Clinical trial NCT04280705
Conditions: COVID-19
Keywords: Adaptive COVID-19 Efficacy Multicenter novel coronavirus Safety ACTT
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2020-02-21; Completion date: 2020-05-21
Enrollment: 1062 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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. To evaluate the clinical efficacy, as assessed by time to recovery, of different investigational therapeutics as compared to the control arm.

Detailed description:
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.

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. 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.

Contacts:

20-0006 Central Contact

Telephone: 1 (301) 7617948

Email: DMIDClinicalTrials@niaid.nih.gov

Arms: arm 1: 200 mg of Remdesivir placebo administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of Remdesivir placebo while hospitalized for up to a 10 days total course. n=286. arm 2: 200 mg of Remdesivir administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of Remdesivir while hospitalized for up to a 10 days total course. n=286.
Interventions: intervention 1: Placebo intervention 2: Remdesivir
Intervention descriptions: intervention 1: The supplied placebo lyophilized formulation is identical in physical appearance to the active lyophilized formulation and contains the same inactive ingredients. Alternatively, a placebo of normal saline of equal volume may be given if there are limitations on matching placebo supplies. intervention 2: Drug 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 ingredient, the lyophilized formulation of Remdesivir contains the following inactive ingredients: water for injection, sulfobutylether beta-cyclodextrin sodium (SBECD), and hydrochloric acid and/or sodium hydroxide.

Protocol documents:
ICF_000.pdf: 
Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 1 of 16   
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 25 Feb 2020 
Revised 4 Mar 2020 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (#) 
Version Date: 2/28/2020 
Page 1 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
RESEARCH PARTICIPANT INFORMED CONSENT 
AND PRIVACY AUTHORIZATION FORM 
 
Sponsor / Study Title: 
  
Division of Microbiology and Infectious Diseases (DMID), 
National Institute of Allergy and Infectious Diseases 
(NIAID), National Institutes of Health (NIH) / “A 
Multicenter, Adaptive, Randomized, Blinded, Controlled 
Trial on Safety and Efficacy of Investigational Therapeutics 
for the Treatment of COVID-19 in Hospitalized Adults with 
Laboratory Confirmed COVID-19 Infections” 
 
Protocol Number: 
 
NIH IRB Number: 
 
20-0006 
 
20I0073 
Principal Investigator: 
(Study Doctor) 
 
Study Site: 
Richard Davey, Jr, MD 
 
 
National Institutes of Health, Clinical Center 
 
Telephone: 
 
 (24 Hours) 
 
 
Address: 
National Institutes of Health 
NIH Clinical Center 
10 Center Drive 
Bethesda, MD    20814 
 
 
 
KEY INFORMATION 
 
This consent form describes a clinical research study and is designed to help you decide if you 
would like to be a part of the study. A clinical research study helps doctors test new ways to treat 
a disease. One way to do this is by studying new drugs, to see if they could be used as medicines. 
In a study, the drugs are ‘experimental,’ which means they have not been proven to work. That is 
why studies are needed to find out if new drugs are safe and work in people. 
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 2 of 16   
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 25 Feb 2020 
Revised 4 Mar 2020 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (#) 
Version Date: 2/28/2020 
Page 2 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
This section provides the information we believe is most helpful and important to you in making 
your decision about participating in this study. More information that may help you decide can 
be found in other sections of the document. 
 
What you should know about this study:   
• You are being asked to join this clinical research study because you are currently 
hospitalized with an illness known as COVID-19 caused by the new coronavirus, SARS 
CoV-2.  
• Read this consent form carefully or have someone you trust read it to you. Take as much 
time as you need to understand the study. 
• Ask the study team to explain any words or information that you do not understand. 
• You are a volunteer and you do not have to join this study. Your other option is to 
continue receiving any other care you have already been receiving. If you join the study, 
you can change your mind later. You can decide not to take part, or you can quit at any 
time. There will be no penalty or loss of benefits if you decide not to join or to quit the 
study.  
• During the study, we will tell you if we learn any new information that might affect 
whether you wish to continue to be in the study. 
 
What is this study about? 
There are no approved medications to treat COVID-19 because it is a new disease caused by a 
virus that was just identified in 2019 in China. Some people who become sick with COVID-19 
have serious disease and must be hospitalized. A small percent of hospitalized patients die. This 
study will test a drug in adults that are hospitalized with COVID-19. The drug has been tested 
before in humans with other diseases. In this study, we would like to make sure that it is safe for 
use in humans with COVID-19 and see if it can improve patients’ health when they are sick with 
COVID-19. 
 
What drug is being studied? 
We are studying a drug called remdesivir. This drug has been studied in animals and in people. It 
is given as an infusion, which means that it is given through a plastic tube attached to a needle 
that is put into a vein in the arm. 
 
To find out if remdesivir (the study drug) works, we need to compare it to getting something that 
does not have the drug in it, something called a placebo. The placebo looks like the study drug 
but does not have the drug in it. Using a placebo is common in research studies. The placebo is 
also given as an infusion. Some people in the study will get the placebo.  
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 3 of 16   
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 25 Feb 2020 
Revised 4 Mar 2020 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (#) 
Version Date: 2/28/2020 
Page 3 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
Will you get the study drug or placebo? 
There are 2 study groups. If you join the study, you will be randomly put into one of two groups. 
This is decided by chance. Out of every 2 people on this study, 1 will get the study drug and 1 
will get placebo. You will have a 50:50 chance of getting the study drug.  You and the study staff 
will not know what group you are in or if you are getting the study drug or the placebo. When 
the study is over, we hope to learn if the study drug is safe and if it was successful in treating 
people with COVID-19.   
 
What will happen on this study? 
If you agree to join this study, we will first do some tests to make sure it is safe for you to join. 
This includes tests of your blood and a swab of the back of your throat (also known as an OP 
swab). Only hospitalized adults 18 years old and older who are not pregnant and test positive for 
COVID-19 can join this study.  
 
If you qualify for this study and decide to join, you will get 1 infusion of study drug or placebo 
every day while you are a patient in the hospital. You will not get infusions after you are 
discharged from the hospital. The maximum number of infusions you will receive is 10.  You 
will come back to the site for study visits on Days 15 and 29. We will take one blood sample and 
one OP swab sample from you on Days 1, 3, 5, 8, and 11 as long as you remain a patient in the 
hospital, and at the follow-up study visits on Days 15 and 29. We will use the blood and OP 
swab samples for research and safety tests. Your total amount of time on this study will be about 
29 days. You will not be compensated for taking part in the study.   
 
What are the main study risks? 
The study drug has been given to a small number of healthy (not sick) people in research studies 
in the United States. It has also been given to Ebola survivors in West Africa and to people with 
Ebola in the Democratic Republic of Congo (DRC) in Africa. Some of these people had side 
effects. The most common side effects included abnormal liver function test results, abnormal 
blood clotting test results, constipation, nausea, vomiting, decreased appetite, and headache. The 
abnormal liver function tests lasted longer than a few days but came back to normal levels during 
the studies. 
 
The needle used to draw blood or place the tube in your arm for the infusion of study drug can 
hurt. A bruise may appear where it was put in. You may also have swelling, and the area may be 
sore. These things are common and should go away in a couple of days. There is a very small 
chance of an infection where you have the tube in your arm. An infection could be treated with 
antibiotics. 
 
 
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 4 of 16   
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 25 Feb 2020 
Revised 4 Mar 2020 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (#) 
Version Date: 2/28/2020 
Page 4 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
Some people may have some side effects after the infusion. Other people may have no side 
effects. People can have allergic reactions to drugs, including hives, trouble breathing, or other 
allergic responses. This is very rare but is also a possible effect of any drug. Allergic reactions 
may be severe or life-threatening. You will be monitored closely during the infusions, and short-
term medical care will be provided if there are side effects from the infusions that can be treated. 
 
Most side effects are temporary and should not last more than a few days. Since this is a new 
drug that we are still studying, it may cause other changes that could hurt or bother you that we 
do not know about. It is important that you always tell the study staff if you have any problems 
and always keep in touch with them. 
 
Are there benefits to being in the study? 
You may not benefit from being in this study. If the study drug works and you received the study 
drug on this study, you may benefit by getting better sooner or having less severe disease. 
 
What instructions do you need to follow? 
You should not drink any alcohol for 14 days after you start receiving the study drug on Day 1. 
Also, you should not take any over-the-counter, nonprescription medicines or herbal products for 
the 14 days after you start receiving study drug. If you feel that you need medicines or herbal 
products, you should talk to a member of the study team first. 
 
For Women, Risks Related to Pregnancy 
If you are a woman, you cannot be enrolled in this study if you are: 
• Pregnant 
• Planning to become pregnant during the study 
• Nursing a child 
 
If you are pregnant or nursing a child during the study, there may be risks to you, the embryo, 
fetus, or nursing child. If you can become pregnant, you must use an acceptable nonhormonal 
method of birth control, from screening until 30 days after your last dose of study drug. Please 
speak to the study doctor or staff about acceptable methods of birth control. You should not 
participate in this study if you can become pregnant but cannot use one of these birth control 
methods. Some methods of birth control will not work when you are taking certain drugs. Be 
aware that women can still become pregnant even if using an acceptable birth control method.  
 
 
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 5 of 16   
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 25 Feb 2020 
Revised 4 Mar 2020 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (#) 
Version Date: 2/28/2020 
Page 5 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
If you become pregnant while you are in this study, you should report this immediately to the 
study staff and you will not receive any further study vaccinations. With your permission, the 
study doctor or study staff will ask about your health, collect information from you through the 
outcome of your pregnancy, and collect scheduled blood samples. The study doctor may share 
this information with the study sponsor and with the Advarra Institutional Review Board (IRB), 
a group of people who review research studies to protect the rights and welfare of research 
participants. 
 
For Males 
Men who are not permanently sterile must agree to use condoms with female partners, and not to 
donate sperm, from the first study dose vaccination until 3 months after the last study dose. 
 
If your partner becomes pregnant, she will be asked to sign a separate consent form to allow the 
study staff to collect information about the pregnancy and its outcome. 
 
The rest of this document will describe more about the research study. This information should 
be considered before you make your choice. Members of the study team will talk with you about 
the information described in this document. 
 
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document. 
 
1. 
What will happen if you want to join this study? 
 
If you think you may want to join this study, we will describe the study and answer any 
questions you may have. You can also talk to your friends and family about the study.  
 
If you agree to be in the study, we will ask you to sign and date this consent form. When you 
sign your name on the consent form and date it, it means that you agree to be in the study. You 
can change your mind at any time and leave the study. If you decide not to join the study or to 
leave the study later, you will not lose any regular health care services you already are getting. 
Up to 394 hospitalized adults with COVID-19 will be in this study. 
 
 
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 6 of 16   
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 25 Feb 2020 
Revised 4 Mar 2020 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (#) 
Version Date: 2/28/2020 
Page 6 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
We will ask you some questions about your health, including whether you have liver or kidney 
disease, allergies to medications, and if you received any medications from your doctor during 
this illness. We will also perform a physical exam, measure your weight, get an OP swab sample 
to test for the virus, and take some of your blood to determine if your liver and kidneys are 
working well. If you are a woman who is capable of getting pregnant, we will do a pregnancy 
test. A member of the study team will explain these tests further. When we have the results, we 
will explain them to you and provide counseling.  
 
2. 
What does the study involve? 
 
If you qualify for the study and decide to join, you will get 1 infusion every day while you are a 
patient in the hospital. The maximum number of infusions you will receive is 10.  The infusion 
will be either study drug or placebo, depending on what group you are in. The infusion takes 
about 1 hour and will be done in the hospital. We will watch you closely for side effects during 
the infusion and for 1 hour after the infusion.  After you are discharged from the hospital, you 
will not receive any more infusions.   
 
We will take one blood sample and one OP swab sample from you on Days 1, 3, 5, 8, and 11 as 
long as you remain a patient in the hospital. You will come back to the site for study visits on 
Days 15 and 29. During these follow-up visits, we will ask how you are feeling and if you have 
been sick. We will take one blood sample and one OP swab sample at Days 15 and 29.  
 
We will use the blood and OP swab samples for research and safety tests. OP swab samples will 
be tested for presence of the virus that causes COVID-19.  
 
We will obtain some information about you from your inpatient hospital records, such as 
whether you are receiving oxygen or need additional help breathing and what types of other 
medicines you are being given as part of your clinical care.  This information will help us 
determine how sick you are and whether you are improving. 
 
As part of this study, we will get extra blood samples from you. We will use your coded 
information, leftover samples, and extra blood samples for secondary research. Secondary 
research is research that is not part of this study, and the research is not planned yet.  This extra 
research will occur in the future and it will help us to understand how the study drug works and 
to develop new treatments and lab tests. This secondary research will not include genetic testing. 
When you give consent, you will be taking part in the study and allowing for your samples to be 
used for secondary research.  
 
Your total amount of time on this study will be about 29 days. 
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 7 of 16   
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 25 Feb 2020 
Revised 4 Mar 2020 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (#) 
Version Date: 2/28/2020 
Page 7 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
3. 
What could be the side effects from the infusions? 
 
The study drug has been given to a small number of healthy (not sick) people in research studies 
in the United States to test for safety of the drug. It has also been given to Ebola survivors in 
West Africa and to people with acute Ebola virus disease in the DRC. Some of these people had 
side effects. The most common side effects included: 
• Abnormal liver function test results 
• Abnormal blood clotting test results 
• Constipation 
• Nausea 
• Vomiting 
• Decreased appetite 
• Headache 
 
Less common side effects (seen in 1 person) included: 
• Dizziness 
• Itching 
• Shaking of the leg and arm 
• Indigestion 
 
The abnormal liver function tests lasted longer than a few days but came back to normal levels 
during the studies. You will receive results from the tests during your participation. If you have 
any abnormal test results that may require more medical care, we will share these results with 
you. 
 
None of the side effects in these studies have been serious. Some people may have some side 
effects after the infusion. Other people may have no side effects. These side effects are 
temporary and should not last more than a few days. 
 
The study drug and placebo both contain a compound that in animals caused changes in the 
kidneys but did not affect how well the kidneys worked. The animals’ kidneys went back to 
normal after the drug was stopped. We have not seen any kidney problems in humans who have 
taken remdesivir. We will be following your kidney function during the study to check for 
kidney damage. 
 
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 8 of 16   
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 25 Feb 2020 
Revised 4 Mar 2020 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (#) 
Version Date: 2/28/2020 
Page 8 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
4. 
What are the other risks or discomforts of the study? 
 
We will insert a new, clean needle into a vein in your arm to take blood and to put in the sterile 
tube that we use for the study infusions. You may feel a pinch when the needle goes through 
your skin. A bruise may appear where it was put in. You may also have swelling, and the area 
may be sore. These things are common and should go away in a couple of days. There is a very 
small chance of an infection where you have the tube in your arm. An infection could be treated 
with antibiotics. 
 
Since this is a new drug that we are still studying, it may cause other changes that could hurt or 
bother you that we do not know about. People can have allergic reactions to drugs, including 
hives, trouble breathing, or other allergic responses. This is very rare but is also a possible effect 
of any drug. Allergic reactions may be severe or life-threatening. 
 
If you become pregnant, there may be unknown risks to the fetus or unborn child, or risks that 
we did not anticipate. There may be long-term effects of the drug being studied that could 
increase the risk of harm to a fetus. You need to wait until after the study before you become 
pregnant. If you think or know you have become pregnant during the study, please contact the 
research team member. You will not receive any more study drug. The team will ask your 
permission to follow-up with you about your health and the health of your baby until the end of 
your pregnancy. 
 
The study drug was given to some people who were sick with Ebola virus disease in a study in 
DRC. One of these people died from a heart attack after receiving the study drug. However, this 
person was very sick with Ebola, so we cannot say if the heart attack was caused by the study 
drug or the Ebola disease. None of the healthy people who have received the study drug in other 
studies have had heart problems. 
 
Short-term medical care will be provided if there are side effects from the infusions that can be 
treated. It is important that you always tell the study staff if you have any problems and always 
keep in touch with them.  
 
We will be careful to keep your study information confidential, but there is a small risk that 
someone not involved in the study could get this information. 
 
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 9 of 16   
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 25 Feb 2020 
Revised 4 Mar 2020 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (#) 
Version Date: 2/28/2020 
Page 9 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
5. 
Are there benefits to being in the study? 
 
You may not benefit from being in this study. If the study drug works and you received it on this 
study, you may benefit by getting better sooner and/or getting less severe disease. If we find that 
the study drug does work, it will continue to be tested in more study volunteers until it can be 
approved as a treatment for COVID-19. Your participation in this study is important to learn 
more about the study drug, including if it is safe and works in hospitalized patients with COVID-
19. It will help in the development of treatments for COVID-19 and may in the future help 
people all over the world.  
 
Before you decide whether to be in this study, we will discuss other options that are available to 
you. Instead of being in this study, you could continue to receive regular supportive hospital care 
for patients with coronavirus.  
 
If we find out any new information that may affect your choice to participate in this study, we 
will contact you to explain what we have learned. This may be information we have learned 
while doing this study or information we have learned from other scientists doing similar 
research in other places. 
 
6. 
What will happen to your samples and personal information? 
 
We will store your samples and data (information) until we are able to test all samples for the 
virus that causes COVID-19. Your stored samples and data will be marked with a code and not 
with your name. Only researchers linked to this study can get the codes. 
 
Your study information will be placed in a secure electronic system. It will not include your 
name. This information cannot be traced back to you. Your samples will not be sold. You will 
not be paid for any products that result from this research.  
 
The only risk of allowing us to store your samples would be an accidental release of your 
identity. 
 
 
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 10 of 16   
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 25 Feb 2020 
Revised 4 Mar 2020 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (#) 
Version Date: 2/28/2020 
Page 10 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
Some of the blood collected for this study may not be needed to do the research tests and these 
leftover samples we plan to store and use along with your information (identified only by ID 
codes) for secondary research. Secondary research is research that is not part of this study but 
will be performed in the future. You will not be told about the future research. Also, we will 
collect extra blood samples (between 2 and 3 teaspoons when other blood is drawn) to store and 
use for secondary research. Secondary research may help us understand how remdesivir works, 
study other infections or diseases, or develop other treatments. The types of research may include 
development of new laboratory tests to better understand responses to infection or for studies to 
better understand virus infections, including the SARS-CoV-2 infection. If you do not want to 
give leftover and extra samples for secondary research, you can not be in this study. 
 
You may change your mind about secondary research and withdraw consent for the storage and 
use of your coded samples or information at any time. You will need to contact the study doctor 
using the contact information listed on page 1 of this form. We will do our best to follow your 
wishes but cannot promise that we will always be able to destroy your samples or data. For 
example, if your samples were already used, we would not be able to destroy them. 
 
Your samples collected during this study may be used for commercial profit (even if identifiers 
are removed) and you will not share in this profit. 
 
In addition to the planned use and sharing described above, we might remove all identifiers and 
codes from your specimens and data and use or share them with other researchers for future 
research at the NIH or other places.  When we or the other researchers access your anonymized 
data, there will be no way to link the specimens or data back to you.  We will not contact you 
to ask your permission or otherwise inform you before we do this. If we do this, we would not 
be able to remove your specimens or data to prevent their use in future research studies, even if 
you asked, because we will not be able to tell which are your specimens or data. 
 
NIH policies require that your clinical and other study data be placed in an internal NIH database 
that is accessible to other NIH researchers for future research. These researchers will not have 
access to any of your identifiers, such as your name, date of birth, address, or medical record 
number; and your data will be labeled with only a code. We cannot offer you a choice of whether 
your data to be placed in this database or not.  If you do not wish to have your data placed in this 
database, you should not enroll in this study.   
 
7. 
What do you need to do for follow-up on this study? 
 
If you feel sick at any time during the study, it is important that you quickly tell the study team at 
the hospital or call the study contact number you were given if you have been discharged from 
the hospital. We may ask you to return to the clinic for a medical exam.  


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 11 of 16   
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 25 Feb 2020 
Revised 4 Mar 2020 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (#) 
Version Date: 2/28/2020 
Page 11 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
 
8. 
Will it cost you anything to be in this study? 
 
It will not cost you anything to be in this study. NIH does not bill health insurance companies or 
participants for any research or related clinical care that you receive at the NIH Clinical Center. 
 
9. 
Will you be paid if you join this study? 
 
You will not receive any monetary compensation for your participation in this study.  
 
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines. 
NIAID will cover some or all of your travel expenses related to participation in this study. This 
may include direct payments or reimbursements for expenses related to transportation, lodging, 
and meals. The amount and form of these payments are determined by the NIAID Central Travel 
Policy for Research Protocol Participants. We will give you a copy of this policy. 
 
10. 
Who is watching over this study? 
 
A Data and Safety Monitoring Board (DSMB) will be looking at the study information very 
closely. The DSMB is made up of doctors and other people who are not directly involved in the 
study and who have a good understanding of severe coronanvirus infections and research studies. 
The DSMB may recommend changing the study or stopping the study earlier than planned if 
they think it is not safe to continue. The local ethics and health authorities and the U.S. Food and 
Drug Administration (FDA) will also be watching over this study and have the authority to stop 
the study at any time.   
 
