinded for an individual subject if required for safety assessment. The DSMB will review 
grouped and unblinded data in the closed session only. At each meeting, the DSMB will make a 
recommendation as to the advisability of proceeding with study interventions (as applicable), and 
to continue, modify, or terminate this trial. 
 
10.1.7 
Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial subjects are 
protected and that the reported trial data are accurate, complete, and verifiable. Clinical 
monitoring also ensures that conduct of the trial is in compliance with the currently approved 
protocol/ amendment(s), ICH, GCP, and with applicable regulatory requirement(s) and Sponsor 
requirements. Clinical monitoring will also verify that any critical study procedures are 
completed following specific instructions in the protocol-specific MOP. 
 
Monitoring for this study will be performed by DMID or their designee. Details of clinical site 
monitoring are documented in a clinical monitoring plan (CMP). The CMP describes in detail 
who will conduct the monitoring, at what frequency monitoring will be done, at what level of 
detail monitoring will be performed, and the distribution of monitoring reports. Monitoring visits 
will include, but are not limited to, review of regulatory files, accountability records, CRFs, 
ICFs, medical and laboratory reports, site study intervention storage records, training records, 
and protocol and GCP compliance. Site monitors will have access to each participating site, 
study personnel, and all study documentation according to the DMID-approved site monitoring 
plan. Study monitors will meet with site PIs to discuss any problems and outstanding issues and 
will document site visit findings and discussions. 
10.1.8 Data Handling and Record Keeping 

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10.1.8.1 Data Collection and Management Responsibilities 
Data collection is the responsibility of the study personnel at the participating clinical study site 
under the supervision of the site PI. The site PI must maintain complete and accurate source 
documentation. 
 
Clinical research data from source documentation (including, but not limited to, AE/SAEs, 
concomitant medications, medical history, physical assessments, clinical laboratory data) will be 
entered by the clinical study site into CRFs via a 21 CFR Part 11-compliant internet data entry 
system provided by the SDCC. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. AEs and concomitant medications will be coded according to the most 
current versions of MedDRA and WHODrug, respectively. 
 
The SDCC for this study will be responsible for data management, quality review, analysis, and 
reporting of the study data. 
 
The IND Sponsor is responsible for review of data collection tools and processes, and review of 
data and reports. 
 
A separate study specific Study Data Standardization Plan (SDSP) appendix will be developed 
which describes the technical recommendations for the submission of human study data and 
related information in a standardized electronic format throughout product development. 
 
At the end of the study, a copy of all datasets including annotated CRFs and data dictionary will 
be provided to DMID. 
10.1.8.2 Study Record Retention 
Study related records, including the regulatory file, study product accountability records, consent 
forms, subject source documents and electronic records should be maintained for a period of 2 
years following the date a marketing application is approved for the investigational product for 
the indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified. These documents should be retained for a longer period, 
however, if required by local policies or regulations. No records will be destroyed without the 
written consent of DMID. Consent forms with specimen retention linked to identifiable 
specimens will be maintained for as long as the specimens remain in identifiable format, and a 
minimum of three years after use of the identifiable specimens in nonexempt human subject 
research. 
10.1.8.3 Source Records 
Source data are all information in original records (and certified copies of original records) of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Each participating site will maintain 
appropriate medical and research records for this trial, in compliance with ICH GCP, regulatory, 
and institutional requirements. Data recorded in the CRF derived from source documents should 
be consistent with the data recorded on the source documents.  

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It is understood that biocontainment may necessitate alternative processes for storing consents 
and other source documents. Each site will determine and document this process. 
 
Interview of subjects is sufficient for obtaining medical history. Solicitation of medical records 
from the subject’s primary care provider is not required. 
10.1.9  Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, any process that is 
noted in the protocol and refers to details in the protocol-specific MOP, or GCP requirements or 
any critical study procedures with specific instructions in ancillary documents referenced in the 
protocol such as a protocol-specific MOP. 
 
The noncompliance may be either on the part of the subject, the investigator, or the study site 
staff. Following a deviation(s), corrective actions should be developed by the site and 
implemented promptly. All individual protocol deviations will be addressed in subject study 
records. 
 