 
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 12 of 16   
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 25 Feb 2020 
Revised 4 Mar 2020 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (#) 
Version Date: 2/28/2020 
Page 12 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
11. 
Confidentiality Protections Provided in this Study 
 
Will my medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private. However, we cannot guarantee total privacy. Organizations that may look at and/or 
copy your medical records for research, quality assurance, and data analysis include: 
• The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people. 
• The Advarra Institutional Review Board. 
• The study Sponsor, the NIAID, NIH, or their agent(s), including regulatory oversight 
bodies within it. 
• Qualified representatives from Gilead Sciences, Inc, the pharmaceutical company who 
produces remdesivir. 
 
 
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified. In most cases, the NIH will not release 
any information about your research involvement without your written permission. However, if 
you sign a release of information form, for example, for an insurance company, the NIH will 
give the insurance company information from your medical record. This information might 
affect (either favorably or unfavorably) the willingness of the insurance company to sell you 
insurance. 
 
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you.  
 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act.  
 
Certificate of Confidentiality 
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.   
 
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.   
 
 
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 13 of 16   
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 25 Feb 2020 
Revised 4 Mar 2020 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (#) 
Version Date: 2/28/2020 
Page 13 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
The Certificate does not protect your information when it:   
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or  
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA);  
3. is for other research; 
4. is disclosed with your consent.  
 
The Certificate does not prevent you from voluntarily releasing information about yourself or 
your involvement in this research.  
 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self 
or others including, for example, child abuse and neglect, and by signing below you consent to 
those disclosures. Other permissions for release may be made by signing NIH forms, such as the 
Notice and Acknowledgement of Information Practices consent. 
 
Privacy Act 
The Federal Privacy Act generally protects the confidentiality of your NIH medical information 
that we collect under the authority of the Public Health Service Act.  In some cases, the Privacy 
Act protections differ from the Certificate of Confidentiality.  For example, sometimes the 
Privacy Act allows release of information from your record without your permission, for 
example, if it is requested by Congress. Information may also be released for certain research 
purposes with due consideration and protection, to those engaged by the agency for research 
purposes, to certain federal and state agencies, for HIV partner notification, for infectious disease 
or abuse or neglect reporting,  to tumor registries, for quality assessment and medical audits, or 
when the NIH is involved in a lawsuit.  However, NIH will only release information from your 
medical record if it is permitted by both the Certificate of Confidentiality and the Privacy Act. 
 
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 14 of 16   
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 25 Feb 2020 
Revised 4 Mar 2020 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (#) 
Version Date: 2/28/2020 
Page 14 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
12. 
Will the study require any of your other health care providers to share 
your health information with the researchers of this study? 
 
As a part of this study, the researchers may ask to see your health care records from your other 
health care providers. You will be asked to give us a list of other health care providers that you 
use. 
 
To do this research, we will need to collect, use, and share your private health information. Your 
private information may include things learned from the procedures described in this consent 
form, as well as information from your medical record. You will be asked to sign and date a 
separate document to authorize the collection, use, and disclosure of your personal health 
information. 
 
13. 
What other things should you know about this research study? 
 
A. ClinicalTrials.gov 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This 
Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
B. Conflict of Interest 
 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for 
conflicts of interest. This process is detailed in a COI Guide. You may ask your research 
team for a copy of the COI Guide or for more information. Members of the research team 
who do not work for NIH are expected to follow these guidelines or the guidelines of their 
home institution, but they do not need to report their personal finances to the NIH. 
 
Gilead Sciences, Inc., the company that makes remdesivir, is providing remdesivir for this 
study to NIH without charge. No NIH investigator involved in this study receives payments 
or other benefits from any company whose drug, product or device is being tested. However, 
there are some research partners not associated with the NIH working on this study who may 
receive payments or benefits, limited by the rules of their workplace. 
 
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 15 of 16   
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 25 Feb 2020 
Revised 4 Mar 2020 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (#) 
Version Date: 2/28/2020 
Page 15 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
C. Whom to Contact About This Study? 
 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the Investigator at the 
telephone number listed on the first page of this consent document. If you seek emergency 
care, or hospitalization is required, alert the treating physician that you are participating in 
this research study. You may also call the NIH Clinical Center Patient Representative at 301-
496-2626, or the NIH Office of IRB Operations at 301-402-3713. 
 
An institutional review board (IRB) is an independent committee established to help protect 
the rights of research participants If you have any questions about your rights as a research 
participant, and/or concerns or complaints regarding this research study, contact: 
 
• By mail: 
Study Subject Adviser 
Advarra IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• or call toll free:    877-992-4724 
• or by email:          adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00042130. 
 
D. What should you do if you are injured or ill as a result of being in this study? 
 
The NIH Clinical Center will provide short-term medical care for any injury resulting from 
your participation in research here. In general, no long-term medical care or financial 
compensation for research-related injuries will be provided by the NIH, the NIH Clinical 
Center, or the Federal Government. However, you have the right to pursue legal remedy if 
you believe that your injury justifies such action. 
  
 
 
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 16 of 16   
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 25 Feb 2020 
Revised 4 Mar 2020 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (#) 
Version Date: 2/28/2020 
Page 16 of 16 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
Adult Research Participant: I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions. I consent to participate in this study. 
 
 
 
 
 
Signature of Research Participant 
 
Print Name of Research 
Participant 
 
Date 
 
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the 
explanation about this study and have been given the opportunity to discuss it and to ask questions. I 
am legally authorized to make research decisions on behalf of the adult participant unable to consent 
and have the authority to provide consent to this study. As applicable, the information in the above 
consent was described to the adult participant unable to consent who agrees to participate in the 
study. 
 
 
 
 
 
Signature of LAR 
 
Print Name of LAR 
 
Date 
 
Investigator: 
 
 
 
 
 
Signature of Investigator 
 
Print Name of Investigator 
 
Date 
 
 

SAP_002.pdf: 
CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
 
 
STATISTICAL ANALYSIS PLAN 
for 
DMID Protocol: 20-0006 
Study Title: 
A Multicenter, Adaptive, Randomized Blinded 
Controlled Trial of the Safety and Efficacy of 
Investigational Therapeutics for the Treatment of 
COVID-19 in Hospitalized Adults 
 
NC04280705 
 
Version 3.0 
 
DATE: 29-MAY-2020 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL  
 
 


Statistical Analysis Plan - DMID Protocol: 20-0006  
Version 3.0 
29MAY2020 
- ii - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
STUDY TITLE 
Protocol Number Code: 
DMID Protocol: 20-0006 
Development Phase: 
Phase 3 
Products: 
Remdesivir 
Placebo 
Form/Route: 
IV 
Indication Studied: 
COVID-19 
Sponsor: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
Clinical Trial Initiation Date: 
February 21, 2020 
Clinical Trial Completion Date: 
Trial Ongoing 
Date of the Analysis Plan: 
May 29, 2020 
Version Number: 
3.0 
This study was performed in compliance with Good Clinical Practice. 
Information contained in this publication is the property of Division of Microbiology and Infectious Diseases and is confidential. This 
information may not be disclosed to third parties without written authorization from Division of Microbiology and Infectious Diseases. This 
report may not be reproduced, stored in a retrieval system or transmitted in any form or by any means - electronic, mechanical, recording or 
otherwise - without the prior authorization from Division of Microbiology and Infectious Diseases. This document must be returned to Division 
of Microbiology and Infectious Diseases upon request. 
 


Statistical Analysis Plan - DMID Protocol: 20-0006  
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TABLE OF CONTENTS 
STUDY TITLE ............................................................................................................................... II 
TABLE OF CONTENTS ...............................................................................................................III 
LIST OF ABBREVIATIONS ....................................................................................................... VI 
1. 
PREFACE .....................................................................................................................8 
2. 
INTRODUCTION ........................................................................................................9 
2.1. 
Purpose of the Analyses ................................................................................................9 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................11 
3.1. 
Study Objectives .........................................................................................................11 
3.2. 
Endpoints ....................................................................................................................12 
3.3. 
Study Definitions and Derived Variables ...................................................................13 
3.3.1. 
Baseline Value ............................................................................................................13 
3.3.2. 
Recovery and Time to Recovery ................................................................................14 
3.3.3. 
Clinical Status At Specific Timepoints .......................................................................14 
3.3.4. 
Time to Clinical Status Improvement .........................................................................14 
3.3.5. 
Time to Discharge or NEWS of ≤ 2 ...........................................................................15 
3.3.6. 
Days of Non-invasive ventilation/high-flow oxygen .................................................15 
3.3.7. 
Days of Ventilation/ECMO ........................................................................................15 
3.3.8. 
Days of Oxygen ..........................................................................................................16 
3.3.9. 
Days of Hospitalization ..............................................................................................16 
3.3.10. 
Time to Death .............................................................................................................16 
3.3.11. 
Composite Endpoint of Death, SAEs, Severe AEs, Discontinuation of Study 
Infusions .....................................................................................................................16 
4. 
INVESTIGATIONAL PLAN .....................................................................................17 
4.1. 
Overall Study Design and Plan ...................................................................................17 
4.2. 
Selection of Study Population ....................................................................................18 
4.2.1. 
Treatments Administered ............................................................................................19 
4.2.2. 
Identity of Investigational Product(s) .........................................................................19 
4.2.3. 
Method of Assigning Subjects to Treatment Groups (Randomization) .....................19 
4.2.4. 
Selection of Doses in the Study ..................................................................................19 
4.2.5. 
Selection and Timing of Dose for Each Subject .........................................................19 
4.2.6. 
Blinding ......................................................................................................................20 


Statistical Analysis Plan - DMID Protocol: 20-0006  
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Table of Contents (continued) 
 
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4.2.7. 
Prior and Concomitant Therapy ..................................................................................20 
4.2.8. 
Treatment Compliance ................................................................................................21 
4.3. 
Efficacy and Safety Variables ....................................................................................21 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................25 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................28 
6.1. 
General Principles .......................................................................................................28 
6.2. 
Timing of Analyses .....................................................................................................29 
6.2.1. 
Early Sample Size Reassessment ................................................................................29 
6.2.2. 
Interim analyses ..........................................................................................................29 
6.2.3. 
Final Analyses ............................................................................................................29 
6.3. 
Analysis Populations ..................................................................................................30 
6.3.1. 
Intention-to-Treat (ITT) and Treated Populations ......................................................30 
6.4. 
Covariates and Subgroups ..........................................................................................30 
6.5. 
Missing Data ...............................................................................................................32 
6.6. 
Interim Analyses and Data Monitoring ......................................................................33 
6.6.1. 
Interim Safety Analyses ..............................................................................................33 
6.6.2. 
Interim Efficacy Review .............................................................................................33 
6.7. 
Multicenter Studies .....................................................................................................34 
6.8. 
Multiple Comparisons/Multiplicity ............................................................................34 
7. 
STUDY SUBJECTS ...................................................................................................35 
7.1. 
Disposition of Subjects ...............................................................................................35 
7.2. 
Protocol Deviations ....................................................................................................35 
8. 
EFFICACY EVALUATION ......................................................................................36 
8.1. 
Primary Efficacy Analysis ..........................................................................................36 
8.1.1. 
Primary Analyses ........................................................................................................36 
8.1.2. 
Supplemental and Sensitivity Analyses ......................................................................37 
8.2. 
Secondary Efficacy Analyses .....................................................................................38 
8.2.1. 
Ordinal Scale Outcomes (Key Secondary Outcome Measure) ...................................38 
8.2.2. 
NEWS .........................................................................................................................39 
8.2.3. 
Days of Oxygenation ..................................................................................................39 
8.2.4. 
Incidence of New Oxygen use ....................................................................................40 


Statistical Analysis Plan - DMID Protocol: 20-0006  
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Table of Contents (continued) 
 
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8.2.5. 
Days of Non-Invasive Ventilation/High-Flow Oxygen ..............................................40 
8.2.6. 
Incidence of New Non-Invasive Ventilation/High-Flow Oxygen ..............................40 
8.2.7. 
Days of Invasive Mechanical Ventilation/ECMO ......................................................40 
8.2.8. 
Incidence of New Non-Invasive Ventilation/High-Flow Oxygen ..............................40 
8.2.9. 
Days of Hospitalization ..............................................................................................41 
8.3. 
Exploratory Efficacy Analyses ...................................................................................41 
9. 
SAFETY EVALUATION ..........................................................................................42 
9.1. 
Demographic and Other Baseline Characteristics ......................................................42 
9.1.1. 
Prior and Concurrent Medical Conditions ..................................................................42 
9.1.2. 
Prior and Concomitant Medications ...........................................................................42 
9.2. 
Measurements of Treatment Compliance ...................................................................43 
9.3. 
Adverse Events ...........................................................................................................43 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ....................43 
9.5. 
Pregnancies .................................................................................................................44 
9.6. 
Clinical Laboratory Evaluations .................................................................................44 
9.7. 
Vital Signs and Physical Evaluations .........................................................................45 
9.8. 
Concomitant Medications ...........................................................................................45 
9.9. 
Other Safety Measures ................................................................................................45 
10. 
PHARMACOKINETICS ...........................................................................................46 
11. 
IMMUNOGENICITY ................................................................................................47 
12. 
OTHER ANALYSES .................................................................................................48 
13. 
REPORTING CONVENTIONS ................................................................................49 
14. 
TECHNICAL DETAILS ............................................................................................50 
15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ............................................................................................51 
16. 
REFERENCES ...........................................................................................................54 
17. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..............................................55 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................56 
APPENDIX 2. FIGURE MOCK-UPS ........................................................................................94 
APPENDIX 3. LISTINGS MOCK-UPS ...................................................................................113 
 


Statistical Analysis Plan - DMID Protocol: 20-0006  
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BEEC 
Blinded Endpoint Evaluation Committee 
CI 
Confidence Interval 
CoV / COV 
Coronavirus 
CRF / eCRF 
Case Report Form / Electronic Case Report Form 
CSR 
Clinical Study Report 
DAIDS 
Division of AIDS 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data and Safety Monitoring Board 
ECMO 
Extracorporeal Membrane Oxygenation 
FDA 
Food and Drug Administration 
GMT 
Geometric Mean Titer 
GMFR 
Geometric Mean Fold Rise 
ICH 
International Conference on Harmonisation 
ITT 
Intention to Treat 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
Milligram 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NEWS 
National Early Warning Score 
NIH 
National Institutes of Health 
OP 
Oropharyngeal 
PCR 
Polymerase Chain Reaction 
PI 
Principal Investigator 
PT 
Preferred Term / Prothrombin Time 
RCD 
Reverse Cumulative Distribution  
RNA 
Ribonucleic Acid 


Statistical Analysis Plan - DMID Protocol: 20-0006  
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SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS 
Severe Acute Respiratory Syndrome 
SD 
Standard Deviation 
SDCC 
Statistical and Data Coordinating Center 
SOC  
System Organ Class 
US 
United States 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


Statistical Analysis Plan - DMID Protocol: 20-0006  
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1. 
PREFACE 
The Statistical Analysis Plan (SAP) for “A Multicenter, Adaptive, Randomized Blinded 
Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of 
COVID-19 in Hospitalized Adults” (DMID Protocol 20-0006) describes and expands upon the 
statistical information presented in the protocol. This protocol is an adaptive protocol with 
different stages. Each stage will have a separate SAP. This SAP is for ACTT-1: Remdesivir vs 
Placebo. 
This document describes all planned analyses and provides reasons and justifications for these 
analyses. It also includes sample tables, listings, and figures planned for the final analyses. 
Regarding the final analyses and Clinical Study Report (CSR), this SAP follows the International 
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use (ICH) Guidelines, as indicated in Topic E3 (Structure and Content of Clinical Study 
Reports), and more generally is consistent with Topic E8 (General Considerations for Clinical 
Trials) and Topic E9 (Statistical Principles for Clinical Trials). The structure and content of the 
SAP provides sufficient detail to meet the requirements identified by the FDA and ICH, while all 
work planned and reported for this SAP will follow internationally accepted guidelines published 
by the American Statistical Association and the Royal Statistical Society for statistical practice. 
This document contains: a review of the study design, general statistical considerations, 
comprehensive statistical analysis methods for efficacy and safety outcomes, and a list of 
proposed tables, figures and listings. Within the table, figure, and listing mock-ups (Appendices 
1, 2, and 3), references to CSR sections are included. Any deviation from this SAP will be 
described and justified in protocol amendments and/or in the CSR, as appropriate. The reader of 
this SAP is encouraged to also review the study protocol for details on conduct of the study and 
the operational aspects of clinical assessments. 
 


Statistical Analysis Plan - DMID Protocol: 20-0006  
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2. 
INTRODUCTION 
Coronaviruses (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 [reference 1 in protocol]. 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. 
During the COVID-19 outbreak, incidence of cases has rapidly increased such that on January 5, 
2020 there were 59 confirmed cases, 278 cases on January 20, 2118 cases on January 26, and 
more than 80,000 cases and 2700 deaths as of February 25, 2020 according to various 
international health reporting agencies. 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. Outbreak forecasting and modeling suggest that these numbers will continue to 
rise [reference 2 in protocol]. On March 11, 2020, WHO characterized COVID-19 as a 
pandemic. 
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.  
2.1. 
Purpose of the Analyses 
This Statistical Analysis Plan (SAP) encompasses all interim analyses and the final analysis of 
primary and secondary outcome measures. These analyses will assess the efficacy and safety of 
remdesivir in comparison with Placebo and will be included in the Clinical Study Report. This 
protocol is an adaptive design and, if the design is modified, the SAP will be amended 
accordingly. The protocol for DMID 20-0006 calls for a planned interim efficacy analysis once 
roughly 50% of the targeted number of recoveries have been observed, and ongoing safety 
analyses. Safety interim analyses occur more frequently to review safety data in the event that 
the experimental agent inflicts harm. The goal of the efficacy interim analyses is to review 
endpoint data in order to recommend whether the current study arm should proceed or to stop 
early for benefit or futility. 


Statistical Analysis Plan - DMID Protocol: 20-0006  
Version 3.0 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
The version 3.0 amendment to this SAP was written after the interim analysis results were 
presented to the DSMB on April 27, 2020. Per DSMB recommendation, the results were then 
provided to blinded NIAID study leadership. Due to the urgent public health imperative 
presented by the COVID-19 pandemic, the interim efficacy results were disclosed publicly 
(NIAID April 29, 2020 News Release). Per discussions with the FDA, the timing of the final 
analyses was modified from the original plan (see Section 6.2). 
As the ACTT1 Interim Analysis DSMB meeting has already occurred, details of the interim 
analyses for the DSMB meetings are not modified in version 3.0. However, edits have been 
made to the planned final analyses. A summary of all changes to this document is provided in 
Section 15. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
Primary Objective 
The overall objective of the study is to evaluate the clinical efficacy of different investigational 
therapeutics relative to the control arm in patients hospitalized with COVID-19 as assessed by 
the time to recovery up to Day 29. 
Secondary Objectives 
The key secondary objective is to evaluate the clinical efficacy of different investigational 
therapeutics relative to the control arm in patients hospitalized with COVID-19 as assessed by 
the 8-point ordinal clinical status scale at Day 15. 
The other secondary objectives are to: 
1. Evaluate clinical efficacy of different investigational therapeutics as compared to the control 
arm as assessed by: 
• Clinical Severity 
o 8-Point Clinical Status Ordinal scale: 
 Time to an improvement of one category and two categories from Day 1 
(baseline) on the clinical status 8-point ordinal scale. 
 Subject clinical status using 8-point ordinal scale at Days 3, 5, 8, 11, 15, 22, and 
29.  
 Mean change in the clinical status 8-point ordinal scale from Day 1 to Days 3, 5, 
8, 11, 15, 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. 
o Oxygenation: 
 Days requiring oxygen through Day 29. 
 Incidence and duration of new oxygen use through Day 29. 
o Non-invasive ventilation/high flow oxygen: 
 Days of non-invasive ventilation/high flow oxygen through Day 29. 
 Incidence and duration of new non-invasive ventilation or high flow oxygen use 
through Day 29. 
o Invasive Mechanical Ventilation / extracorporeal membrane oxygenation (ECMO): 
 Days of ventilator/ECMO through Day 29. 