It is the responsibility of the site PI and personnel to use continuous vigilance to identify and 
report deviations within five working days of identification of the protocol deviation, or within 
five working days of the scheduled protocol-required activity. All deviations must be promptly 
reported to DMID per the protocol deviation reporting procedures. Protocol deviations must be 
sent to the local IRB/IEC per their guidelines. The site PI and personnel are responsible for 
knowing and adhering to their IRB requirements. A completed copy of the DMID Protocol 
Deviation Form must be maintained in the Regulatory File, as well as in the subject’s chart if the 
deviation is subject specific. 
10.1.10 Publication and Data Sharing Policy 
Following completion of the study, results of this research will be published in a scientific 
journal. As this is an adaptive study and given the public health urgency to disseminate results, 
data from individual comparisons (i.e. the initial 2 study arms) can be published when those arms 
are fully enrolled and all subjects in those arms are followed through to completion of the study.  
 
Data will be available immediately following publication, with no end date, with data sharing at 
the discretion of the Sponsor. Sites may also obtain individual or country level data from the 
database for separate publications is desired. Publication may occur prior to completion of a final 
clinical study report for the entire trial. 
10.1.11 Human Data Sharing Plan 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
• NIH Public Access Policy, which ensures that the public has access to the published 
results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon 
acceptance for publication. 

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10.1.12 Publication 
Following completion of the study, the protocol team is expected to publish the results of this 
research in a scientific journal. This study will adhere to the following publication and data 
sharing policies and regulations: 
• This study will comply with the NIH Public Access Policy, which ensures that the public 
has access to the published results of NIH funded research. As such, the final peer-
reviewed journal manuscripts will accessible to the public on PubMed Central no later 
than 12 months after publication. 
10.1.13 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. DMID has established policies and procedures for all study group members 
to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
10.2 
Additional Considerations 
10.2.1 
Research Related Injuries 
For any potential research related injury, the site PI or designee will assess the subject. Study 
personnel will try to reduce, control, and treat any complications from this study. Immediate 
medical treatment may be provided by the participating study site. As needed, referrals to 
appropriate specialist or other health care facilities will be provided to the subject. The site PI 
should then determine if an injury occurred as a direct result of the tests or treatments that are 
done for this trial. 
 
Immediate medical treatment may be provided by the participating site, such as giving 
emergency medications to stop immediate allergic reactions. No financial compensation will be 
provided to the subject by NIAID, NIH or the participating site for any injury suffered due to 
participation in this trial. 
 
10.3 
Abbreviations 
Abbreviation 
Definition 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
BP 
Blood Pressure 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 

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Abbreviation 
Definition 
CMS 
Clinical Material Services 
Cr 
Creatinine 
CRF 
Case Report Form 
CROMS 
Clinical Research Operations and Management Support 
CSR 
Clinical Study Report 
CQMP 
Clinical Quality Management Plan 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases 
EC 
Ethics Committee 
EMR 
Electronic Medical Record 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
Hgb 
Hemoglobin 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICD 
International Classification of Diseases 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
Intravenous 
MCG 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East Respiratory Syndrome 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NDA 
New Drug Application 
NEWS 
National Early Warning Score 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OP 
Oropharyngeal  
PHI 
Protected Health Information 
PI 
Principal Investigator 
PLT 
Platelet 
PP 
Per Protocol 
PT 
Prothrombin Time 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS 
Severe Acute Respiratory Syndrome 
SDCC 
Statistical and Data Coordinating Center 
SDSP 
Study Data Standardization Plan 

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Abbreviation 
Definition 
SNP 
Single Nucleotide Polymorphisms 
SOA 
Schedule of Assessments 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T. Bili 
Total Bilirubin 
UP 
Unanticipated Problem 
US 
United States 
WBC 
White Blood Cell 
10.4 
Protocol Amendment History 
Version/Date 
 
 
Section 
Description of 
Change 
Brief Rationale 
2.0 
2MAR2020 
 
 
 
Overall 
This version addresses the comments received from 
the US FDA, Japanese PDMA, DSMB, IRBs, and 
NIAID scientific review. 
 
Improved clarity and 
brevity 
Multiple areas throughout the document were 
reworded to improve clarity (recognized after 
implementation) and edited to minimize redundant 
statements. 
1.1 
Number of sites 
increased from 50 to 
approximately 75 
Given the currently unpredictable epidemiology, 
additional sites will improve the ability to enroll the 
study in a timely manner. 
 
Sample size increased 
Version 1 sample size table and statements in the text 
did not align. The new assumptions use a slightly 
smaller treatment effect (OR 1.75) and the 8-
category scale and give the sample size of 440. 
 
Addition of phone call 
on Day 22 
Recent information from the outbreak in China 
suggest some COVID-19 patients worsen between 2 
and 4 weeks of illness. We added Day 22 because of 
concerns that the peak illness may be missed. There 
are also concerns if the more severe population will 
be discharged by Day 29. 
 
Ordinal scale was 
increased to 8 
categories. 
This addresses the concern raised by several reviews 
that “Hospitalized not on oxygen” is two separate 
populations – those still needing medical care and 
those kept in hospital just for infection control. 
 
Objectives and 
endpoints were put 
into table format 
Multiple comments that the tabular form of 
objectives and endpoints (that was previously in 
Section 4) was much easier to read and understand. 

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Added inclusion 
criteria for admission 
to hospital 
This was implied throughout the document, but never 
stated in the inclusion criteria. 
 
Inclusion criteria #8 
Contraceptive requirement aligned to new IB from 
February 21, 2020 
 
Phase of study 
Changed to phase 3. After discussion with company, 
and new IB that outlines safety data of > 500 
subjects, the company thought this was more 
accurately called a phase 3 trial. 
1.2 
Schedule of 
Assessments updated 
To include Day 22. Footnotes also revised for clarity. 
2.2 
Background updated 
To reflect current understanding of SARS-CoV, 
COVID-19, and new data from IB. 
3. 
Separating objectives 
about non-invasive 
from invasive 
mechanical 
ventilation 
Elsewhere in the protocol, it was mentioned that this 
data would be captured separately, but it mistakenly 
never made into an endpoint. 
 
Added Day 14 
mortality 
To allow better assessment of short and long term 
mortality. 
4 
Rewritten for clarity 
These paragraphs were substantially rewritten, but 
aside from the changes note above the content is not 
different. 
8 
Screening is more 
detailed 
These edits reflect so ambiguity discovered with the 
first enrollment. 
8.1.2 
Efficacy assessments 
more detailed 
More detail is provided to facilitate these 
assessments. Also, each component that contribute to 
the categories will not be captured separately. This 
will allow the ordinal scale as structured, but also 
will allow analysis of alternative ordinal scales. 
8.1.3.1 
Viral load in plasma 
and resistance 
The assessment of viral load in plasma and detection 
of resistance was previously noted on the SOA, but 
never discussed in the text. This has now been added 
in this section. 
9.2 
Sample size 
calculations 
With the addition of one category to the ordinal 
scale, the estimates per category must change leading 
to new tables. 
3.0 
27MAR2020 
 
 
 
Improved clarity  
Multiple areas throughout the document were 
reworded to improve clarity (issues that arose with 
implementation)  
 
Flexibility 
The pandemic has limited ability for people to be 
seen in followup due to infection control and 
restrictions on travel. Additionally, staff at some sites 
have limited ability to go into rooms due to limited 

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personal protective equipment. So flexibility has 
been added where possible while still ensuring safety 
and good scientific data.  
1.1 
Sample Size Increase 
The sample size was changed to reflect ensuring 
sufficient samples for the endpoint of interest which 
400 subjects with a “recovered” status (per the 
primary objective). Additionally, enrollment is 
permitted after the 400 recoveries up to April 20 to 
provide additional data about important subgroups. 
 
Primary Endpoint 
Given evolving data, the precise day of assessment 
of the primary endpoint is not clear. Modeling of the 
prior endpoint suggested if the day is chosen 
incorrectly, the power is significantly decreased. So 
the primary endpoint has been changed from a 
ordinal scale on a given day to days to recovery (the 
best three categories of the ordinal scale.  
 
Key secondary 
endpoint 
The prior primary endpoint has been labeled as the 
key secondary endpoint. 
 
Inclusion Criteria #5 
Given delays of PCR results in some sites (given 
number of tests and throughput within the lab), the 
PCR positive requirement has been written to allow 
flexibility if the PCR results are delayed.  
 