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 Incidence and duration of new mechanical ventilation or ECMO use through Day 
29.  
• Hospitalization 
o Duration of hospitalization (in days) through Day 29.  
• Mortality 
o 14-day mortality. 
o 28-day mortality.  
2. Evaluate the safety of the intervention through 28 days of follow-up 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 cell count (WBC) 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). 
Exploratory Objective  
The exploratory objective is to evaluate the virologic efficacy of different investigational 
therapeutics as compared to the control arm as assessed by: 
• Percentage of subjects with SARS-CoV-2 detectable in (oropharyngeal) OP sample at 
Day 3, 5, 8, 11, 15, and 29.  
• Quantitative SARS-CoV-2 virus in OP sample at Day 3, 5, 8, 11, 15, and 29.  
• Development of resistance of SARS-CoV-2 in OP sample at Day 3, 5, 8, 11, 15, and 29. 
• Quantitative SARS-CoV-2 virus in blood at Day 3, 5, 8, and 11. 
3.2. 
Endpoints 
Primary Endpoint 
Time to recovery, where recovery is defined as clinical status in states 1, 2, or 3 of the 8-point 
ordinal scale, censored at Day 29.   
• Clinical status of a subject (8-point ordinal scale) is defined below: 
8. Death; 
7. Hospitalized, on invasive mechanical ventilation or ECMO; 
6. Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
5. Hospitalized, requiring supplemental oxygen; 


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4. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 
3. Hospitalized, not requiring supplemental oxygen - no longer requiring ongoing 
medical care; 
2. Not hospitalized, limitation on activities and/or requiring home oxygen; 
1. Not hospitalized, no limitations on activities 
Secondary Endpoints 
The key secondary endpoint is clinical status (8-point ordinal scale) on Day 15.  
The other secondary endpoints are: 
• Ordinal outcome assessed daily while hospitalized and on Days 15, 22, and 29. 
• NEWS assessed daily while hospitalized and on Days 15 and 29.  
• Days of supplemental oxygen (if applicable).  
• Days of non-invasive ventilation/high-flow oxygen (if applicable). 
• Days of invasive mechanical ventilation/ECMO (if applicable). 
• Days of hospitalization. 
• Date and cause of death (if applicable). 
• SAEs. 
• Grade 3 and 4 adverse events 
• 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 Endpoint 
• 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). 
3.3. 
Study Definitions and Derived Variables  
3.3.1. 
Baseline Value 
For efficacy assessments, the baseline value will be defined as the last value obtained prior to 
randomization. For safety assessments, the baseline value will be defined as the last value 
obtained prior to the first dose of study product. 


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3.3.2. 
Recovery and Time to Recovery 
The primary efficacy outcome measure is the time to recovery. Recovery will be defined as 
having a value of 1, 2, or 3 on the clinical status 8-point ordinal scale. The time to recovery will 
be defined as the elapsed time (in days) from randomization to the earliest day at which a subject 
reaches recovery.  Note that since clinical status assessments are recorded as defined in 
Section 4.3, the day that is being assessed (not necessarily the day the response is collected) will 
be used to determine the timing of events. For example, a subject with a score of 5 recorded on 
Days 1 - 3 and a score of 3 recorded on Day 4 will have a time to recovery equal to 3 days. It is 
also possible that a subject has a clinical status score > 3 reported for a particular day but was 
subsequently discharged on the same day.  For these scenarios where a subject is discharged with 
no reported clinical score of 1, 2, or 3 will be considered recovered at the time of discharge. 
Any subjects that are lost to follow-up or terminated early prior to an observed recovery will be 
censored at the day of their last observed assessment. Subjects who complete follow-up but do 
not experience recovery will be censored at the day of their Day 29 visit. All deaths within Day 
29 (and prior to recovery) will be considered censored at 28 days. Note that we do not expect 
many subjects to worsen after discharge.  
However, we will evaluate whether any discharged subjects subsequently experience a worse 
clinical status and sensitivity analyses will be conducted accordingly. For these analyses, 
subjects who recover but are later re-admitted will not be considered a recovery but will instead 
be censored at 28 days. Sensitivity analyses will be performed where subjects who were 
crossover treated with remdesivir (per April 29, 2020 Protocol Administrative Letter) will be 
censored at the time of remdesivir treatment initiation. In addition, the analyses will be replicated 
where subjects who were unblinded, regardless of whether they received crossover treatment of 
remdesivir or not, will be censored at the time of unblinding. 
3.3.3. 
Clinical Status At Specific Timepoints 
The key secondary analyses include evaluation of the clinical status score at Day 15. For this 
outcome, Study Visit Day 15 is the timepoint of interest, not necessarily the actual study day. 
The score collected at the study visit corresponding to Day 15 will be used for this outcome. For 
analyses of this outcome, imputation of the clinical score may be performed following the rules 
described in Section 6.5. 
Additional analyses are clinical status at Days 3, 5, 8, 11, 15, 22, and 29. As the with above, the 
scores that will be used are those collected at the study visits corresponding to those days. 
Sensitivity analyses of the key secondary outcome will be performed where subjects who were 
unblinded and crossover treated with remdesivir prior to Day 15 will have their latest CSO score 
pre-remdesivir treatment carried forward to Day 15. A similar process will be used for the 
unblinding sensitivity analysis. 
3.3.4. 
Time to Clinical Status Improvement 
Additional analyses will evaluate the time to improvement of at least one point on the clinical 
status 8-point ordinal scale. That is, improvement will be defined as a decrease of at least one 
point on the 8-point scale compared to the baseline value (e.g. from 5 to 4; from 5 to 3) and the 
time to improvement will be defined as the elapsed time (in days) from randomization to the 


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earliest day of observed improvement. Note that since clinical status assessments are recorded as 
defined in Section 4.3, the day that is being assessed (not necessarily the day the response is 
collected) will be used to determine the timing of events. 
For analyses of this outcome, imputation of the clinical score may be performed following the 
rules described in Section 6.5. 
Any subjects that are lost to follow-up or terminated early prior to an observed improvement will 
be censored at the day of their last observed assessment. Subjects who complete follow-up but do 
not experience improvement will be censored at the day of their Day 29 visit. All deaths within 
Day 29 (and prior to improvement) will be considered censored at 28 days. 
An alternative definition of improvement will also be used where improvement will be defined 
as a decrease of at least two points on the 8-point scale compared to the baseline value (e.g. from 
5 to 3; from 5 to 2). The timing and censoring definitions will follow similarly to the above. 
Sensitivity analyses will be performed where subjects who were unblinded and retreated with 
remdesivir will be censored at the time of remdesivir treatment initiation. A similar process will 
be used for the unblinding sensitivity analysis. 
3.3.5. 
Time to Discharge or NEWS of ≤ 2 
The time to discharge or NEWS of ≤ 2 will be defined as the elapsed time (in days) from 
baseline to the earliest day at which either of the following occur: 
• Discharge from hospital 
• Reported NEWS of ≤ 2 which is maintained for 24 hours 
For the latter bullet, to meet this criterion, scores of ≤ 2 must be reported on consecutive study 
visits. The timing of the event will be set to the day of the second assessment. 
All deaths that occur before discharge or before an observed NEWS of ≤ 2 will be considered 
censored at 28 days. 
3.3.6. 
Days of Non-invasive ventilation/high-flow oxygen 
Non-invasive ventilation/high flow-oxygen days will be defined as the number of days where the 
clinical status score is equal to 6. After discharge, the CRF question regarding days of ventilation 
will be used. The total number of days will be the sum of all reported days, regardless of whether 
the days occur consecutively or in disjoint intervals. See Section 6.5 for the plan for handling 
subjects who do not have data through Day 29 or die prior to Day 29. 
3.3.7. 
Days of Ventilation/ECMO 
Ventilator / ECMO days will be defined as the number of days where the clinical status score is 
equal to 7. After discharge, the CRF question regarding days of ventilation will be used.  The 
total number of days will be the sum of all reported days, regardless of whether the days occur 
consecutively or in disjoint intervals. See Section 6.5 for the plan for handling subjects who do 
not have data through Day 29 or die prior to Day 29. 


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3.3.8. 
Days of Oxygen 
Oxygen days will be defined as the number of days where the clinical status score is equal to 5, 
6, or 7. After discharge, the CRF question regarding days of oxygenation will be used.  The total 
number of days will be the sum of all reported days, regardless of whether the days occur 
consecutively or in disjoint intervals. See Section 6.5 for the plan for handling subjects who do 
not have data through Day 29 or die prior to Day 29. 
3.3.9. 
Days of Hospitalization 
Duration (in days) of hospitalization will be defined as the number of days from randomization 
to discharge. For the secondary outcome, duration of the initial hospitalization will be used only. 
See Section 6.5 for the plan for handling subjects who do not have data through Day 29 or die 
prior to Day 29. 
3.3.10. 
Time to Death 
For analysis of time to death, the time to death will be defined as the elapsed time (in days) from 
randomization (or treatment administration for the safety analysis) to death. Any subjects that are 
lost to follow-up or terminated early prior to death will be censored at the day of their last 
observed assessment or last captured event (e.g. the end date of an adverse event). If it is learned 
that a subject who terminated early had subsequently died prior to Day 29, then the subject will 
be classified as dead.  Subjects who complete follow-up will be censored at the earliest of their 
Day 29 visit and (actual Day 29). Deaths that occur after Day 29 will be censored at Day 29. 
Similar censoring methods will be used for the 14-day mortality analyses in that deaths that 
occur after Day 15 will be censored at Day 15 and subjects who are confirmed alive through Day 
15 will be censored at Day 15.  Subjects whose last observed assessment or last capture event 
(e.g. the end date of an adverse event) is prior to Day 15 will be censored at that last observed 
assessment/event.  
Sensitivity analyses will be performed where subjects who were unblinded and retreated with 
remdesivir will be censored at the time of remdesivir treatment initiation. A similar process will 
be used for the unblinding sensitivity analysis. 
3.3.11. 
Composite Endpoint of Death, SAEs, Severe AEs, Discontinuation of Study 
Infusions 
A safety composite endpoint will be defined as the occurrence of at least one of the following 
through Day 29: 
1. Death 
2. SAE 
3. Grade 3 or 4 AE 
The time to this composite endpoint will be defined as the elapsed time (in days) from baseline 
to the earliest date of any of the events. Any subjects that are lost to follow-up or terminated 
early prior to experiencing any of the events will be censored at the day of their last observed 
assessment. Subjects who complete follow-up but do not experience any of the events will be 
censored at the day of their Day 29 visit.  


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
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 
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.  
Recruitment will continue until there are 400 subjects with a “recovered” status (per the primary 
objective). The primary analysis will be based the total number of subjects enrolled to achieve 
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. The primary analysis will include data from 
both severity groups using a stratified log-rank test. 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 the planned sample 
size. 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 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 


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remaining arms. Randomization will be stratified by site and severity (severe versus mild-
moderate). See Section 4.2.3 for more information on randomization and stratification.  
4.2. 
Selection of Study Population 
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.  
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. 
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 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. ALT/AST > 5 times the upper limit of normal. 


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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. 
4.2.1. 
Treatments Administered  
Subjects will receive either remdesivir through an IV in a loading (200 mg) dose followed by up 
to 9 maintenance (100 mg) doses or placebo at an equal volume at the same schedule. 
4.2.2. 
Identity of Investigational Product(s) 
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 
ingredient, the lyophilized formulation of remdesivir contains the following inactive ingredients: 
water for injection, sulfobutylether β-cyclodextrin sodium (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. Due to limitations on 
placebo supplies, normal saline may be given at an equal volume as a placebo in place of the 
lyophilized formulation. 
4.2.3. 
 Method of Assigning Subjects to Treatment Groups (Randomization) 
Enrollment and randomization of subjects is done online using the enrollment module of 
Advantage eClinical®. 
Eligible subjects will be randomized and assigned in a 1:1 ratio to either remdesivir or placebo, 
with stratification by site and disease severity (Mild/Moderate disease or Severe disease). The 
randomization is based on a variable blocked scheme to provide an approximately balanced 
allocation to the treatment groups during the study. If arms are added or removed later in the 
study, randomization will continue in an equal allocation manner. 
4.2.4. 
Selection of Doses in the Study 
The dose of remdesivir used in this study will be the same dose that was has been used in the 
human Ebola clinical trials.  
4.2.5. 
Selection and Timing of Dose for Each Subject 
Each subject is randomly assigned to a treatment group as described in Section 4.2.3. Study 
product is given on Day 1 as a loading dose and daily up to 9 days after as maintenance doses. 
The dose should be given the same time each day (+/- 2 hours). 


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4.2.6. 
Blinding 
The treatment will be prepared by the licensed pharmacist and administered by blinded study 
personnel or hospital staff. All follow-up safety and efficacy evaluations will be performed by 
blinded clinic staff. 
The unblinded pharmacist at each site will refer to the Treatment Key provided for the trial by 
the SDCC to determine the treatment for the subjects. The pharmacist will maintain an open 
label code (provided by the SDCC) under locked/secured conditions and will follow the 
randomization code. Due to limitation on placebo supplies, normal saline may be given at an 
equal volume as a placebo in place of the lyophilized formulation. In this case, IV bags of study 
treatment (both Remdesivir and placebo) will be covered to mask the slight color difference 
between the Remdesivir solution and placebo to maintain the study blind. 
After the public disclosure of the interim results, an unblinding procedure was added (per April 
29, 2020 Protocol Administrative Letter) in which an investigator could unblind a subject and 
potentially initiate remdesivir treatment if one of the following criteria is met: 
1. Potential remdesivir treatment, only for subjects meeting all of the following criteria: 
a. On study (i.e. have not completed the Day 29 visit) 
b. Hospitalized 
c. It is clinically indicated (i.e., those that are doing poorly) 
2. Subject/LAR request, only for subjects meeting one of the following criteria: 
a. Subject is no longer hospitalized and has completed the study (on or after Day 29 
visit), or 
b. After death. 
4.2.7. 
Prior and 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-10 or the SARS-CoV-2 infection 
(i.e., post-exposure prophylaxis) 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 form. 
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 treatment clinician. Additionally, there should be plans on how the 
concomitant drugs are stopped for additive toxicities (Protocol Section 6.1.4). If there are NO 
written policies or guidelines for local standard of care, concomitant use of any other 
experimental treatment or off-label use of marketed medications intended as specific treatment 
for COVID-10 or SARS-CoV-2 infection are prohibited. This includes medications that target 
the host immune response. 


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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.  
Of note, acetaminophen is prohibited during the study through Day 15, even if clinically 
indicated for a subject. 
4.2.8. 
Treatment Compliance 
All subjects should receive a loading dose and up to 9 maintenance doses while hospitalized. If a 
subject is no longer hospitalized, then infusions will no longer be given. Any dose that is missed 
is not made up; the total course should not exceed 10 calendar days even if an infusion is missed. 
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. 
All doses will be recorded on the appropriate eCRF. Total volume and whether the IV was 
slowed or halted will be recorded to track compliance. 
4.3. 
Efficacy and Safety Variables 
For each study day while the patient is hospitalized, the clinical status will be recorded on an 8-
point ordinal scale as follows: 
• Day 1 – The clinical assessment at the time of randomization. 
• Day 2 - The most severe assessment occurring at any time between randomization and 
midnight the day of randomization. 
• Day 3+ - The most severe assessment occurring from midnight to midnight (00:00 to 
23:59) of the prior day (e.g., the value recorded on Day 3 will be the most severe 
outcome that occurred on Day 2). 
where the clinical status scale is defined as follows: 
8. Death; 
7. Hospitalized, on invasive mechanical ventilation or ECMO; 
6. Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
5. Hospitalized, requiring supplemental oxygen; 
4. Hospitalized, not requiring supplemental oxygen- requiring ongoing medical care 
(COVID-19 related or otherwise; 
3. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical 
care; 


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2. Not hospitalized, limitation on activities; 
1. Not hospitalized, no limitations on activities 
A modified version of the ordinal scale will be used in sensitivity analyses of the primary and 
secondary outcomes. The modified scale will be as follows:  
8. Death; 
7. Hospitalized, on invasive mechanical ventilation or ECMO; 
6. Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
5. Hospitalized, requiring supplemental oxygen; 
4. Hospitalized, not requiring supplemental oxygen- requiring ongoing medical care 
(COVID-19 related or otherwise; 
3. Not hospitalized, limitation on activities; 
2. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical 
care; or Not hospitalized, no limitations on activities. 
That is, category 1 and 3 of the original scale will be combined into the lowest category. 
NEWS has demonstrated an ability to discriminate subjects at risk of poor outcomes. This score 
is based on 7 clinical parameters (see Table 1). This should be evaluated at the first assessment 
of a given study day and prior to administration of study product. The 7 parameters can be 
obtained from the hospital chart using the last measurement prior to the time of assessment and a 
numeric score 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 N, the Day N score is obtained 
and recorded as the Day N score. 
Table 1: 
Categories of the NEWS scale. 
 


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Oxygenation, Non-invasive ventilation/high flow oxygen, Invasive Mechanical Ventilation / 
extracorporeal membrane oxygenation (ECMO), hospitalization and mortality will be assessed 
using results of the 8-point ordinal scale and post discharge eCRF questions.  
Safety will be assessed by the following: 
• Cumulative incidence of serious adverse events (SAEs) through 28 days of follow-up. 
• Cumulative incidence of Grade 3 and 4 AEs. 
• Discontinuation or temporary suspension of infusions (for any reason) 
• Changes in white cell count, absolute neutrophil count, hemoglobin, platelets, creatinine, 
glucose, total bilirubin, ALT, AST, and PT over time. 
Clinical labs will be drawn on Days 1, 3, 5, 8, 11 and on Day 15 and 29 if the subject is able to 
return to the clinic or is still hospitalized. 
Virologic efficacy is an exploratory endpoint and will be assessed by the following: 
• Qualitative and quantitative PCR for SARS-CoV-2 in OP swab on Days 1; 3, 5, 8, 11 
(while hospitalized); and Day 15 and 29 (if able to return to clinic or still hospitalized). 
• Qualitative and quantitative PCR for SARS-CoV-2 in blood on Days 1; 3, 5, 8, 11 (while 
hospitalized). 
The schedule of study procedures is provided in Table 2 below. 


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Table 2: 
Schedule of Study Procedures (from protocol version 3.0) 
  
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 
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 swab8 
  
X5 
Day 3, 5, 8, 11 (all ± 1 day) 
if hospitalized 
X7 
 
X7 
 
Blood for serum (for 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)), 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 randomization. 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, these visits may be conducted 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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5. 
SAMPLE SIZE CONSIDERATIONS 
Sample Size for Primary Analysis 
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. 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 3 provides power for 
various recovery rate ratios. 
Table 3: 
Number of recoveries needed for 85% power assuming a type I error rate of 
5% for various recovery ratios. 
Recovery ratio 
(θ) 
Number of recoveries needed 
for 85% power 
1.25 
723 
1.30 
523 
1.35 
400 
1.40 
318 
Sample Size for Key Secondary Analysis 
The key secondary endpoint of the effect of treatment on Clinical Status at Day 15 will be 
analyzed using a proportional odds model. In this model, the odds ratio represents the ratio of the 
odds of a given score or better for the two arms of the study. The sample size to detect a given 
odds ratio for 1:1 randomization using a 2-tailed test at level alpha (Whitehead 1993) is given by 
12൫𝑧𝑧α/2 + 𝑧𝑧β൯
2
θ2(1 −∑
𝑝𝑝𝑖𝑖
3
𝐾𝐾
𝑖𝑖=1
), 
where θ 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 4 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.  


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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. 
Table 4: 
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 
 


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Table 5: 
Sample size calculations for scenarios in Table 2 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 
 
Table 6: 
Treatment ordinal outcome proportions under an odds ratio of 1.75 for five 
scenarios in Table 5 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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6. 
GENERAL STATISTICAL CONSIDERATIONS 
6.1. 
General Principles 
This is a double-blind, placebo controlled randomized trial with a two-sided type I error rate of 
0.05. Secondary hypotheses have been ordered according to relative importance. These will be 
described according to the appropriate summary statistics, e.g.  
• Percentages/proportions/odds ratios for categorical data.  For tabular summaries of 
percentages/proportions, the denominator (e.g. number of subjects with non-missing data) 
will be displayed. 
• Means, median, and range for continuous data, median for time-to-event data.  
Confidence intervals will be generated; for the primary analysis, the confidence level will take 
into account the group-sequential design of the trial (see Section 6.6 and Section 8.1) whereas 
95% confidence intervals will be generated for secondary and exploratory outcomes. For hazard 
ratio and odds ratio estimates, Wald confidence intervals will be used. For other efficacy 
outcomes, Wilson or Score confidence intervals will be used. For safety outcomes, exact (e.g. 
Clopper-Pearson) confidence intervals will be used. 
When calculating treatment effects (e.g. differences, hazard ratios, odds ratios) and when using 
treatment arm as a covariate in regression modeling, the placebo arm will be used as the 
reference group. For regression modeling that uses strata variables defined in Section 6.4, the 
first stratum listed for each variable in that section will be used as the reference group.   
For the final time-to-event analyses, the following SAS pseudocode will be used to perform 
stratified analyses to generate stratum-specific median time to event estimates and confidence 
intervals, stratum-specific Kaplan-Meier curves, and to perform the log-rank test. For any 
unstratified analyses, code can be used after the removal of the strata … ; line. 
 
proc lifetest data=dataset plots=(s); 
   time TimeVariable * CensorVariable(1); 
   strata StrataVariable; 
   test TreatmentVariable; 
run; 
Note that the interim efficacy analyses will be performed using R.  For all interim and final 
analyses, the software used will calculate the log rank statistic using the formula in Section 8.1.1. 
To perform a stratified Cox proportional hazards model for the final analysis and generate the 
treatment arm hazard ratio along with its confidence interval, the following pseudocode will be 
used.  For any unstratified analyses, code can be used after the removal of the strata … ; line 
and strata variable in the class statement. 
 
proc phreg data=dataset; 
   class StrataVariable(ref=StrataLabel) TreatmentVariable(ref=PlaceboLabel); 
   model TimeVariable * CensorVariable(1) = TreatmentVariable; 
   strata StrataVariable; 
   hazardratio TreatmentVariable / diff=ref cl=Wald; 
   ods output HazardRatios = HRest; 
run; 


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The following SAS pseudocode will be used to perform the final proportional odds model with 
treatment arm and disease severity as covariates and to generate the treatment odds ratio, p-
value, and predicted probabilities of the ordinal scale levels by treatment arm and disease 
severity: 
proc logistic data=dataset  
plots(only)=effect(x=ResponseVariable 
sliceby=DiseaseSeverityVariable*TreatmentVariable individual connect); 
   class DiseaseSeverityVariable(param=ref ref=Mild/ModerateLabel)  
   TreatmentVariable(param=ref ref=PlaceboLabel); 
   model ResponseVariable = TreatmentVariable StrataVariable; 
   oddsratio TreatmentVariable; 
   ods output OddsRatiosWald = ORest; 
run; 
6.2. 
Timing of Analyses 
6.2.1. 
Early Sample Size Reassessment 
A blinded estimate of the proportion of recoveries will be computed during the trial to evaluate 
whether the total sample size will provide the number of recoveries.  
6.2.2. 
Interim analyses 
A DSMB will monitor ongoing results to ensure patient 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 
analyses are described in Section 6.6.1 and Section 6.6.2 below as well as a separate guidance 
document for the DSMB.  
6.2.3. 
Final Analyses 
After the DSMB meeting on April 27, 2020, the interim results were provided to the sponsor and 
the interim analyses were performed again on an April 28, 2020 database freeze (unlocked 
dataset). The results of these analyses were made public on April 29, 2020. Subsequent to this, 
the plan for the final analyses (and corresponding datasets) was modified to the following: 
• A preliminary analysis of the primary, key secondary, and major safety outcomes will be 
performed on unlocked, partially clean version of data and events that occurred up to 
April 28, 2020. This preliminary analysis dataset was used for the analyses and 
summaries included in the “Remdesivir for the Treatment of Covid-19 – Preliminary 
Report” article published in The New England Journal of Medicine on May 22, 2020 
(DOI: 10.1056/NEJMoa2007764) and will be used for the preliminary report, whose 
summaries will coincide with the summaries provided in the article. This dataset will not 
be used for any further analyses apart from the preliminary report. 
• 
A fully cleaned and locked version of data and events that occurred up to April 28, 2020 
will be denoted as the “early analysis set”. Section 7, Section 8, and Section 9 denote 
which summaries will be provided as part of this report, but will focus largely on primary 
outcome, key secondary outcome, and mortality. 


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• 
The final analyses of all outcomes and planned summaries/listings will be performed on 
the final full locked database and provided in an addendum to the final report. This is the 
fully cleaned and locked version of all data and events that occurred at any time during 
this trial and will be denoted as the “full analysis dataset”. 
6.3. 
Analysis Populations 
Summaries and analysis of safety data will be presented for the Treated Population. Summaries 
and analysis of efficacy data will be presented for the intent-to-treat (ITT) population and a 
Treated population.  
6.3.1. 
Intention-to-Treat (ITT) and Treated Populations 
The intent-to-treat (ITT) population includes all subjects who were randomized.  
The treated population includes all randomized subjects who received any study drug infusion, 
even if the infusion was halted or slowed.   
For the main analyses of the primary and secondary efficacy outcomes, subjects in both 
populations will be classified by the treatment arm and disease severity stratum to which they 
were randomized. For safety, subgroup, and sensitivity analyses, subjects may be classified by 
their randomized or actual disease severity and placebo subjects who cross over and are treated 
with remdesivir will be censored/excluded as described in Section 3 and Section 8. 
6.4. 
Covariates and Subgroups 
Subgroup analyses for the main efficacy outcomes (i.e. the primary and key secondary analyses) 
will evaluate the treatment effect across the following subgroups:  
• Geographic region: 
o US sites; Non-US sites 
o North American sites; Asian sites; European sites  
• Duration of symptoms prior to enrollment 
o Quartiles 
o <= 10 days; > 10 days 
o <= Median; > Median 
• Race (White; Black/African American; Asian; Other) 
• Comorbidities  
o None; Any 
o None, One, Two or more 
o Obese; Non-Obese 
• Age (<40; 40-64; 65 and older),  
• Sex (Female; Male),  


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• Severity of disease  
o Randomization stratification: Mild/Moderate; Severe.  
o Actual disease severity at baseline: Mild/Moderate; Severe 
o Baseline ordinal scale category: 4; 5; 6; 7 
Additionally, main analyses of all secondary outcomes will evaluate the treatment effect across 
the following subgroups: 
• Duration of symptoms prior to enrollment (<= Median; > Median) 
• Severity of disease  
o Randomization stratification: Mild/Moderate; Severe.  
o Actual disease severity at baseline: Mild/Moderate; Severe 
o Baseline ordinal scale category: 4; 5; 6; 7 
The analyses of time to improvement will also be repeated in the subset of the randomized 
subjects who enrolled with a baseline clinical score of 7. As part of these analyses, the sensitivity 
analyses described in Section 3.3.4 regarding unblinded and retreated subjects will be performed 
in this subset, as well. 
There will also be a sensitivity analysis of the primary, key secondary, and mortality outcomes to 
evaluate the effect of concomitant therapy including experimental treatment and off-label use of 
marketed medications that are intended as treatment for COVID-19 and are given to patient prior 
to and during the study. Subjects who report use of the following categories of 
therapies/treatments will be censored at the time of the earliest start date of any of the 
therapies/treatments: 
• Protease inhibitors 
• Polymerase inhibitors 
• Other drugs used to treat COVID (off-label, experimental use) 
• Corticosteroids 
• Other anti-inflammatory drugs: 
− JAK inhibitors 
− Tyrosine kinase inhibitors 
− TNF inhibitors 
− Interleukin inhibitors 
− Interferons 
− Plasma 
− Immunoglobulins 
− T-cell therapies (anti-PD-1 monoclonal antibodies) 


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− Selective T-cell co-stimulation blockers 
− B-cell therapies (CD 20 monoclonal antibodies) 
For the recovery analyses, if a subject recovered prior to use of any of the medications/therapies, 
then the subject will still be counted as a recovery in the sensitivity analysis. For the analysis of 
the key secondary outcome, if a subject reports use of any of the medications/therapies prior to 
their Day 15 assessment, then the subject’s last clinical status score prior to medication/therapy 
use will be used as their Day 15 outcome. For the mortality analyses, subjects will be censored at 
the time of medication/therapy initiation.  Additional modeling of efficacy/mortality outcomes 
using restricted medication use as a covariate may be investigated in exploratory analyses. 
In addition, the effect of treatment on the primary and key secondary efficacy outcomes will be 
explored via regression modeling controlling for age and duration of symptoms prior to 
enrollment as continuous covariates. 
6.5. 
Missing Data 
All attempts will be made to collect all data per protocol. Any data point that appears to be 
erroneous or inexplicable based on clinical judgment will be investigated as a possible outlier. If 
data points are identified as outliers, sensitivity analyses may be performed to examine the 
impact of including or excluding the outliers. Any substantive differences in these analyses will 
be reported.   
For time to event outcomes, subjects who are lost to follow-up or terminate the study prior to 
Day 29 and prior to observing/experiencing the event will be censored at the time of their last 
observed assessment. Subjects who die prior to observing/experiencing the event will be 
censored at Day 29. 
For the analysis of the key secondary outcome, subjects who are discharged but are subsequently 
re-admitted prior to Day 15 without a reported clinical score, their clinical score will be imputed 
at 7, which is the highest value for a hospitalized subject. 
For the analyses of the secondary outcomes that involve clinical score (i.e. the key secondary 
outcome and time to improvement), if a subject is discharged from the hospital without a 
previously or concurrently reported clinical score of 1 or 2, then their clinical score at the time of 
discharge will be imputed as 2, which is the highest value for a non-hospitalized subject. 
For the modified version of the ordinal score described in Section 4.3, if a subject is discharged 
from the hospital without a previously or concurrently reported clinical score of 2 or 3, then their 
clinical score at the time of discharge will be imputed as 3, which is the highest value for a non-
hospitalized subject. 
For the analyses of the secondary outcomes described in Section 3.3, the following imputation 
rules will be used for subjects who are lost to follow-up, terminate early from the study, or do not 
have further outcome data available after discharge for any reason: 
• Days of Non-invasive ventilation/high-flow oxygen: 
o If the subject’s clinical status scale is 6 at the last observed assessment, then the 
subject will be considered to be on non-invasive ventilation/high-flow oxygen 


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through Day 29. The endpoint will be total days when assessments are available plus 
all imputed days following the last observed assessment. 
o If the subject is not on non-invasive ventilation/high-flow oxygen at the last observed 
assessment, then the subject will be considered to not be on non- invasive 
ventilation/high-flow oxygen for the remainder of follow-up. Thus, no additional 
imputed days will be added to the number of days recorded on available assessments. 
• Days of ventilation/ECMO: 
o If the subject’s clinical status scale is 7 at the last observed assessment, then the 
subject will be considered to be on ventilation/ECMO through Day 29. The endpoint 
will be total days when assessments are available plus all imputed days following the 
last observed assessment. 
o If the subject is not on ventilation/ECMO at the last observed assessment, then the 
subject will be considered to not be on ventilation/ECMO through Day 29. Thus, no 
additional imputed days will be added to the number of days recorded on available 
assessments. 
• Days of Oxygen: 
o If the subject’s clinical status score is 5, 6, or 7 at the last observed assessment, then 
the subject will be considered to be on oxygen through Day 29. The endpoint will be 
total days when assessments are available plus all imputed days following the last 
observed assessment. 
o If the subject is not on oxygen at the last observed assessment, then the subject will 
be considered to not be on oxygen through Day 29. Thus, no additional imputed days 
will be added to the number of days recorded on available assessments. 
• Days of Hospitalization 
o If the subject is discharged and no further hospitalization data are available, then the 
subject will be assumed to not have been readmitted. Thus, no additional imputed 
days will be added to the number of days recorded on available assessments. If a 
subject dies while hospitalized, the number of days of hospitalization will be imputed 
as 28 days. 
6.6. 
Interim Analyses and Data Monitoring 
6.6.1. 
Interim Safety Analyses 
Interim safety data will be available electronically in real time. No formal interim safety analyses 
are planned. 
6.6.2. 
Interim Efficacy Review 
Interim efficacy analyses will be conducted after at approximately 50% of total information.  The 
information fraction at an interim analysis will be computed as 𝑡𝑡= 𝑟𝑟/400, where 𝑟𝑟 is the 
number of recoveries by the time of the data freeze date for the interim analysis. The Lan-
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primary endpoint using an overall two-sided type-I error rate of 0.05. Specifically, two one sided 
boundaries are constructed at level 0.025 using the spending function 
𝛼𝛼∗(𝑡𝑡) = 2[1 −Φ{2.241/𝑡𝑡
1
2 }], 
 
where Φ is the standard normal distribution function. Lan-DeMets software from the University 
of Wisconsin, now available in the R package `ldbounds’, will be used to calculate boundaries. 
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.  
Section 6.2.3 describes the plan for the final analyses of the early and final analysis sets. 
6.7. 
Multicenter Studies 
Data will be pooled across all clinical sites. Secondary analyses of the primary outcome will 
account for site via stratification by geographic region as noted in Section 6.4. 
A sensitivity analysis of the primary outcome will be performed to assess the impact of 
individual sites on the observed treatment effect. Letting M be the total number of sites, the 
primary analysis will be repeated by excluding a single clinical site and performing the analyses 
on the remaining M-1 sites. This process will be repeated so that estimates are generated for each 
of the M-1 subset datasets. Presentations from these analyses are described in Section 8.1.2. 
6.8. 
Multiple Comparisons/Multiplicity 
There is only one primary outcome measure. The study utilizes a group-sequential design to 
control the overall type I error rate while allowing for formal interim analyses of the primary 
outcome measure (as described in Section 6.6 and Section 8.1). There is no planned adjustment 
for multiple comparisons in any secondary or exploratory analyses. 


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7. 
STUDY SUBJECTS 
7.1. 
Disposition of Subjects 
A summary of the reasons that subjects were screened but not enrolled will be tabulated 
(Table 7). 
The composition of analysis populations, including reasons for subject exclusion will be 
summarized by treatment group and disease severity (Table 8). The summaries will be provided 
for both the early and full analysis sets. A subject listing of analysis population eligibilities for 
the early and full analysis sets will be generated (Listing 1). 
The disposition of subjects will be tabulated by treatment group, disease severity and site 
(Table 9). Study milestones included in the table will be the total number of subjects that were 
screened, randomized, received a loading dose, received all expected maintenance doses, 
completed all expected blood draws, completed Study Day 15 visit, completed Study Day 22 
visit, and completed Study Day 29 visit. In addition, the number of subjects who were unblinded 
to their treatment and the number of subjects with crossover remdesivir treatment will be 
summarized. For the calculation of percentages, subjects who die will not be included in the 
denominators for visits/assessments beyond their death. The number of subjects unblinded and 
crossover treated at each site will also be summarized (Table 10). 
Treatment compliance (number of subjects who had their required infusions halted/slowed and 
the number of subjects with missed doses) will be summarized by treatment group (Table 11). 
A flowchart showing the disposition of study subjects, adapted from the Consort Statement [4] 
will be generated (Figure 1). This figure will present the number of subjects screened, 
randomized, lost to follow-up, and analyzed, by treatment group and disease severity. This figure 
will be generated for both the early and full analysis sets. 
A listing of subjects who discontinued dosing or terminated study follow-up and the reason will 
be generated (Listing 2). 
7.2. 
Protocol Deviations 
Subject-specific protocol deviations will be summarized by the reason for the deviation, the 
deviation category, treatment group, disease severity and (separately) site for all subjects 
(Table 12 and Table 13). All subject-specific protocol deviations and non-subject specific 
protocol deviations will be included in listings (Listing 3 and Listing 4). 


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8. 
EFFICACY EVALUATION 
8.1. 
Primary Efficacy Analysis 
8.1.1. 
Primary Analyses 
All the summaries described in this section will be generated for both the early and the full 
analysis sets. 
The primary analysis uses the stratified log rank test to compare treatment to control through 
Day 29 with respect to time to recovery, as defined in Section 3.3. Stratification is based on 
mild/moderate versus severe disease at baseline. As noted in Section 3.3, all deaths within 29 
days will be considered censored at Day 29 with respect to time to recovery. Conceptually, a 
death corresponds to an infinite time to recovery, but censoring at any time greater than or equal 
to Day 29 gives the same answer as censoring at Day 29; both correspond to giving deaths the 
worst rank.   
Let MM and S denote the Mild/Moderate and Severe subgroups, respectively. The z-score 
associated with the stratified log rank test is 
𝑍𝑍=
∑
(𝑂𝑂𝑖𝑖−
𝑀𝑀𝑀𝑀
𝐸𝐸𝑖𝑖) + ∑(𝑂𝑂𝑖𝑖−𝐸𝐸𝑖𝑖)
𝑆𝑆
 
ඥ∑
𝑉𝑉𝑖𝑖+ ∑𝑉𝑉𝑖𝑖
𝑆𝑆
𝑀𝑀𝑀𝑀
. 
The sums are over recovery times 𝑡𝑡𝑖𝑖 in the mild/moderate and severe subgroups, 𝑂𝑂𝑖𝑖 is the 
number of treatment arm participants recovering at time 𝑡𝑡𝑖𝑖,  and 𝐸𝐸𝑖𝑖 and 𝑉𝑉𝑖𝑖 are the null expected 
value and variance of the number of treatment recoveries calculated using the hypergeometric 
distribution.  Specifically, if 𝑛𝑛𝑇𝑇𝑇𝑇 and 𝑛𝑛𝐶𝐶𝐶𝐶 denote the numbers of patients `at risk’ in the two arms 
in a given stratum at 𝑡𝑡𝑖𝑖, and 𝑟𝑟𝑖𝑖 is the total number of recoveries at 𝑡𝑡𝑖𝑖, then 𝐸𝐸𝑖𝑖= 𝑟𝑟𝑖𝑖𝑛𝑛𝑇𝑇𝑇𝑇/(𝑛𝑛𝑇𝑇𝑇𝑇+ 𝑛𝑛𝐶𝐶𝐶𝐶) 
and 𝑉𝑉𝑖𝑖= 𝑟𝑟𝑖𝑖(𝑛𝑛𝑖𝑖−𝑟𝑟𝑖𝑖)𝑛𝑛𝑇𝑇𝑇𝑇𝑛𝑛𝐶𝐶𝐶𝐶/[𝑛𝑛𝑖𝑖
2(𝑛𝑛𝑖𝑖−1)], where 𝑛𝑛𝑖𝑖= 𝑛𝑛𝑇𝑇𝑇𝑇+ 𝑛𝑛𝐶𝐶𝐶𝐶. The 𝑂𝑂𝑖𝑖, 𝐸𝐸𝑖𝑖, 𝑎𝑎𝑎𝑎𝑎𝑎 𝑉𝑉𝑖𝑖 are computed 
separately within the mild/moderate and severe strata. 
As noted in Section 6.6.2, to maintain an overall two-sided type-I error rate of 0.05, the Lan-
DeMets spending function analog of the O’Brien-Fleming boundary will be used to derive the 
cumulative error spending and boundaries for the interim analyses. 
The log rank test will be performed using the pseudocode provided in Section 6.1. The following 
pseudocode can be used to compute the bounds for the final analyses and compare to the 
calculated log-rank statistic. The Boundaries dataset will contain the updated boundaries 
calculated from the interim analyses using the actual information levels observed at the interim 
analyses. 
 
data Parms_LogR; 
   set logrankp(rename=(Statistic=Estimate)); 
   if Variable='TreatmentVariable'; 
   _Scale_='Score'; 
   _Stage_= AnalysisNumber; 
   keep Variable _Scale_ _Stage_ StdErr Estimate; 
run; 
 
proc seqtest Boundary=Boundaries 
             Parms(Testvar=TreatmentVariable)=Parms_LogR 


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             infoadj=prop 
             boundaryscale=score 
             ; 
   ods output Test=FinalResults ParameterEstimates = LogHRest; 
run; 
If the trial is stopped at the interim analysis, then to derive the p-value, hazard ratio estimate, and 
confidence interval for the early and final analysis sets, stage-wise ordering of the sample space 
will be used [5]. The resulting p-value, median unbiased estimate, and confidence interval will 
be presented in the final report. If the trial is not stopped early, then the fixed sample estimates of 
the statistics using an alpha level of 5% will be computed and reported for the early and final 
analysis sets. The SAS pseudocode above provides estimates for the log hazard ratio and so the 
estimates will be exponentiated and reported. 
The primary analysis will be performed in the ITT analysis population. The treatment hazard 
ratio estimate and confidence interval and p-value from the stratified log rank test will be 
presented (Table 14). The median time to event and 95% confidence interval will be summarized 
by treatment arm and disease severity. In addition, stratum-specific estimates of the treatment 
hazard ratio from Cox models run within each of the disease severity strata will be presented. 
Kaplan-Meier curves for each treatment arm will be presented, supplemented with the hazard 
ratio estimate, p-value, and the number of subjects at risk in each arm and severity stratum at 
Days 1, 3, 5, 7, 11, 15, 22, and 29 (Figure 2). 
Subject listings of the ordinal scale results by day will be generated (Listing 5). 
8.1.2. 
Supplemental and Sensitivity Analyses 
For all supplemental and sensitivity analyses of the primary outcome, p-values will not be 
reported, and 95% confidence levels will be used for confidence interval estimates.  
The primary analysis will be repeated in the Treated analysis population where subjects who are 
ineligible at baseline will be censored at enrollment. The tabular and graphical summaries 
described in the previous section will be replicated for this Treated analysis. 
Sensitivity analyses will be performed using Cox proportional hazards models to estimate the 
hazard ratio.  First, an ITT analysis will be performed in which subjects who die prior to 
recovering are treated as experiencing a competing risk in the Fine-Gray proportional hazards 
regression model. Second, a Cox model will be fit with binary indicators for treatment group and 
disease severity (Mild/Moderate vs. Severe [separate models for randomized stratum and actual 
stratum]) as well as a treatment * disease severity interaction term. The models will be fit to the 
ITT analysis population. The treatment group hazard ratios and CIs will be reported for both sets 
of models and the interaction term p-value will be reported for the interaction models. 
The primary analysis will also be repeated using the other subgroups defined in Section 6.4 in 
place of disease severity. Each subgroup will be considered separately and the tabular and 
graphical summaries described in the previous section will be replicated for each subgroup. The 
tabular summary will also include results from an analysis of time to recovery controlling for age 
and duration of symptoms as continuous covariates. A forest plot will be generated to display the 
overall treatment hazard ratio estimate and CI from each of the within-stratum analyses 
(Figure 6). These analyses will be performed in the ITT and Treated populations.  