Inclusion Criteria #6 
Removed auscultation requirement given challenges 
of accurate auscultation while in full PPE.  
 
Exclusion Criteria #2 
Cutoff of eGFR to 30 was decreased after discussion 
with the manufacturer and FDA.  
 
Sites 
Increased to 100 given unpredictable epidemiology 
of COVID-19 
 
DSMB 
Given the rapid pace of enrollment, the prior plans 
for DSMB oversight are not practical, so this has 
been modified with input from the DSMB on when 
they would like to have interim reviews.  
2.3.2 
Drug interaction 
Corrected erroneous statements about CYP 
inhibition.  
5.3 
Vulnerable Subjects 
Allow inclusion of those that are incapable of 
consent such as cognitively impaired. Prior version 
noted consent by a LAR, but it was not described in 
this section.  
6 
Study Product 
Updated throughout for 2 issues. First, the newly 
manufactured lot of remdesivir is in 100mg vials. 
Second, there is limited supply of placebo and the 
options for using saline with an opaque bag for the 
control infusion was added.  
6.5 
Concomitant Therapy 
There has been significant increased in use of off 
label therapies for COVID-19, including many 
repurposed agents and therapies targeting immune 

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11. REFERENCES 
 
1. Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, Xing F, Liu J, Yip CC, Poon RW, 
Tsoi HW, Lo SK, Chan KH, Poon VK, Chan WM, Ip JD, Cai JP, Cheng VC, Chen H, 
Hui CK, Yuen KY. 2020. A familial cluster of pneumonia associated with the 2019 novel 
coronavirus indicating person-to-person transmission: a study of a family cluster. The 
Lancet. Jan 24. pii: S0140-6736(20)30154-9. doi: 10.1016/S0140-6736(20)30154-9. 
2. Wu JT, Leung K, Leung GM. 2020. Nowcasting and forecasting the potential domestic 
and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a 
modelling study. The Lancet, Jan 31. pii: S0140-6736(20)30260-9. doi: 10.1016/S0140-
6736(20)30260-9. 
3. M. K. Lo et al., GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and 
Paramyxoviruses. Sci. Rep. 7, 43395 (2017).  
4. T. K. Warren et al., Therapeutic efficacy of the small molecule GS-5734 against Ebola 
virus in rhesus monkeys. Nature 531, 381–385 (2016). 
5. M. K. Lo et al., Remdesivir (GS-5734) protects African green monkeys from Nipah virus 
challenge. Sci. Transl. Med. 11, eaau9242 (2019). 
6. Mulangu S. et. al. J. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1910993. PMID: 
31774950. 
7. T. P. Sheahan et al., Broad-spectrum antiviral GS-5734 inhibits both epidemic and 
zoonotic coronaviruses. Sci. Transl. Med. 9, eaal3653 (2017). 
8. T. P. Sheahan et al., Comparative therapeutic efficacy of remdesivir and combination 
lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat. Commun. 11, 222 
(2020). 
response. So additional wording was added to cover 
these scenarios to minimize additional confounding 
medications.  
8.1.3 
Sample Processing  
Some sites are reporting needing to process samples 
in BSL-3 and/or have limitations on processing, 
shipping, storage, etc. of samples. So wording was 
added to allow exclusion of these samples (which 
may be cost prohibitive)  
8.2 
Venipuncture volume 
This table was corrected for total volumes, but not 
new samples were added.  
9 
Statistical 
Considerations 
This section was rewritten to given the change in 
sample size. 
10.1.1 
Informed consent 
Given isolation and infection control issues with 
COVID-19, traditional consenting documentation is 
not always possible. This section was rewritten to 
allow alternative consent processes and 
documentation as long as these are acceptable to the 
site’s IRB.  

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9. M. L. Agostini et al., Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is 
mediated by the viral polymerase and the proofreading exoribonuclease. MBio 9, 
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10. E. de Wit et al., Middle East respiratory syndrome coronavirus (MERS-CoV) causes 
transient lower respiratory tract infection in rhesus macaques. Proc. Natl. Acad. Sci. 
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11. E. de Wit et al., Prophylactic and therapeutic remdesivir (GS-5734) treatment in the 
rhesus macaque model of MERS-CoV infection. Proc. Natl. Acad. Sci. U.S.A. (2020). 
12. NCT04257656: A Phase 3 Randomized, Double-blind, Placebo-controlled, Multicenter 
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lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J 
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severe acute respiratory syndrome: a preliminary study. JAMA 2003;290:3222–3228. 
15. Wong VW, Dai D, Wu AK, et al. Treatment of severe acute respiratory syndrome with 
convalescent plasma. Hong Kong Med J 2003;9:199–201. 
16. Barnard DL, Hubbard VD, Burton J, et al. Inhibition of severe acute respiratory 
syndrome-associated coronavirus (SARSCoV) by calpain inhibitors and beta-D-N4-
hydroxycytidine. Antivir Chem Chemother 2004;15:15–22. 
17. Chu CM, Cheng VC, Hung IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: 
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23. Yamamoto N, Yang R, Yoshinaka Y, et al. HIV protease inhibitor nelfinavir inhibits 
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24. Zheng B, He ML, Wong KL, et al. Potent inhibition of SARS-associated coronavirus 
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25. Cinatl J, Morgenstern B, Bauer G, et al. Glycyrrhizin, an active component of liquorice 
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Country specific appendix 
The following language applies only to Clinical Research Sites located in the United States. 
10.2.2 Public Readiness and Emergency Preparedness Act 
The drug Remdesivir and the efforts for this clinical trial are covered under the Public Readiness 
and Emergency Preparedness Act (PREP Act) and the Declaration issued by the Secretary of the 
U.S. Department of Health and Human Services under that Act. Under the PREP Act and the 
Declaration, covered persons (such as manufacturers, distributers, program planners, and other 
qualified persons who prescribe, administer or dispense study product) are immune from liability 
from the administration, or use of a covered countermeasure, such as Remdesivir . The PREP 
Act provides immunity for covered persons from liability, unless the injury was caused by 
willful misconduct. The Declaration invoking the PREP Act for COVID-19 covered 
countermeasures was made on March 17, 2020 and is retroactively effective from February 4, 
2020. 
The PREP Act also established the Countermeasures Injury Compensation Program (CICP) to 
provide compensation for serious injuries or death that occur as the direct result of the 
administration or use of certain countermeasures. Any requests for compensation must be filed 
within one year of the administration or use of the covered countermeasure. Requests for 
Benefits must be made to the Health Resources and Services Administration’s (HRSA) 
Countermeasures Injury Compensation Program (http://www.hrsa.gov/cicp/) by filing a Request 
for Benefits Form and all required medical records and supporting documentation. Additional 
information on filing a Request for Benefits is available on the CICP’s website at 
http://www.hrsa.gov/cicp/.  Compensation may then be available for reasonable and necessary 
medical benefits, lost wages and/or death benefits to eligible individuals for certain injuries in 
accordance with regulations published by the Secretary of HHS (found at 42 CFR part 110).  
If an individual suffers a serious physical injury or death from the administration or use of a 
covered countermeasure in this study, the individual, the individual’s legal or personal 
representative, the administrator/executor of a deceased individual’s estate, or certain survivors 
may request benefits from the CICP.  A serious physical injury means an injury that warranted 
hospitalization (whether or not the person was actually hospitalized) or that led to a significant 
loss of function or disability. The CICP is the payer of last resort. This means that it only covers 
expenses or provides benefits that other third-party payers (such as health insurance, the 
Department of Veterans Affairs, or Workers’ Compensation programs) do not have an obligation 
to pay. 
If the Secretary of HHS does not make a final determination on the individual’s request within 
240 days, or if the individual decides not to accept the compensation, the injured individual or 
his representative may pursue a tort claim in the US District Court for the District of Columbia, 
but only if the claim involves willful misconduct and meets the other requirements for suit under 
the PREP Act. Any award is reduced by any public or private insurance or worker’s 
compensation available to the injured individual. Awards for non-economic damages, such as 
pain, suffering, physical impairment, mental anguish, and loss of consortium are also limited. If 
the individual accepts compensation, or if there is no willful misconduct, then the individual does 
not have a tort claim that can be filed in a US Federal or a State court.