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In addition, a forest plot will be generated for the “leave one out” sensitivity analyses described 
in Section 6.7; hazard ratio estimates and CIs will be provided for each subgroup that leaves a 
single site out. 
An additional sensitivity analysis will evaluate the effect of recoveries that were not sustained as 
indicated in Section 3.3.2. 
As noted in Section 6.4, analyses that take into account concomitant medication will be 
performed. The primary analysis will be repeated, where subjects who take prohibited 
medications will be treated as treatment failures and will be censored at the time of medication 
use.  
As noted in Section 3.3.2, an analysis of the primary outcome where placebo subjects has 
crossover treatment with remdesivir are censored at the time of retreatment will be performed. 
To support this sensitivity analysis, a summary of the clinical status scores assessed on the day of 
retreatment and the following day will be provided (Table 21). A spaghetti plot of the clinical 
status scores by study day will be provided for all placebo subjects, where the subjects who are 
retreated will be highlighted (Figure 9). 
Two corroborative summaries will also be generated. A summary of the number and percentage 
of subjects in each treatment group who recovered (and are alive), did not recover (and are 
alive), and died by Day 29 will be summarized. The summary will also include the numbers and 
percentages, grouping deaths and non-recoveries together(Table 23). The summaries will also be 
provided by the duration of symptoms categorizations specified in Section 6.4. 
Other censoring techniques and additional analyses of the primary outcome may be performed. 
8.2. 
Secondary Efficacy Analyses 
This section describes the planned analyses for the secondary efficacy outcome measures.  
Where applicable, refer to Section 6.1 for SAS pseudocode. Analyses of mortality will be 
described in Section 9.4. 
Analyses of the key secondary outcome measure will be explored in the specified subgroups 
described in Section 6.4. Analyses of the other secondary outcome measures will be performed 
by treatment arm only and repeated for specified subgroups described in Section 6.4 and 
Section 6.7 via stratified analyses. As with the analyses described in Section 8.1.2, tabular 
summaries will follow the structure of the main tabular summaries planned for each outcome 
with the modification that stratified estimates will be provided in separate rows. Forest plots will 
display confidence intervals of outcomes/estimates across subgroups, where applicable.  
All secondary efficacy analyses will be performed in the ITT population. Treated analyses will 
be explored to investigate consistency of results compared to the ITT analyses. 
8.2.1. 
Ordinal Scale Outcomes (Key Secondary Outcome Measure) 
For the analysis of the key secondary outcome measure, the distribution of the 8-point ordinal 
clinical status scale with 8 categories at Study Visit Day 15 (not necessarily actual study day 15), 
the outcome will be analyzed using a proportional odds model with treatment arm and disease 
severity as covariates. The treatment odds ratio estimated from the model will be presented along 


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with the p-value (Table 24). Predicted individual probabilities of scale levels by treatment arm 
and disease severity will be summarized graphically (Figure 10).  
As noted in Section 3.3, sensitivity analyses will be performed to account for subjects who are 
unblinded as well as placebo subjects who are unblinded and crossover treated with remdesivir. 
These analyses will be performed in the ITT population. 
Multiple supplemental analysis of this key secondary outcome will be performed. Time to 
improvement by at least one category in the clinical status 8-point scale (see Section 3.3). The 
log rank test will be performed using a Cox proportional hazards model to test whether the 
curves differ between treatment arms. The median time to event and CI in each treatment group 
will be summarized along with the treatment hazard ratio estimate and log rank p-value 
(Table 26). Differences in time-to-event endpoints by treatment arm will be summarized with 
Kaplan-Meier curves (Figure 11). Number at risk, hazard ratio and log rank p-values will be 
presented on the figures. The analyses (and tabular and graphical summaries) will be repeated 
using the outcome of time to improvement in two categories of the ordinal scale defined in 
Section 3.3. Both time to improvement (one and two categories) analyses will be repeated using 
the censoring plan described in Section 3.3 for subjects who are retreated with remdesivir 
(Table 28). In addition, a subgroup analysis time to improvement among subjects enrolled with a 
clinical score of 7 will be performed using the retreatment censoring plan (Table 29). 
The above analyses will be repeated with the following modification to the ordinal scale 
described in Section 4.3 (Table 29). 
The number and proportion of subjects along with 95% confidence intervals by category of 
clinical status will be presented by treatment arm at Study Visit (not necessarily actual) Days 1, 
3, 5, 8, 11, 15 and 29 (Table 34). A figure will present stacked bar charts by day with side by 
side bars for each treatment arm (Figure 13). Histograms will be generated to display the ordinal 
scale value distributions over time in each treatment group (Figure 14). 
8.2.2. 
NEWS 
The median time to discharge or to a NEWS of ≤ 2 and CI will be summarized by treatment 
group (Table 36). The hazard ratio and log rank p-values will be provided with the summaries. 
Differences in time-to-event endpoints by treatment arm will be summarized with Kaplan-Meier 
curves. Number at risk, hazard ratio and log rank p-values will be included on the figures 
(Figure 15).  
The mean, standard deviation (SD), median, minimum, and maximum NEWS at Baseline and 
Study Visit (not necessarily actual) Days 3, 5, 8, 11, 15 and 29 will be presented by treatment 
arm as well as change from baseline at each post-Day 1 visit (Table 39). A figure with mean and 
SD over time will also be presented by treatment arm (Figure 16). 
Subject listings of NEWS responses (overall and individual components) by day will be 
generated (Listing 6). 
8.2.3. 
Days of Oxygenation 
Duration of oxygenation days will be summarized in a table using medians and quartiles by 
treatment arm (Table 41). This will only include subjects in category 5, 6, or 7 at enrollment. 
Analyses will be performed in the ITT population, Treated population, and a subset of the 


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Treated population of treated subjects only as subjects who are not treated are terminated from 
the study immediately and are included in the ITT/Treated analyses with a count of 1 day.  Bee 
swarm plots of oxygen days by treatment arm will be generated, where subject whose days are 
imputed to the maximum of 28 days due to death are grouped separately from subjects who do 
not die (Figure 17). 
8.2.4. 
Incidence of New Oxygen use 
The incidence and duration of new oxygen use will be analyzed by treatment arm. This will only 
include subjects in category 4 at enrollment. New use will be identified by a post-enrollment 
score of at least 5; the number of subjects reporting new use and the incidence rate (and CI) will 
be reported. 
8.2.5. 
Days of Non-Invasive Ventilation/High-Flow Oxygen 
Duration of non-invasive ventilation/high flow oxygen days will be summarized in a table using 
medians and quartiles by treatment arm.  This will only include subjects in category 6 or 7 at 
enrollment. Analyses will be performed in the ITT population, Treated population, and a subset 
of the Treated population of treated subjects only as subjects who are not treated are terminated 
from the study immediately and are included in the ITT/Treated analyses with a count of 1 day.  
Bee swarm plots of non-invasive ventilation/high flow oxygen days by treatment arm will be 
generated, where subject whose days are imputed to the maximum of 28 days due to death are 
grouped separately from subjects who do not die.   
8.2.6. 
Incidence of New Non-Invasive Ventilation/High-Flow Oxygen 
The incidence and duration of new Non-Invasive Ventilation/High-Flow Oxygen use will be 
analyzed by treatment arm. This will only include subjects in category 4 or 5 at enrollment. The 
incidence of new oxygen use will be analyzed by treatment arm. This will only include subjects 
in category 4 at enrollment. New use will be identified by a post-enrollment score of at least 6. 
The number of subjects reporting new use and the incidence rate (and CI) will be reported.  
8.2.7. 
Days of Invasive Mechanical Ventilation/ECMO 
Duration of invasive Mechanical Ventilation/ECMO days will be summarized in a table using 
medians and quartiles by treatment arm. This will only include subjects in category 7 at 
enrollment. Analyses will be performed in the ITT population, Treated population, and a subset 
of the Treated population of treated subjects only as subjects who are not treated are terminated 
from the study immediately and are included in the ITT/Treated analyses with a count of 1 day.  
Bee swarm plots of invasive Mechanical Ventilation/ECMO days, and days hospitalized by 
treatment arm will be generated, where subject whose days are imputed to the maximum of 28 
days due to death are grouped separately from subjects who do not die.  
8.2.8. 
Incidence of New Non-Invasive Ventilation/High-Flow Oxygen 
The incidence and duration of new Non-Invasive Ventilation/High-Flow Oxygen use will be 
analyzed by treatment arm. This will only include subjects in category 4, 5, or 6 at enrollment. 
The incidence of new oxygen use will be analyzed by treatment arm. This will only include 


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subjects in category 4 at enrollment. New use will be identified by a post-enrollment score of 7. 
The number of subjects reporting new use and the incidence rate (and CI) will be reported. 
8.2.9. 
Days of Hospitalization 
Duration of hospitalization days will be summarized in a table using medians and quartiles by 
treatment arm (Table 47). Incidence of readmittance will also be summarized. Analyses will be 
performed in the ITT population, Treated population, and a subset of the Treated population of 
treated subjects only as subjects who are not treated are terminated from the study immediately 
and are included in the ITT/Treated analyses with a count of 1 day. Bee swarm plots of days 
hospitalized by treatment arm will be generated, where subject whose days are imputed to the 
maximum of 28 days due to death are grouped separately from subjects who do not die.  
8.3. 
Exploratory Efficacy Analyses 
Analyses of exploratory outcome measures are not covered in this SAP. 


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9. 
SAFETY EVALUATION 
9.1. 
Demographic and Other Baseline Characteristics 
Summaries of age, sex, height, weight, BMI, ethnicity, and race will be presented by treatment 
group as well as geographic region, duration of symptoms prior to enrollment, and disease 
severity (Table 49 and Table 50). Ethnicity will be categorized as Hispanic or Latino, or not 
Hispanic and not Latino. In accordance with NIH reporting policy, subjects may self-designate 
as belonging to more than one race or may refuse to identify a race, the latter reflected in the 
CRF as “No” to each racial option.  Both demographic tables will be repeated to assess baseline 
differences between remdesivir subjects, placebo subjects who are not retreated with remdesivir, 
and placebo subjects who are retreated with remdesivir (Table 51 and Table 52). 
Individual subject listings will be presented for all demographics and baseline characteristics 
(Listing 7). 
9.1.1. 
Prior and Concurrent Medical Conditions 
Focused medical history is obtained at the screening visit that includes the following: 
• Day of onset of COVID-19 symptoms 
• History of chronic medical conditions related to inclusion and exclusion criteria 
• Medication allergies 
• Review medications and therapies for this current illness. 
Medical history is limited to the following conditions: asthma, cancer, chronic kidney disease, 
chronic liver disease, chronic oxygen requirement, chronic respiratory disease, congestive heart 
failure, coronary artery disease, diabetes I and II, hypertension, immune deficiency, and obesity. 
All current illnesses and past pre-existing medical conditions will be MedDRA® coded using 
MedDRA dictionary version 22.0 or higher. Summaries of subjects’ pre-existing medical 
conditions will be presented by treatment group (Table 53). 
Individual subject listings will be presented for all medical conditions (Listing 8). 
9.1.2. 
 Prior and Concomitant Medications  
Medication history (concomitant medications) includes a review of all current medications and 
medications taken within 7 days prior to enrollment through approximately Day 11 or early 
termination (if Day 11), whichever occurs first.  
Summaries of medications that were started prior to dosing and continuing at the time of dosing 
will be presented by WHO Drug Terms 2 and 3 and treatment group (Table 54). Summaries of 
overall use of prohibited medications/therapies listed in Section 6.4 as well as use by select study 
days will also be generated (Table 55 and Table 56). 
Individual subject listings will be presented for all concomitant medications (Listing 9). 


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9.2. 
Measurements of Treatment Compliance 
The subject disposition table will summarize the number of subjects that were screened, 
randomized, received a loading dose, received all maintenance doses, each maintenance dose, 
completed all blood draws, and completed Study Day 29 visit. In addition, the number of 
subjects with halted, slowed, or missed doses will be summarized by treatment arm (See 
Section 7). 
Individual subject listings will be presented for all subjects who discontinued dosing (Listing 2). 
Individual subject listings will be presented for all subjects who missed, halted or slowed any 
doses (Listing 10). 
9.3. 
Adverse Events 
For the calculation of incidence of adverse events (i.e., on a per subject basis), each subject will 
only be counted once and any repetitions of adverse events within a subject will be ignored; the 
denominator will be the number of subjects in the Treated population. All adverse events 
reported will be included in the summaries and analyses. 
An overall summary by treatment arm and disease severity of adverse events is presented that 
includes subjects with at least one event, at least one related event, at least one SAE, at least one 
related SAE and at least one AE leading to early termination (Table 57). 
Adverse events occurring in 5% of subjects (by MedDRA preferred term) in any treatment group 
will be presented (Table 58). 
The proportion of subjects reporting at least one adverse event will be summarized by MedDRA 
system organ class and preferred term for each treatment arm, disease severity and overall. 
Denominators for percentages are the number of subjects in the Treated population. 
The following summaries for adverse events will be presented by MedDRA system organ class, 
preferred term, disease severity and treatment group: 
• Subject listing of non-serious adverse events (Listing 11); 
• Bar chart of non-serious related adverse events by severity and MedDRA system organ 
class (Figure 21); 
• Bar chart of non-serious related adverse events by maximum severity and MedDRA 
system organ class (Figure 22); 
All the summaries described in this section will be generated for both the early and the full 
analysis sets. 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse 
Events 
A listing of death and other serious adverse events will be presented, including Subject ID, 
treatment group, Adverse Event Description, Associated Dose Number, Number of Days Post 
Dose (Duration), Number of Days Post Dose the Event Became Serious, Reason Reported as an 
SAE, Severity, Relationship to Treatment, Alternate Etiology if not Related, Action Taken with 


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Study Treatment, Subject Discontinuation, Outcome, MedDRA SOC, and MedDRA PT 
(Listing 12 and Listing 13).  
The number of subjects who die by Day 15 and Day 29 will be presented by treatment arm. The 
14- and 28-day crude mortality rate, which will use the number of subjects in the treatment group 
and analysis population as the denominator, will be presented (Table 59). The analysis will be 
repeated censoring placebo subjects who were retreated with remdesivir at the time of 
retreatment. 
Mortality through Day 15 and 29 will also be analyzed as a time to event endpoint (see 
Section 3.3). A table will present median time to event along with 95% confidence intervals 
overall for each treatment arm along with the hazard ratio estimate and log rank p-values 
(Table 61). Differences in time-to-event endpoints by treatment will be summarized with 
Kaplan-Meier curves (Figure 23). Analyses of mortality will be performed in the ITT and the 
Treated analysis populations and will be performed on both the early and the full analysis sets. 
The ITT tabular summaries will be repeated censoring placebo subjects who were retreated with 
remdesivir at the time of retreatment.  Similarly, the summaries will be repeated censoring 
subjects who were unblinded at the time of unblinding. 
Rates of Grade 3 and 4 AE occurrence will be compared between treatment arms using 
Barnard’s exact test and presented (Table 63). Rates of SAE occurrence will also be compared 
between treatment arms using Barnard’s exact test and presented. Further, the composite 
endpoint of the occurrence of death, SAE, or Grade 3 or 4 AE described in Section 3.3 will be 
analyzed as a time to event outcome. A table will present median time to event along with 95% 
confidence intervals overall for each treatment arm along with the hazard ratio estimate and log 
rank p-values (Table 64). Differences in time-to-event endpoints by treatment will be 
summarized with Kaplan-Meier curves (Figure 24). 
9.5. 
Pregnancies 
For any subjects in the Treated population who become pregnant during the study, every attempt 
will be made to follow these subjects to completion of pregnancy to document the outcome, 
including information regarding any complications with pregnancy and/or delivery. Note that the 
CSR will not be delayed to wait for outcomes of any pregnancies; an addendum to the CSR 
would be provided in such a scenario. A set of listings of pregnancies and outcomes will be 
presented (Listing 14, Listing 15, Listing 16 , Listing 17, Listing 18). 
9.6. 
Clinical Laboratory Evaluations 
Clinical safety laboratory adverse events are collected Day 1, 3, 5, 8, 11 and Day 15 and 29 if 
able to return to clinic or still hospitalized. Parameters evaluated include white blood cell count, 
absolute neutrophil count, eGFR, platelet count, hemoglobin concentration, creatinine, glucose, 
total bilirubin, ALT, AST, and PT/INR. Laboratory safety parameters will be graded according 
to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, version 2.1 (July 2017).  
The distribution of Grade 3 and 4 chemistry and hematology laboratory results by maximum 
severity, time point, disease severity and treatment group will be presented (Table 65).  


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Descriptive statistics including mean, median, standard deviation, maximum, and minimum 
values and change from baseline by time point, for all and each chemistry and hematology 
laboratory parameter will be summarized by disease severity and treatment arm (Table 66). 
Changes in chemistry and hematology laboratory values will be presented in line graphs over 
time with mean and SD plotted by disease severity and treatment arm (Figure 25).  
Listings will provide a complete listing of individual chemistry and hematology laboratory 
results with applicable reference ranges (Listing 19). 
9.7. 
Vital Signs and Physical Evaluations 
Vital sign measurements include pulse, systolic blood pressure, respiratory rate, SpO2 and oral 
temperature. Vital signs were assessed as part of the NEW score (assessed daily while 
hospitalized and on Day 15) and will be listed in Listing 6.  
Targeted Physical examinations are performed at Day 1 and are performed post-baseline only 
when needed to evaluate possible adverse events. At the screening visit, the targeted physical 
examination is focused on lung auscultation. Physical exam findings per subject will be detailed 
in a listing (Listing 20). 
9.8. 
Concomitant Medications 
Concomitant medications will be coded to the Anatomical Therapeutic Classification using the 
WHO Drug Dictionary. The use of prior and concomitant medications taken during the study 
will be recorded on the CRFs. Concomitant medication use will be presented in a subject listing 
(Listing 20). The use of concomitant medications during the study will be summarized by ATC1, 
ATC2 code, disease severity and treatment group for the Treated population (Table 54). The 
summaries will be repeated for the subgroups defined in Section 6.4. 
9.9. 
Other Safety Measures 
No additional safety analyses are planned. 
 


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10. 
PHARMACOKINETICS 
Not applicable. 
 


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11. 
IMMUNOGENICITY 
Not applicable. 


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12. 
OTHER ANALYSES 
Not applicable. 


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13. 
REPORTING CONVENTIONS 
P-values ≥0.001 and ≤0.999 will be reported to 3 decimal places; p-values less than 0.0005 will 
be reported as “<0.001” and p-values greater than 0.9995 will be reported as “>0.999”.   
The mean, standard deviation, and other statistics will be reported to1 decimal place greater than 
the original data. The minimum and maximum will use the same number of decimal places as the 
original data.  
Proportions will be presented as 2 decimal places; values greater than zero but <0.005 will be 
presented as “<0.01”. Percentages will be reported to the nearest whole number; values greater 
than zero but < 0.5% will be presented as “<1”; values greater than 99.5% but less than 100% 
will be reported as >99.  
Estimated parameters, not on the same scale as raw observations (e.g. regression coefficients) 
will be reported to 3 significant figures. 


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14. 
TECHNICAL DETAILS 
SAS version 9.4 or above, or R language and environment for statistical computing 3.6.1 or 
above, will be used to generate all tables, figures and listings. 


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15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY 
OR PLANNED ANALYSES 
The following are the changes in the SAP from version 2.0 to 3.0: 
Throughout document/multiple sections: 
• Typos and errors were fixed and clarifications to text were added where necessary.   
• This plan was updated to describe the two sets of final analyses to be performed: the early 
data set and the final data set. Language was added to Section 6.2, Section 7, Section 8, 
and Section 9 regarding which summaries would be provided for both the early and the 
final data sets. 
• The Treated analysis population was added which replaced the MITT and safety analysis 
populations. 
• Sensitivity analyses that explore placebo subjects who were unblinded and treated with 
remdesivir while on study were added. 
Section 2.1: 
• A description of the interim analysis and public disclosure of interim results was added. 
Section 3.3.1: 
• It was clarified that for efficacy data, the last value obtained prior to randomization 
would be defined as the baseline value, whereas for safety data, the last value obtained 
prior to the first received dose would be the baseline value. 
Section 3.3.3: 
• It was clarified that for clinical status analysis at specified days, the data used for those 
analyses would be the data collected at the study visit corresponding to that day and not 
necessarily the actual study day.  Corresponding language was updated throughout 
Section 8. 
Section 3.3.10: 
• The definition of time to death by Study Day 15 and 29 was clarified and a description of 
the censoring plan was added. 
Section 4: 
• Language was updated throughout to match the language in version 3.0 of the protocol. 
Section 4.3: 
• Language describing the modified ordinal scale was moved from Section 8 to this 
section. 
Section 6.4: 
• Additional subgroups to be explored were added. 
• The specific list of restricted concomitant therapies/treatments to be explored in the 
sensitivity analyses was added. 


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Section 6.5: 
• Details of imputation methods that were left out of the previous version of the SAP were 
added. 
Section 6.7: 
• An additional analysis to explore the effect of clinical site on the primary outcome was 
added.  Corresponding language was added to Section 8.1.2. 
Section 8.1.2: 
• The description of the analyses that control for age and duration of symptoms was moved 
from Section 6.4 to this section. 
Section 9.1.1: 
• The section was fixed to denote that summaries would be provided for each of the 
solicited comorbidities and summaries would not be provided by MedDRA SOC/PT. 
Section 9.3: 
• As no solicited adverse events are not collected, the term “unsolicited” was removed 
throughout the section and corresponding shells. 
Section 9.4: 
• It was clarified that the mortality rate to be estimated and reported will be the crude 
mortality rate that uses the total number of subjects in the analysis population as the 
denominator. 
• It was clarified that mortality estimates would be provided for both the ITT and treated 
analysis populations. 
• The time-to-event analysis of death by Day 15 was erroneously left out of the plan; this 
analysis was added. 
Section 9.6: 
• Duplicative summaries were removed. 
Section 9.7: 
• As vital signs will be listed as part of the NEWS listing, the separate vital signs listing 
was removed. 
Table, figure, and listing shells: 
• Table and figure shells were provided for planned sensitivity analyses. 
• Tables and listings that provided duplicative results/summaries were removed from the 
list of shells. 
• Where possible, tables were combined in order to present related summaries together 
(e.g. the within-stratum hazard ratio estimates for the time to recovery analyses were 
inserted into the primary time to recovery tables and the separate within-stratum hazard 
ratio tables were removed). 


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• Multiple table, figure, and listing shells and/or their programming notes were modified to 
fix errors, provide clarifications, or provide a more concise or more appropriate 
presentation of the results. 


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16. 
REFERENCES 
1. Schoenfeld, D. 1981. The asymptotic properties of nonparametric tests for comparing 
survival distributions. Biometrika. 68 (1): 316–319. 
2. Cao, Wang, Wen et al. 2020.  A trial of lopinavir–ritonavir in adults hospitalized with 
severe covid-19.  New DOI: 10.1056/NEJMoa2001282. 
3. Whitehead, J. 1993.  Sample size calculations for ordered categorical data.  Statistics in 
Medicine 12, 2257-2271.   
4. Drummond R. CONSORT Revised: Improving the Reporting of Randomized Clinical 
Trials. JAMA. 2001; 285(15):2006-2007. 
5. Jennison C., Turnbull B.W. 2000. Group sequential methods with applications to clinical 
trials.  Chapman & Hall, Boca Raton. 
 


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17. 
LISTING OF TABLES, FIGURES, AND LISTINGS  
Table, figure, and listing shells are presented in Appendices 1, 2, and 3. 
The formatting of the final version of a table, figure, or listing may differ from what is presented 
in the shell or the presentation of the results may be changed, however the key content will 
remain unchanged. Additional summaries/data points may be included in the final version of a 
table, figure, or listing, as well. Additional tables, figures, and listings may be generated to 
supplement the planned output.  
 


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APPENDIX 1. TABLE MOCK-UPS 
LIST OF TABLES 
Table 1: 
Categories of the NEWS scale. ...................................................................................22 
Table 2: 
Schedule of Study Procedures (from protocol version 3.0) ........................................24 
Table 3: 
Number of recoveries needed for 85% power assuming a type I error rate of 
5% for various recovery ratios. ...................................................................................25 
Table 4: 
Possible scenarios for the distribution of ordinal outcomes for the control 
arm at day 15. .............................................................................................................26 
Table 5: 
Sample size calculations for scenarios in Table 2 for a two-arm study 
assuming 85% power, a two-sided type I error rate of 5%, and various true 
odds ratios. ..................................................................................................................27 
Table 6: 
Treatment ordinal outcome proportions under an odds ratio of 1.75 for five 
scenarios in Table 5 at day 15. ....................................................................................27 
Table 7: 
Ineligibility Summary of Screen Failures ...................................................................60 
Table 8: 
Analysis Population Eligibilities by Treatment Group and Disease Severity ............61 
Table 9: 
Subject Disposition by Treatment Group and Disease Severity .................................62 
Table 10: Subject Unblinding and Crossover Treatment by Site ...............................................63 
Table 11: Treatment Compliance by Treatment Group ..............................................................64 
Table 12: Distribution of Protocol Deviations by Category, Type, Treatment Group, 
and Disease Severity ...................................................................................................65 
Table 13: Distribution of Protocol Deviations by Category, Type, and Site ..............................66 
Table 14: Time to Recovery by Treatment Group and Disease Severity ...................................67 
Table 15: Time to Recovery by Treatment Group and Disease Severity: Fine-Gray and 
Interaction Modeling ..................................................................................................67 
Table 16: Time to Recovery by Treatment Group within Subgroups – ITT Population ............67 
Table 17: Time to Recovery by Treatment Group within Subgroups – Treated 
Population ...................................................................................................................67 
Table 18: Time to Recovery by Treatment Group and Disease Severity: Readmittance 
Sensitivity Analysis – ITT Population ........................................................................67 
Table 19: Time to Recovery by Treatment Group and Disease Severity: Concomitant 
Medication Sensitivity Analysis – ITT Population ....................................................67 
Table 20: Time to Recovery by Treatment Group and Disease Severity: Unblinding 
and Crossover Treatment Sensitivity Analysis – ITT Population ..............................67 
Table 21: Summary of Clinical Status Score Assessed the Day of and the Day 
following Remdesivir Treatment – Placebo Subjects treated with Remdesivir .........69 


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Table 22: Summary of Recoveries and Deaths by Day 29 – ITT Population .............................70 
Table 23: Odds Ratio for Inferior Clinical Status Score at Study Visit Day 15 by 
Treatment Using a Proportional Odds Model – ITT Population ................................71 
Table 24: Odds Ratio for Inferior Clinical Status Score at Study Visit Day 15 by 
Treatment Using a Proportional Odds Model – Treated Population ..........................71 
Table 25: Odds Ratio for Inferior Clinical Status Score at Study Visit Day 15 by 
Treatment Using a Proportional Odds Model – Unblinding and Crossover 
Treatment Sensitivity Analysis – ITT Population ......................................................71 
Table 26: Time to Improvement on the 8-Point Ordinal Scale by Treatment Group .................72 
Table 27: Time to Improvement on the 8-Point Ordinal Scale by Treatment Group: 
Remdesivir Retreatment Sensitivity Analysis ............................................................72 
Table 28: Time to Improvement on the 8-Point Ordinal Scale by Treatment Group – 
Remdesivir Retreatment Sensitivity Analysis on Subjects with Clinical 
Status Score of 7 at Enrollment ..................................................................................72 
Table 29: Time to Improvement by at least Two Clinical Status Categories on the 8-
Point Ordinal Scale by Treatment Group: Alternate Ordinal Scale ...........................72 
Table 30: Time to Improvement by at least One Clinical Status Category on the 8-
Point Ordinal Scale by Treatment Group within Subgroups – ITT Population .........72 
Table 31: Time to Improvement by at least One Clinical Status Category on the 8-
Point Ordinal Scale by Treatment Group within Subgroups – Treated 
Population ...................................................................................................................72 
Table 32: Time to Improvement by at least Two Clinical Status Categories on the 8-
Point Ordinal Scale by Treatment Group within Subgroups – ITT Population .........72 
Table 33: Time to Improvement by at least Two Clinical Status Categories on the 8-
Point Ordinal Scale by Treatment Group within Subgroups – Treated 
Population ...................................................................................................................72 
Table 34: Clinical Status Scores by Treatment Group and Study Visit – ITT Population .........73 
Table 35: Clinical Status Scores by Treatment Group and Study Visit – Treated 
Population ...................................................................................................................73 
Table 36: Time to Discharge or to a NEWS of ≤ 2 by Treatment Group ...................................74 
Table 37: Time to Discharge or to a NEWS of ≤ 2 by Treatment Group within 
Subgroups – ITT Population .......................................................................................74 
Table 38: Time to Discharge or to a NEWS of ≤ 2 by Treatment Group within 
Subgroups – Treated Population .................................................................................74 
Table 39: Change from Baseline of NEWS by Treatment Group and Study Visit – ITT 
Population ...................................................................................................................75 
Table 40: Change from Baseline of NEWS by Treatment Group and Study Visit – 
Treated Population ......................................................................................................75 


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Table 41: Oxygen Use by Treatment Group ...............................................................................76 
Table 42: Oxygen Use by Treatment Group within Subgroups .................................................76 
Table 43: Non-invasive Ventilation/High-Flow Oxygen Use by Treatment Group ...................76 
Table 44: Non-invasive Ventilation/High-Flow Oxygen Use by Treatment Group 
within Subgroups ........................................................................................................76 
Table 45: Ventilation/ECMO Use by Treatment Group .............................................................76 
Table 46: Ventilation/ECMO Use by Treatment Group within Subgroups ...............................76 
Table 47: Hospitalization by Treatment Group ..........................................................................77 
Table 48: Hospitalization by Treatment Group within Subgroups .............................................77 
Table 49: Categorical Demographic and Baseline Characteristics by Disease Severity 
and Treatment Group – ITT Population .....................................................................78 
Table 50: Continuous Demographic and Baseline Characteristics by Disease Severity 
and Treatment Group – ITT Population .....................................................................80 
Table 51: Categorical Demographic and Baseline Characteristics by Disease Severity 
and Treatment Group  and Remdesivir Retreatment – ITT Population ......................81 
Table 52: Continuous Demographic and Baseline Characteristics by Disease Severity 
and Treatment Group and Remdesivir Retreatment – ITT Population .......................81 
Table 53: Summary of Subjects with Pre-Existing Medical Conditions Treatment 
Group - Treated Population ........................................................................................82 
Table 54: Number and Percentage of Subjects with Prior and Concurrent Medications 
by WHO Drug Classification, Disease Severity, and Treatment Group – 
Treated Population ......................................................................................................83 
Table 55: Number and Percentage of Subjects Reporting Use of Prohibited 
Medications by Disease Severity, and Treatment Group – Treated Population .........84 
Table 56: Prohibited Medication Use by Study Day, Disease Severity, and Treatment 
Group – Treated Population ........................................................................................85 
Table 57: Overall Summary of Adverse Events – Treated Population .......................................86 
Table 58: Adverse Events Occurring in 5% of Subjects in Any Treatment Group by 
MedDRA System Organ Class and Preferred Term, and Treatment Group - 
Treated Population ......................................................................................................87 
Table 59: Deaths by Day 15 or Day 29 by Treatment Group .....................................................88 
Table 60: Deaths by Day 15 or Day 29 by Treatment Group – Unblinding and 
Crossover Treatment Sensitivity Analysis ..................................................................88 
Table 61: Time to Death through Day 15 and 29 by Treatment Group ......................................89 
Table 62: Time to Death through Day 15 and 29 by Treatment Group – Unblinding 
and Crossover Treatment Sensitivity Analysis ...........................................................89 


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Table 63: Subjects Experiencing Grade 3 or 4 AEs and SAEs through Day 29 by 
Treatment Group– Treated Population .......................................................................90 
Table 64: Analysis of Time to Death, SAEs, or Grade 3 or 4 AEs by Treatment Group 
– Treated Population ...................................................................................................91 
Table 65: Abnormal Laboratory Results of Grade 3 or 4 by Parameter, Maximum 
Severity, Time Point, and Treatment Group – Treated Population ............................92 
Table 66: Summary Statistics of Laboratory Results by Parameter, Study Visit Day, 
and Treatment Group – Treated Population ...............................................................93 
 
 


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Table 7: 
Ineligibility Summary of Screen Failures 
Inclusion/Exclusion 
Category 
Inclusion/Exclusion Criterion 
na 
%b 
All Subjects 
Total number of subjects failing any eligibility 
criterion or were eligible but not enrolled 
x 
100 
Inclusion and Exclusion Number of subjects failing any eligibility criterion 
x 
xx 
Inclusion 
Any inclusion criterion 
x 
xx 
 
[inclusion criterion 1] 
x 
xx 
 
[inclusion criterion 2] 
x 
xx 
 
[inclusion criterion 3] 
x 
xx 
Exclusion 
Any exclusion criterion 
x 
xx 
 
[exclusion criterion 1] 
x 
xx 
 
[exclusion criterion 2] 
x 
xx 
 
[exclusion criterion 3] 
x 
xx 
Eligible but Not 
Enrolled 
 
x 
xx 
a More than one criterion may be marked per subject. 
b Denominator for percentages is the total number of screen failures. 
 
Programming Notes; 
Protocol Version 3.0 included an additional inclusion criteria; footnote the addition of the inclusion/exclusion 
criteria based on protocol version and specify date it occurred and how many subjects were under the previous 
version of the criteria. 
Subjects who are eligible but not enrolled will be counted in the denominator. 
 


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Table 8: 
Analysis Population Eligibilities by Treatment Group and Disease Severity 
 
 
Remdesivir 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Analysis 
Population 
Inclusion / Reason for Exclusion 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
n 
% 
n 
% 
% 
n 
n 
% 
n 
% 
n 
% 
Intention-to-Treat 
Population 
Included in Population 
x 
xx 
x 
Xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Treated Population  Included for Population 
x 
xx 
x 
Xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Excluded from Population 
x 
xx 
x 
Xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
    Did Not Receive at least one 
Infusion 
x 
xx 
x 
Xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
N = Number of subjects randomized to the specified arm/disease severity stratum 
 


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Table 9: 
Subject Disposition by Treatment Group and Disease Severity 
Subject Disposition  
Remdesivir 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Randomized 
x 
100 
x 
100 
x 
100 
x 
100 
x 
100 
x 
100 
Received Loading Dose 
x 
xx 
x 
xx 
x 
Xx 
x 
xx 
x 
xx 
x 
xx 
Completed All Blood Draws   
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Completed All OP swab collections   
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Completed Follow-up (Study Day 8) 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Completed Follow-up (Study Day 11) 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Completed Follow-up (Study Day 15) 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Completed Follow-up (Study Day 22) 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Completed Follow-up (Study Day 29) 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Unblinded during follow-up 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Retreated with Remdesivir during 
follow-up 
- 
- 
- 
- 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
N= Number of subjects enrolled  
 
Programming Notes: 
To count a subject as completing all blood draws, a subject had to have the following questions from the visit 
CRFs answered as a Yes or NA (not required) up through their discharge/death: 
• Was blood collected for hematology, chemistry, and/or liver tests? 
• Was blood drawn for PCR assays? 
Note: in LB – there should be a result in LBSTRESN for each visit or LBSTAT=NOT DONE and 
LBREASND = Not required. 
To count a subject as completing all OP swab collections, a subject had to have the following question from 
the visit CRFs answered as a Yes or N/A (not required) up through their discharge/death. 
• Was oropharyngeal swab collected? 
• Was a swab collected for viral load and/or shedding 
To count a subject for each Study Day, the subject had to complete the visit for that day. Study Day 8 = 
VISITNUM=108, Study Day 11 = VISITNUM=111, Study Day 15 = VISITNUM=115, Study Day 22 = 
VISITNUM=122, Study Day 29 = VISITNUM=129 
 
 


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Table 10: 
Subject Unblinding and Crossover Treatment by Site 
Site 
Number of Subjects Unblinded 
Number of Subjects Crossover Treated 
Site 1 
x 
x 
Site 2 
x 
x 
Site 3 
x 
x 
Site 4 
x 
x 
Site 5 
x 
x 
… 
… 
… 
 
Programming Notes: Only sites with at least one unblinded subject will be included in the table. 


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Table 11: 
Treatment Compliance by Treatment Group 
Disposition 
Remdesivir 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Proportion 
Difference 
n 
% 
95%CIa 
n 
% 
95%CI 
n 
% 
95%CI 
% 
95%CI 
Received Loading Dose 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x.x, x.x 
Completed all 10 Infusions 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x.x, x.x 
Completed less than 10 
Infusions due to Discharge 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x.x, x.x 
Completed less than 10 
Infusions due to Death 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x.x, x.x 
Had Any Infusions Halted or 
Slowed 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x.x, x.x 
Missed Any Maintenance Dose 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x.x, x.x 
N = Number of subject enrolled 
A required infusion is counted as complete even if it was halted or slowed. A required full infusion is counted as completed as long as it was not 
halted nor slowed. 
95% CI for proportions obtained by Clopper-Pearson 
95% CI for difference in proportions obtained by the exact method 
 
Programming Notes: 
Received Loading Dose: Subjects received the first treatment: EC.ECTPT = DOSE 1, EC.ECPSTRG=200, 
ECADJ is missing. 
 
Had any infusions halted or slowed: EC.ECADJ is not missing through day 10 or through discharge from 
hospital or death. 
Missed any maintenance dose:  EC.ECOCCUR=N through day 10 or through discharge from hospital or 
death. 
95% CI for proportions obtained by Clopper-Pearson: 
proc freq; 
Table treatment*analysisvariable / binomial; 
ods output binomialcls=outputdsn; 
run; 
 
95% CI for difference in proportions obtained by the exact method: 
proc freq; 
Table treatment*analysisvariable / riskdiff (cl=exact); 
run; 
 
 


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Table 12: 
Distribution of Protocol Deviations by Category, Type, Treatment Group, and Disease Severity 
Category 
Deviation Type 
Remdesivir 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Mild-Moderate  
(N=X) 
Severe 
(N=X) 
Mild-Moderate  
(N=X) 
Severe 
(N=X) 
Mild-Moderate  
(N=X) 
Severe 
(N=X) 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
Eligibility/enrollment 
Any type 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Did not meet inclusion criterion 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Met exclusion criterion 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ICF not signed prior to study procedures 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Treatment administration schedule 
Any type 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Out of window visit 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Missed visit/visit not conducted 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Missed treatment administration 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Delayed treatment administration 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Follow-up visit schedule 
Any type 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Out of window visit 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Missed visit/visit not conducted 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Protocol procedure/assessment 
Any type 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Incorrect version of ICF signed 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Blood not collected 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Oropharyngeal swab not collected 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Other specimen not collected 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Specimen result not obtained 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Required procedure not conducted 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


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Category 
Deviation Type 
Remdesivir 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Mild-Moderate  
(N=X) 
Severe 
(N=X) 
Mild-Moderate  
(N=X) 
Severe 
(N=X) 
Mild-Moderate  
(N=X) 
Severe 
(N=X) 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
 
Required procedure done incorrectly 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Study product temperature excursion 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Specimen temperature excursion 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Treatment administration 
Any type 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Required procedure done incorrectly 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Study product temperature excursion 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Blinding policy/procedure 
Any type 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Treatment unblinded 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
N = number of subjects enrolled 
 
Tables with similar format: 
Table 13: 
Distribution of Protocol Deviations by Category, Type, and Site 
 


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Table 14: 
Time to Recovery by Treatment Group and Disease Severity 
Analysis Population 
Treatment Group 
Disease Severity 
n 
Median Time to 
Recovery 
HR 
P-value 
 
Estimate 
95% CI 
Estimate 
95% CI 
ITT Population 
Remdesivir (N=X) 
Mild/Moderate 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Remdesivir (N=X) 
Severe 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Remdesivir (N=X) 
Any Severity  
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Repeat for the Treated Population. 
N= Number of subjects in the specified treatment group, disease severity, and analysis population.  
n = Number of recovered subjects.  
HR for the ‘Any Severity’ group is the hazard ratio from the stratified Cox Model.  
P-value calculated using the stratified log-rank test 
 
Tables with similar format: 
Table 15: 
Time to Recovery by Treatment Group and Disease Severity: Fine-Gray and Interaction 
Modeling 
Table 16: 
Time to Recovery by Treatment Group within Subgroups – ITT Population 
Table 17: 
Time to Recovery by Treatment Group within Subgroups – Treated Population 
Table 18: 
Time to Recovery by Treatment Group and Disease Severity: Readmittance Sensitivity 
Analysis – ITT Population 
Table 19: 
Time to Recovery by Treatment Group and Disease Severity: Concomitant Medication 
Sensitivity Analysis – ITT Population 
Table 20: 
Time to Recovery by Treatment Group and Disease Severity: Unblinding and Crossover 
Treatment Sensitivity Analysis – ITT Population 
Programming Notes for Table 15: 
The “Analysis Population” column will be replaced by a “Model” column.  For the Fine-Gray estimates, the 
column will display “Fine-Gray”, for the interaction model, the columns will display “Treatment-Severity 
Interaction (Randomized Severity)” and “Treatment-Severity Interaction (Actual Severity)”, respectively.  For 
the interaction model, the p-value for the interaction term will be provided in a foonote reading “The p-value 
for the treatment by disease severity interaction term was 0.xxxx.”. 
Programming Notes for Tables 16 and 17: 
The “Disease Severity” column will be replaced by a “Subgroup” column. These tables will not display the 
“Any…” rows.  For the analysis controlling for age and symptom duration as continuous covariates, the 
elements for the “Subgroup” column will state “Age and Duration of Symptoms as Continuous Covariates”. 
The elements for the “n” and “Median Time to Recovery” columns will display “-“.   


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Programming Notes for Table 20: 
The “Analysis Population” column will be replaced by a column titled “Unblinding/Crossover Remdesivir 
Treatment”.  The first set of summaries will be for the “Unblinding” sensitivity analyses, and the second set 
will be for the “Crossover Remdesivir Treatment” sensitivity analyses. 
 


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Table 21: 
Summary of Clinical Status Score Assessed the Day of and the Day following Remdesivir 
Treatment – Placebo Subjects treated with Remdesivir 
Placebo Subjects Retreated with Remdesivir (N) 
Ordinal Scale Measure 
Day of Retreatment 
Day following Retreatment 
n 
% 
95% CI 
N 
% 
95% CI 
Death at or before Study Visit (8) 
- 
- 
- 
X 
x 
x.x, x.x 
Hospitalized, on invasive mechanical ventilation or ECMO 
(7) 
x 
x 
x.x, x.x 
X 
x 
x.x, x.x 
Hospitalized, on non-invasive ventilation or high flow 
oxygen devices (6) 
x 
x 
x.x, x.x 
X 
x 
x.x, x.x 
Hospitalized, requiring supplemental oxygen (5) 
x 
x 
x.x, x.x 
X 
x 
x.x, x.x 
Hospitalized, not requiring supplemental oxygen - 
requiring ongoing medical care (COVID-19 related or 
otherwise) (4) 
x 
x 
x.x, x.x 
X 
x 
x.x, x.x 
Hospitalized, not requiring supplemental oxygen - no 
longer requires ongoing medical care (3) 
x 
x 
x.x, x.x 
X 
x 
x.x, x.x 
Not hospitalized, limitation on activities and/or requiring 
home oxygen (2) 
- 
- 
- 
X 
x 
x.x, x.x 
Not hospitalized, no limitations on activities (1) 
- 
- 
- 
X 
x 
x.x, x.x 
No clinical status score reported 
x 
x 
x.x, x.x 
X 
x 
x.x, x.x 
Denominator for percentages is the number of retreated subjects (N) 
 


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Table 22: 
Summary of Recoveries and Deaths by Day 29 – ITT Population  
Treatment 
Group 
Grouping 
Variable 
Subgroup 
Recovered 
Did Not Recover 
Deaths 
Not Recovered or 
Died 
n 
% 
n 
% 
n 
% 
n 
% 
Remdesivir 
(N=X) 
Disease Severity 
Mild/Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
Placebo (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
Remdesivir 
(N=X) 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
Placebo (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
Remdesivir 
(N=X) 
Any Severity  
x 
x 
x 
x 
x 
x 
x 
x 
Placebo (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
Continue for duration of symptoms categories in Section 6.4 
N= Number of subjects in the ITT Population.  
 
Implementation Note: For the symptom categorizations, the Grouping Variable column will display “Duration 
of Symptoms prior to enrollment”. 
 


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Table 23: 
Odds Ratio for Inferior Clinical Status Score at Study Visit Day 15 by Treatment Using a 
Proportional Odds Model – ITT Population 
Covariate 
Treatment Group 
Odds Ratio 
P-value 
Estimate 
95% CI 
Disease Severity 
Remdesivir (N=X) 
x.x 
x.x, x.x 
0.xxx 
Placebo (N=X) 
[Continue for each Section 6.4 
subgroups] 
Remdesivir (N=X) 
x.x 
x.x, x.x 
0.xxx 
Placebo (N=X) 
The specified covariates were included individually in separate models. 
 
Table with similar format: 
Table 24: 
Odds Ratio for Inferior Clinical Status Score at Study Visit Day 15 by Treatment Using a 
Proportional Odds Model – Treated Population 
Table 25: 
Odds Ratio for Inferior Clinical Status Score at Study Visit Day 15 by Treatment Using a 
Proportional Odds Model – Unblinding and Crossover Treatment Sensitivity Analysis – 
ITT Population  


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Table 26: 
Time to Improvement on the 8-Point Ordinal Scale by Treatment Group  
Analysis Population 
Treatment Group 
 
Median Time 
HR 
P-value 
n 
Estimate 
95% CI 
Estimate 
95% CI 
Improvement by at least One Category 
ITT Population 
Remdesivir (N=X) 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Treated Population 
Remdesivir (N=X) 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Improvement by at least Two Categories 
ITT Population 
Remdesivir (N=X) 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Treated Population 
Remdesivir (N=X) 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
N = Number of subjects in the specified treatment group and analysis population.  
n = Number of subjects with improvement.  
HR is the hazard ratio from the Cox Model 
P-value calculated using the Log-rank test  
 
Tables with similar format: 
Table 27: 
Time to Improvement on the 8-Point Ordinal Scale by Treatment Group: Remdesivir 
Retreatment Sensitivity Analysis 
Table 28: 
Time to Improvement on the 8-Point Ordinal Scale by Treatment Group – Remdesivir 
Retreatment Sensitivity Analysis on Subjects with Clinical Status Score of 7 at 
Enrollment 
Table 29: 
Time to Improvement by at least Two Clinical Status Categories on the 8-Point Ordinal 
Scale by Treatment Group: Alternate Ordinal Scale 
Table 30: 
Time to Improvement by at least One Clinical Status Category on the 8-Point Ordinal 
Scale by Treatment Group within Subgroups – ITT Population 
Table 31: 
Time to Improvement by at least One Clinical Status Category on the 8-Point Ordinal 
Scale by Treatment Group within Subgroups – Treated Population 
Table 32: 
Time to Improvement by at least Two Clinical Status Categories on the 8-Point Ordinal 
Scale by Treatment Group within Subgroups – ITT Population 
Table 33: 
Time to Improvement by at least Two Clinical Status Categories on the 8-Point Ordinal 
Scale by Treatment Group within Subgroups – Treated Population 
Programming notes for Tables 30 – 33: 
Instead of the “Analysis Population” column, a column titled “Grouping Variable” will be to the left of 
Treatment Group. Rows will be generated for each subgroup. 
 


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Table 34: 
Clinical Status Scores by Treatment Group and Study Visit – ITT Population 
Study Visit 
Ordinal Scale Measure 
Remdesivir 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
Day 1 
Death at or before Study Visit (8) 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
Hospitalized, on invasive mechanical ventilation or ECMO (7) 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
Hospitalized, on non-invasive ventilation or high flow oxygen devices 
(6) 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
Hospitalized, requiring supplemental oxygen (5) 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
Hospitalized, not requiring supplemental oxygen - requiring ongoing 
medical care (COVID-19 related or otherwise) (4) 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
Hospitalized, not requiring supplemental oxygen - no longer requires 
ongoing medical care (3) 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
Not hospitalized, limitation on activities and/or requiring home oxygen 
(2) 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
Not hospitalized, no limitations on activities (1) 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
No clinical status score reported – Hospitalized subjects 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
No clinical status score reported – Discharged subjects 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
[Repeat for Study Visit Days 3, 5, 8, 11, 15, 22, and 29] 
N = Number of Subject in the ITT Population.  
n = Number of subjects who reported the respective score 
95% CI calculated using Wilson Cis 
Programming Notes:  
proc freq; 
Table treatment*analysisvariable / binomial(wilson); 
    
ods output binomialcls=outputdsn; 
run; 
 
Table with similar format: 
Table 35: 
Clinical Status Scores by Treatment Group and Study Visit – Treated Population 
 


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Table 36: 
Time to Discharge or to a NEWS of ≤ 2 by Treatment Group  
Analysis Population 
Treatment Group 
 
Median Time 
HR 
P-value 
na 
Estimate 
95% CI 
Estimate 
95% CI 
ITT Population 
Remdesivir (N=X) 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Treated Population 
Remdesivir (N=X) 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
N= Number of subjects in the specified treatment group and analysis population.  
n = Number of subjects who discharged or had a NEWS of ≤ 2 prior to Day 29.  
HR is the hazard ratio from the Cox Model 
P-value calculated using the Log-rank test 
 
Table with similar format: 
Table 37: 
Time to Discharge or to a NEWS of ≤ 2 by Treatment Group within Subgroups – ITT 
Population 
Table 38: 
Time to Discharge or to a NEWS of ≤ 2 by Treatment Group within Subgroups – Treated 
Population 
Programming notes for Tables 36 – 37: 
A “Grouping Variable” column will replace the “Analysis Population” column to the left of “Treatment 
Group”.  Rows will be repeated for each subgroup. 
 


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Table 39: 
Change from Baseline of NEWS by Treatment Group and Study Visit – ITT Population 
Study Visit 
Statistic 
Remdesivir 
 (N=X) 
Placebo 
(N=X) 
All Subjects 
(N = X) 
Day 3 
n 
x 
x 
x 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median 
x.x 
x.x 
x.x 
Range (Min, Max) 
x, x 
x, x 
x, x 
Change from Baseline Mean 
(SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
[Repeat for Study Visit Days 5, 8, 11, 15, 22, 29 and Change from Baseline at each] 
 
n = Number of subjects with an assessment at both baseline and the time point being summarized. 
SD = Standard deviation. 
 
Table with similar format: 
Table 40: 
Change from Baseline of NEWS by Treatment Group and Study Visit – Treated 
Population 
 


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Table 41: 
Oxygen Use by Treatment Group 
Analysis Population 
Oxygen Use 
Statistic 
Treatment Group 
Remdesivir 
Placebo 
ITT Population 
On Oxygen at Baseline (N = x) 
Days on Oxygen 
Q1 
x.x 
x.x 
Median 
x.x 
x.x 
Q3 
x.x 
x.x 
Not on Oxygen at Baseline (N = x) 
New Oxygen Use 
n 
x 
x 
Incidence Rate 
x.x 
x.x 
Incidence Rate CI 
x.x, x.x 
x.x, x.x 
Days on Oxygen 
Q1 
x.x 
x.x 
Median 
x.x 
x.x 
Q3 
x.x 
x.x 
Continue for Treated population… 
N = Number of subjects in the specified analysis population and oxygen use category.  
Q1 and Q3 are the first and third quartiles, respectively. 
 
Tables with similar format: 
Table 42: 
Oxygen Use by Treatment Group within Subgroups 
Table 43: 
Non-invasive Ventilation/High-Flow Oxygen Use by Treatment Group  
Table 44: 
Non-invasive Ventilation/High-Flow Oxygen Use by Treatment Group within Subgroups 
Table 45: 
Ventilation/ECMO Use by Treatment Group  
Table 46: 
Ventilation/ECMO Use by Treatment Group within Subgroups 
Programming notes for Tables 41, 43, 45:  
“Analysis Population” will be replaced by “Grouping Variable” column. Summaries will only be generated 
for ITT population. 


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Table 47: 
Hospitalization by Treatment Group  
Analysis Population 
Hospitalization Summary 
Statistic 
Treatment Group 
Remdesivir 
Placebo 
ITT Population 
Days of Initial Hospitalization 
N 
x 
x 
Q1 
x.x 
x.x 
Median 
x.x 
x.x 
Q3 
x.x 
x.x 
Readmittance 
n 
x 
x 
Percentage 
x 
x 
Percentage CI 
x.x, x.x 
x.x, x.x 
Continue for Treated population… 
N = Number of subjects in the specified analysis population.  
Q1 and Q3 are the first and third quartiles, respectively. 
Denominator of readmittance percentages is the number of subjects in the specific analysis population. 
 
Table with similar format: 
Table 48: 
Hospitalization by Treatment Group within Subgroups 
Programming notes for Table 47: 
“Analysis Population” will be replaced by “Grouping Variable” column. Summaries will only be generated 
for ITT population 
 


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Table 49: 
Categorical Demographic and Baseline Characteristics by Disease Severity and Treatment Group – ITT Population 
Demographic 
Category 
Characteristic 
Remdesivir 
Placebo 
All Subjects 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Sex  
Male 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Female 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Ethnicity  
Not Hispanic or Latino 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hispanic or Latino 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Not Reported 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Unknown 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Race  
American Indian or Alaska Native 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Asian 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Native Hawaiian or Other Pacific 
Islander 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Black or African American 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
White 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Multi-Racial 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Unknown 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Geographic Region 
Region 1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
…Continue for all region 
categorizations 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Age 
< 40 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
40-64 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
>=65 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Baseline Clinical 
Status 
7 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
…continue for other scores 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 20-0006  
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Demographic 
Category 
Characteristic 
Remdesivir 
Placebo 
All Subjects 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Duration of 
Symptoms prior to 
enrollment 
Categorization 1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
…Continue for all symptom 
categorizations 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Comorbidities 
List of individual comorbidities… 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Also categorizations: 
0, 1, 2+ 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
N = Number of subjects enrolled.  


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Table 50: 
Continuous Demographic and Baseline Characteristics by Disease Severity and Treatment Group – ITT Population 
Variable 
Statistic 
Remdesivir  
Placebo 
All Subjects 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
Age (years) 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Standard Deviation 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height (cm) 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Standard Deviation 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Weight (Kg) 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Standard Deviation 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
BMI 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Standard Deviation 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Duration of Symptoms 
prior to Enrollment (Days) Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Standard Deviation 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 


Statistical Analysis Plan - DMID Protocol: 20-0006  
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Variable 
Statistic 
Remdesivir  
Placebo 
All Subjects 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
Mild-
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Tables with similar format: 
 
Table 51: 
Categorical Demographic and Baseline Characteristics by Disease Severity and Treatment Group  and Remdesivir Retreatment – 
ITT Population 
Table 52: 
Continuous Demographic and Baseline Characteristics by Disease Severity and Treatment Group and Remdesivir Retreatment – 
ITT Population 
Programming notes for Tables 50 and 51: 
The three major columns for these tables will be “Remdesivir”, “Placebo (Not Retreated)”, and “Placebo (Retreated)” instead of “Remdesivir”, 
“Placebo”, and “All Subjects” 


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Table 53: 
Summary of Subjects with Pre-Existing Medical Conditions Treatment Group - Treated 
Population 
Condition 
Remdesivir 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
None 
x 
xx 
x 
xx 
x 
xx 
Any Condition 
x 
xx 
x 
xx 
x 
xx 
Diabetes I 
x 
xx 
x 
xx 
x 
xx 
Diabetes II 
x 
xx 
x 
xx 
x 
xx 
…continue for all solicited 
conditions… 
… 
… 
… 
… 
… 
… 
N = Number of subjects in the Treated Population; 
n = Number of subjects reporting the condition 
 


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Table 54: 
Number and Percentage of Subjects with Prior and Concurrent Medications by WHO Drug Classification, Disease Severity, and 
Treatment Group – Treated Population 
WHO Drug Code 
Level 1, 
Anatomic Group 
WHO Drug Code 
Level 2, Therapeutic 
Subgroup 
Remdesivir 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Mild-Moderate 
(N=X) 
Severe 
(N=X) 
Mild-Moderate 
(N=X) 
Severe 
(N=X) 
Mild-Moderate 
(N=X) 
Severe 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any Level 1 
Codes 
Any Level 2 Codes 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[ATC Level 1 - 1] 
Any [ATC 1 – 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 3] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[ATC Level 1 – 2] [ATC 2 - 1] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 2] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 3] 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
N = Number of subjects in the Treated Population.  
n=Number of subjects reporting taking at least one medication in the specific WHO Drug Class. 


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Table 55: 
Number and Percentage of Subjects Reporting Use of Prohibited Medications by Disease Severity, and Treatment Group – 
Treated Population 
Medication/Therapies 
Remdesivir 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Mild-Moderate 
(N=X) 
Severe 
(N=X) 
Mild-Moderate 
(N=X) 
Severe 
(N=X) 
Mild-Moderate 
(N=X) 
Severe 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any Medication/Therapy 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Protease inhibitors 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Polymerase inhibitors 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Other drugs used to treat 
COVID-19 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Corticosteroids 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Other anti-inflammatory drugs 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
N = Number of subjects in the Treated Population.  
n=Number of subjects reporting taking at least one medication in the specified category. 


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Table 56: 
Prohibited Medication Use by Study Day, Disease Severity, and Treatment Group – 
Treated Population 
Study Day 
Remdesivir 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Mild-Moderate 
(N=X) 
Severe 
(N=X) 
Mild-Moderate 
(N=X) 
Severe 
(N=X) 
Mild-Moderate 
(N=X) 
Severe 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 1 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 3 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 5 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 8 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Day 11 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
N = Number of subjects in the Treated Population.  
n=Number of subjects reporting taking at least one prohibited medication by the specified study day. 
 
Programming Notes: If the start date of the prohibited medication is on or before the specified (actual) study 
day, then the subject will be denoted as taking the med for that Study Day. 
 


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Table 57: 
Overall Summary of Adverse Events – Treated Population 
Subjectsa with 
Remdesivir 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Mild-Moderate 
(N=X) 
Severe 
(N=X) 
Any Severity 
(N=X) 
Mild-Moderate 
(N=X) 
Severe 
(N=X) 
Any Severity 
(N=X) 
Mild-Moderate 
(N=X) 
Severe 
(N=X) 
Any Severity 
(N=X) 
N 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
At least one adverse 
event 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
At least one related 
adverse event 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
     Moderate (Grade 2)  
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
     Severe (Grade 3)  
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
     Life-threatening 
(Grade 4)  
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
     Death (Grade 5) 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
At least one serious 
adverse event 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one related 
serious adverse event 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one adverse 
event leading to early 
terminationb 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one 
Unanticipated Problem 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
N = Number of subjects in the Treated Population 
aSubjects are counted once for each category regardless of the number of events. 
bAs reported on the Adverse Event eCRF.  
All Grade 3 and 4 AEs are captured as AEs. In addition, any Grade 2 or higher suspected drug-related hypersensitivity reaction is reported as an AE. 
 
 


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Table 58: 
Adverse Events Occurring in 5% of Subjects in Any Treatment Group by MedDRA 
System Organ Class and Preferred Term, and Treatment Group - Treated Population 
Preferred Term 
MedDRA System 
Organ Class 
Remdesivir 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
 
 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
Serious Adverse Events 
PT1 
SOC1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Etc. 
Etc. 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Other (Non-serious) Adverse Events 
PT1 
SOC1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Etc 
Etc 
x 
x 
x 
x 
x 
x 
x 
x 
x 
N = number of subjects in the Treated Population (number of subjects at risk).  
n = number of subjects reporting event.  
Events = total frequency of events reported. 
 
Programming Notes: 
Select all preferred terms/System organ classes where the % for any treatment group or overall is >= 5%.  
Sort preferred terms by descending order of frequency. 


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Table 59: 
Deaths by Day 15 or Day 29 by Treatment Group 
Analysis Population 
Study Day 
Remdesivir 
(N=X) 
Placebo 
(N=X) 
n 
Mortality 
Rate 
Rate 95% 
CI 
n 
Mortality 
Rate 
Rate 95% CI 
ITT Population 
Day 15 
x 
x.x 
x.x, x.x 
x 
x.x 
x.x, x.x 
Day 29 
x 
x.x 
x.x, x.x 
x 
x.x 
x.x, x.x 
Treated Population 
Day 15 
x 
x.x 
x.x, x.x 
x 
x.x 
x.x, x.x 
Day 29 
x 
x.x 
x.x, x.x 
x 
x.x 
x.x, x.x 
N = Number of Subject in the specified treatment group and analysis population.  
n = Number of subjects in a given treatment group who died by the given timepoint 
 
Table with similar format: 
Table 60: 
Deaths by Day 15 or Day 29 by Treatment Group – Unblinding and Crossover Treatment 
Sensitivity Analysis 
 
Programming Notes:  The “Analysis Population” column will be replaced by a column titled 
“Unblinding/Crossover Remdesivir Treatment”.  The first set of summaries will be for the “Unblinding” 
sensitivity analyses, and the second set will be for the “Crossover Remdesivir Treatment” sensitivity analyses. 
 


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Table 61: 
Time to Death through Day 15 and 29 by Treatment Group 
Analysis Population 
Study Day 
Treatment Group 
 
Median Time 
HR 
P-value 
n 
Estimate 
95% CI 
Estimate 
95% CI 
ITT Population 
Day 15 
Remdesivir (N=X) 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Day 29 
Remdesivir (N=X) 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Treated Population 
Day 15 
Remdesivir (N=X) 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Day 29 
Remdesivir (N=X) 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
N= Number of subjects in the specified treatment group and analysis population.  
n = Number of subjects who died by the specified study day.  
HR is the hazard ratio from the Cox Model 
P-value calculated using the Log-rank test 
 
Table with similar format: 
Table 62: 
Time to Death through Day 15 and 29 by Treatment Group – Unblinding and Crossover Treatment Sensitivity Analysis 
 
Programming Notes:  The “Analysis Population” column will be replaced by a column titled “Unblinding/Crossover Remdesivir Treatment”.  The first 
set of summaries will be for the “Unblinding” sensitivity analyses, and the second set will be for the “Crossover Remdesivir Treatment” sensitivity 
analyses. 
 


Statistical Analysis Plan - DMID Protocol: 20-0006  
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Table 63: 
Subjects Experiencing Grade 3 or 4 AEs and SAEs through Day 29 by Treatment Group– Treated Population 
Safety Event Outcome 
Remdesivir 
(N=X) 
Placebo 
(N=X) 
P-value 
n 
% 
95% CI 
n 
% 
95% CI 
Grade 3 or 4 AE 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
0.xxx 
SAE 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
0.xxx 
N = Number of Subject in the Treated Population.  
n = Number of subjects in a given treatment group who experienced the specified safety event outcome. 
95% CI calculated using C-P/Blaker method 
P-value calculated using Barnard’s Exact Test  
 


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Table 64: 
Analysis of Time to Death, SAEs, or Grade 3 or 4 AEs by Treatment Group – Treated Population 
Treatment Group 
n 
Median Time 
HR 
P-value 
 
Estimate 
95% CI 
Estimate 
95% CI 
Remdesivir (N=X) 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
N= Number of subjects in the Treated Population.  
n = Number of subjects who died or experienced SAEs, Grade 3 or 4 AEs, or Discontinuation of Study Infusions.  
HR is the hazard ratio from the Cox Model 
P-value calculated using the Log-rank test 
 


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Table 65: 
Abnormal Laboratory Results of Grade 3 or 4 by Parameter, Maximum Severity, Time Point, and Treatment Group – Treated 
Population 
Laboratory Parameter 
Time Point 
Treatment Group 
N 
Severe/ Grade 3 
 
Life Threatening/ Grade 4 
 
n 
% 
n 
% 
Any Parameter 
Baseline 
Remdesivir  
x 
x 
x 
x 
x 
 
Placebo  
x 
x 
x 
x 
x 
Day 3 
Remdesivir 
x 
x 
x 
x 
x 
 
Placebo  
x 
x 
x 
x 
x 
Day 5 
Remdesivir 
x 
x 
x 
x 
x 
 
Placebo  
x 
x 
x 
x 
x 
Day 8 
Remdesivir 
x 
x 
x 
x 
x 
 
Placebo  
x 
x 
x 
x 
x 
Day 11 
Remdesivir 
x 
x 
x 
x 
x 
 
Placebo  
x 
x 
x 
x 
x 
Day 15 
Remdesivir 
x 
x 
x 
x 
x 
 
Placebo  
x 
x 
x 
x 
x 
Day 29 
Remdesivir 
x 
x 
x 
x 
x 
 
Placebo  
x 
x 
x 
x 
x 
Maximum Severity Post Baseline 
Remdesivir  
x 
x 
x 
x 
x 
 
Placebo  
x 
x 
x 
x 
x 
Each parameter will be summarized individually similar to the above… 
The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. 
 N = Number of subjects in the Treated Population 


Statistical Analysis Plan - DMID Protocol: 20-0006  
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Table 66: 
Summary Statistics of Laboratory Results by Parameter, Study Visit Day, and Treatment Group – Treated Population 
Laboratory 
Parameter 
Study Visit Day 
Treatment Group 
Absolute 
Change from Baseline 
N 
Mean 
SD 
Median 
Min, Max 
N 
Mean 
SD 
Median 
Min, Max 
Parameter 1 
Baseline 
Remdesivir 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
--- 
--- 
--- 
--- 
--- 
 
Placebo 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
--- 
--- 
--- 
--- 
--- 
Day 3 
Remdesivir 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Placebo 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
Day 5 
Remdesivir 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Placebo 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
Day 8 
Remdesivir 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Placebo 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
Day 11 
Remdesivir 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Placebo 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
Day 15 
Remdesivir 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Placebo 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
Day 29 
Remdesivir 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Placebo 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
Continue for all parameters… 
N = Number of subjects in the Treated Population with laboratory data available for the parameter at the specified study visit. 
 


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APPENDIX 2. FIGURE MOCK-UPS 
General Programming Notes for figures: 
• Use the same color for a treatment on the different graphs: 
o Remdesivir = Blue 
o Placebo = Red 
• For severity graphs: 
o Mild = yellow 
o Moderate = orange 
o Severe = light red 
o Life-threatening = red 
o Death = black 
 


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LIST OF FIGURES 
Figure 1: 
CONSORT Flow Diagram .........................................................................................97 
Figure 2: 
Kaplan-Meier Curves of Time to Recovery by Treatment Group – ITT 
Population ...................................................................................................................98 
Figure 3: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group – Treated 
Population ...................................................................................................................98 
Figure 4: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group and Disease 
Severity – ITT Population ..........................................................................................98 
Figure 5: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group and Disease 
Severity – Treated Population ....................................................................................98 
Figure 6: 
Forest Plot of Hazard Ratios of Time to Recovery by Subgroup - ITT 
Population ...................................................................................................................99 
Figure 7: 
Forest Plot of Hazard Ratios of Time to Recovery by Subgroup - Treated 
Population ...................................................................................................................99 
Figure 8: 
Forest Plot of Hazard Ratios of Time to Recovery: Leave One Site Out 
Sensitivity Analysis - ITT Population ........................................................................99 
Figure 9: 
Clinical Status Scores by Study Day – Placebo Recipients ......................................100 
Figure 10: Predicted Probabilities of Scale Rating at Day 15 by Treatment Group and 
Disease Severity – ITT Population ...........................................................................101 
Figure 11: Kaplan-Meier Curves of Time to Improvement by at least One Category of 
Clinical Status Score by Treatment Group – ITT Population ...................................102 
Figure 12: Kaplan-Meier Curves of Time to Improvement by at least Two Categories of 
Clinical Status Score by Treatment Group – ITT Population ...................................102 
Figure 13: Distribution of Clinical Status Scores By Day by Treatment Group – ITT 
Population .................................................................................................................103 
Figure 14: Bar Plots of Clinical Status Scores by Study Day and Treatment Group – 
ITT Population ..........................................................................................................104 
Figure 15: Kaplan-Meier Curves of Time to Discharge or NEWS ≤ 2 by Treatment 
Group – ITT Population ............................................................................................105 
Figure 16: Mean NEWS by Day and Treatment Group – ITT Population ................................106 
Figure 17: Bee Swarm Plot of Oxygen Days by Treatment Group – ITT Population ...............107 
Figure 18: Bee Swarm Plot of Non-invasive Ventilation/High-Flow Oxygen Days by 
Treatment Group – ITT Population ..........................................................................107 
Figure 19: Bee Swarm Plot of Invasive Mechanical Ventilation/ECMO Days by 
Treatment Group – ITT Population ..........................................................................107 
Figure 20: Bee Swarm Plot of Hospitalization Days by Treatment Group – ITT 
Population .................................................................................................................107 


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Figure 21: Frequency of Non-Serious Related Unsolicited Adverse Events by MedDRA 
System Organ Class, Severity, and Treatment Group - Treated Population ............108 
Figure 22: Incidence of Non-Serious Related Unsolicited Adverse Events by MedDRA 
System Organ Class, Severity, and Treatment Group - Treated Population ............109 
Figure 23: Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group 
– Treated Population .................................................................................................110 
Figure 24: Kaplan-Meier Curve of Time to Death, SAE, Discontinuation of Study 
Infusions or Grade 3 or 4 AE through Day 29 by Treatment Group – Treated 
Population .................................................................................................................111 
Figure 25: [Parameter X] Results by Scheduled Visits: Mean Changes from Baseline by 
Treatment Group – Treated Population ....................................................................112 
 
 


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Figure 1: 
CONSORT Flow Diagram 
 
 
Implementation Note: Disease Stratum boxes will be included in the final CONSORT diagram. 
 


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Figure 2: 
Kaplan-Meier Curves of Time to Recovery by Treatment Group – ITT Population 
 
 
Figures with similar format: 
Figure 3: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group – Treated Population 
Figure 4: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group and Disease Severity – 
ITT Population 
Figure 5: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group and Disease Severity – 
Treated Population 
 


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Figure 6: 
Forest Plot of Hazard Ratios of Time to Recovery by Subgroup - ITT Population 
 
 
Figures with similar format: 
Figure 7: 
Forest Plot of Hazard Ratios of Time to Recovery by Subgroup - Treated Population 
Figure 8: 
Forest Plot of Hazard Ratios of Time to Recovery: Leave One Site Out Sensitivity 
Analysis - ITT Population 


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Figure 9: 
Clinical Status Scores by Study Day – Placebo Recipients 
[Shell not provided. The figure will be a spaghetti plot of clinical status scores by actual study day (of the 
assessment). Lines for subjects who are not retreated with remdesivir will be a muted gray color while the 
lines for subjects who are retreated with remdesivir will be a bold red or black color]. 
 


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Figure 10: 
Predicted Probabilities of Scale Rating at Day 15 by Treatment Group and Disease 
Severity – ITT Population 
 
 


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Figure 11: 
Kaplan-Meier Curves of Time to Improvement by at least One Category of Clinical 
Status Score by Treatment Group – ITT Population 
 
 
Figure with similar format: 
Figure 12: 
Kaplan-Meier Curves of Time to Improvement by at least Two Categories of Clinical 
Status Score by Treatment Group – ITT Population 
 


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Figure 13: 
Distribution of Clinical Status Scores By Day by Treatment Group – ITT Population 
 
 
Implementation Note:   Heat map coloring will be used for the clinical score scale. 
 


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Figure 14: 
Bar Plots of Clinical Status Scores by Study Day and Treatment Group – ITT Population 
 
 
Implementation Note:  Each panel will contain bars for Remdesivir and Placebo. 
 


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Figure 15: 
Kaplan-Meier Curves of Time to Discharge or NEWS ≤ 2 by Treatment Group – ITT 
Population 
 
  


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Figure 16: 
Mean NEWS by Day and Treatment Group – ITT Population 
 
  


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Figure 17: 
Bee Swarm Plot of Oxygen Days by Treatment Group – ITT Population 
 
 
Implementation Note: Death swarm will be presented as a circle or similar shape instead of a line. 
 
Figures with similar format: 
Figure 18: 
Bee Swarm Plot of Non-invasive Ventilation/High-Flow Oxygen Days by Treatment 
Group – ITT Population  
Figure 19: 
Bee Swarm Plot of Invasive Mechanical Ventilation/ECMO Days by Treatment Group – 
ITT Population  
Figure 20: 
Bee Swarm Plot of Hospitalization Days by Treatment Group – ITT Population  
 


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Figure 21: 
Frequency of Non-Serious Related Unsolicited Adverse Events by MedDRA System 
Organ Class, Severity, and Treatment Group - Treated Population 
 
 


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Figure 22: 
Incidence of Non-Serious Related Unsolicited Adverse Events by MedDRA System Organ 
Class, Severity, and Treatment Group - Treated Population 
 
 


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Figure 23: 
Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group – Treated 
Population 
 
 


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Figure 24: 
Kaplan-Meier Curve of Time to Death, SAE, Discontinuation of Study Infusions or 
Grade 3 or 4 AE through Day 29 by Treatment Group – Treated Population 
 
 


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Figure 25: 
[Parameter X] Results by Scheduled Visits: Mean Changes from Baseline by Treatment 
Group – Treated Population 
 
 


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APPENDIX 3. LISTINGS MOCK-UPS 
TABLE OF LISTINGS 
Listing 1: Analysis Population Inclusions/Exclusions for Randomized Subjects ....................114 
Listing 2: Subjects who Early Terminated or Discontinued Treatment ....................................115 
Listing 3: Subject-Specific Protocol Deviations .......................................................................116 
Listing 4: Non-Subject-Specific Protocol Deviations ...............................................................117 
Listing 5: Individual Efficacy Response Data: Clinical Status Score Data ..............................118 
Listing 6: Individual Efficacy Response Data: NEWS .............................................................119 
Listing 7: Demographic Data ....................................................................................................120 
Listing 8: Pre-Existing and Concurrent Medical Conditions ....................................................121 
Listing 9: Concomitant Medications .........................................................................................122 
Listing 10: Compliance Data ......................................................................................................123 
Listing 11: Listing of Non-Serious Adverse Events ...................................................................124 
Listing 12: Listing of Non-Fatal Serious Adverse Events ..........................................................125 
Listing 13: Listing of Deaths .......................................................................................................126 
Listing 14: Pregnancy Reports – Maternal Information .............................................................127 
Listing 15: Pregnancy Reports – Gravida and Para ....................................................................128 
Listing 16: Pregnancy Reports – Live Birth Outcomes ..............................................................129 
Listing 17: Pregnancy Reports – Still Birth Outcomes ...............................................................130 
Listing 18: Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion 
Outcomes ..................................................................................................................131 
Listing 19: Clinical Laboratory Results ......................................................................................132 
Listing 20: Physical Exam Findings ...........................................................................................133 
 


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Listing 1: 
Analysis Population Inclusions/Exclusions for Randomized Subjects 
Treatment Group 
Subject ID 
Analysis Population 
Included in Population? 
Reason Subject Excluded 
Included in Early Analysis Set? 
Remdesivir/Placebo 
XXXXX 
Intent-to-Treat 
Yes/No 
NA/xxxxxxxxx 
Yes 
Treated 
Yes/No 
NA/xxxxxxxxx 
 
Programming Notes:  Include randomized subjects only.  Sort Order = Treatment Group, USUBJID.  If subject was included in the early analysis set, 
then display “Yes”.  Otherwise do not display anything. 
 


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Listing 2: 
Subjects who Early Terminated or Discontinued Treatment 
Treatment Group 
 Subject ID 
Category 
Reason for Early Termination or Treatment Discontinuation 
Study Day 
Remdesivir/Placebo 
XXXXX 
Early Termination/Treatment Discontinuation 
xxxxxx 
xxxx 
 
Programming Notes:  Sort Order = Treatment Group, USUBJID, category where Treatment discontinuation is sorted prior to Early termination. If the 
subject discontinued treatment because they were unblinded and crossover treated with remdesivir, then the reason for discontinuation will display 
“Treated with Remdesivir”. 
 


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Listing 3: 
Subject-Specific Protocol Deviations 
Treatment Group 
Disease 
Severity 
Subject ID DV Number Deviation 
Deviation 
Category 
Study 
Day 
Reason for 
Deviation 
Deviation 
Resulted 
in AE? 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Comments 
Remdesivir/Placebo 
Mild/Moderate 
/ Severe 
xxxxx 
xx 
xxx 
xxx 
x 
xxxx 
Yes/No 
Yes/No 
Yes/No 
xxxx 
 
Programming Notes:  Sort Order = Treatment Group, USUBJID, Deviation Number  


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Listing 4: 
Non-Subject-Specific Protocol Deviations 
Site 
Start Date  
End Date 
Deviation 
Reason for 
Deviation 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Category 
Comments 
Xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
Yes/No 
Yes/No 
xxxx 
xxxxx 
 
Programming Notes:  Sort Order = Site, start date, deviation 
 


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Listing 5: 
Individual Efficacy Response Data: Clinical Status Score Data 
Treatment Group  
Disease Severity 
Subject ID 
Study Visit Day of 
Assessment 
Actual Study Day of 
Assessment 
Clinical Status Score  
Clinical Status 
Included in Early 
Analysis Set? 
Remdesivir/Placebo Mild/Moderate / Severe 
xxxxx 
xx 
xx 
xx 
xxxxx 
Yes 
 
Programming Notes:  Sort Order = Treatment Group, USUBJID, Study Day.  Clinical status should match the wording of the scale definitions in Section 
4.3.  If the record was included in the early analysis set, then display “Yes”.  Otherwise do not display anything. 
 


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Listing 6: 
Individual Efficacy Response Data: NEWS 
Treatment Group 
Disease 
Severity 
Subject ID 
Study Visit 
Day 
Actual 
Study Day 
Respiratory 
Rate Score 
O2 
Saturation 
Score 
Any 
Supplemental 
O2 Score 
Temperature 
Score 
Systolic BP 
Score 
Heart Rate 
Score 
Level of 
Consciousness 
Score 
Total Score 
Remdesivir/Placebo 
Mild/Moderate 
/ Severe 
xxxxx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Programming Notes:  Sort Order = Treatment Group, USUBJID, Study Day 
 


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Listing 7: 
Demographic Data 
Treatment Group 
Disease 
Severity 
Subject ID 
Geographic 
Region 
Sex 
Age at 
Enrollment 
(years) 
Ethnicity 
Race 
Duration of 
Symptoms prior 
to Enrollment 
Weight 
(Kg) 
Height 
(Cm) 
BMI 
Included 
in Early 
Analysis 
Set? 
Remdesivir/Placebo 
Mild/Moderate / 
Severe 
xxxxx 
xxx 
xxx 
xx 
xxx 
xxx 
xxx 
xx 
xx 
xxx 
Yes 
 
Programming Notes:  Sort Order = Treatment Group, USUBJID. If subject was included in the early analysis set, then display “Yes”. Otherwise do not 
display anything. 
 


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Listing 8: 
Pre-Existing and Concurrent Medical Conditions 
Treatment Group 
 Subject ID 
MH Number 
Medical History Term 
MedDRA System Organ Class 
MedDRA Preferred Term 
Remdesivir/Placebo 
xxx 
xx 
xxxxx 
xxxx 
xxxx 
 
Programming Notes:  Sort Order = Treatment Group, USUBJID, MH Number 
 


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Listing 9: 
Concomitant Medications 
Treatment Group 
Subject 
ID 
CM 
Number Medication 
Medication Start 
Day 
Medication End 
Day 
Indication 
Taken for an 
AE? 
(AE 
Description; 
Number) 
Taken for a 
condition on 
Medical History? 
(MH Description; 
Number) 
ATC Level 1  
(ATC Level 2) 
Prohibited 
Medication? 
Remdesivir/Placebo 
xxx 
xx 
xxxx 
x 
x 
xxxx 
Yes/No 
Yes/No 
xxxx / xxxx 
Yes/No 
 
Programming Notes:  Sort Order = Treatment Group, USUBJID, CM number 
 
Note: If medication started prior to enrollment and there is no date, then Medication Start Day = Prior to Enrollment 
If medication is ongoing at end of study, the Medication End Day = Ongoing 
 
The “Prohibited Medication?” column refers to whether the medication falls under one of the categories of prohibited medications listed in Section 6.4. 
 


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Listing 10: 
Compliance Data  
Category 
Number of Doses 
Reason for Missing, Halting or Slowing any doses 
Study Day of 
Discharge 
Study Day of 
Death 
Treatment Group: , Subject ID:  
Received 
xx 
-- 
Xxx/NA 
Xxx/NA 
Missed 
xx 
xxxxxx 
Halted/Slowed 
xx 
xxxxxx 
 
Programming Notes:  Sort Order = Treatment Group, USUBJID. 
 


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Listing 11: 
Listing of Non-Serious Adverse Events 
Adverse 
Event 
Study Day 
Duration 
Severity 
Relationship 
to Study 
Treatment 
If Not 
Related, 
Alternative 
Etiology 
Action 
Taken with 
Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ Class 
MedDRA 
Preferred 
Term 
Included in 
Early 
Analysis 
Set? 
Treatment Group: Subject ID: , Disease Severity: , AE Number:  
xxx 
xx 
x 
xxx 
Related/Not 
Related 
xxxx 
xxx 
Yes/No 
xxxx 
xxxx 
xxxx 
Yes 
Comments: xxxx 
 
 
Programming Note: Sort order will be Treatment Group, USUBJID, AE Number. If the event was included in the early analysis set, then display “Yes”.  
Otherwise do not display anything.


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Listing 12: 
Listing of Non-Fatal Serious Adverse Events 
Adverse 
Event 
Study Day 
Duration 
No. of 
Days Post 
Dose the 
Event 
Became 
Serious 
Reason 
Reported 
as an SAE 
Severity 
Relationship 
to Study 
Treatment 
If Not 
Related, 
Alternative 
Etiology 
Action 
Taken 
with Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ 
Class 
MedDRA 
Preferred 
Term 
Included 
in Early 
Analysis 
Set? 
Treatment Group: Subject ID: , AE Number:  
xxxx 
x 
x 
x 
xxxxx 
xxx 
Related/Not 
Related 
xxxx 
xxxx 
Yes/No 
xxxxx 
xxxxx 
xxxxx 
Yes 
Comments: xxxx 
 
Programming Note: Sort order will be Treatment Group, USUBJID, AE Number.  If the event was included in the early analysis set, then display “Yes”.  
Otherwise do not display anything. 
 


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Listing 13: 
Listing of Deaths 
Adverse 
Event 
Study Day 
Duration 
No. of 
Days Post 
Dose the 
Event 
Became 
Serious 
Reason 
Reported 
as an SAE 
Severity 
Relationship 
to Study 
Treatment 
If Not 
Related, 
Alternative 
Etiology 
Action 
Taken with 
Study 
Treatment 
Subject 
Discontinued 
Due to AE 
MedDRA 
System 
Organ 
Class 
MedDRA 
Preferred 
Term 
Included in 
Early 
Analysis 
Set? 
Treatment Group: Subject ID: , AE Number:  
xxxx 
x 
x 
x 
xxxxx 
xxx 
Related/Not 
Related 
xxxx 
xxxx 
Yes/No 
xxxxx 
xxxxx 
Yes 
Comments: xxxx 
 
Programming Note: If the event was included in the early analysis set, then display “Yes”.  Otherwise do not display anything. 
 


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Listing 14: 
Pregnancy Reports – Maternal Information 
Treatment 
Group  
Subject 
ID  
Pregnancy 
Number 
Study Day 
Corresponding 
to Estimated 
Date of 
Conception 
Source of 
Maternal 
Information 
Pregnancy 
Status 
Mother’s 
Pre-
Pregnancy 
BMI 
Mother’s 
Weight 
Gain 
During 
Pregnancy 
Tobacco, 
Alcohol, or 
Drug Use 
During 
Pregnancy? 
Medications 
During 
Pregnancy? 
Maternal 
Complications 
During 
Pregnancy? 
Maternal 
Complications 
During Labor, 
Delivery, or 
Post-Partum? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maternal Complications are included in the Adverse Event listing. Medications taken during pregnancy are included in the Concomitant Medications Listing. 
 


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Listing 15: 
Pregnancy Reports – Gravida and Para 
 
 
 
Live Births 
 
 
 
 
 
Subject 
ID 
Pregnancy 
Number 
Gravida 
Extremely 
PBa 
Very 
Early 
PBa 
Early 
PBa 
Late 
PBa 
Early 
TBb 
Full 
TBb 
Late 
TBb 
Post 
TBb 
Still 
Births 
Spontaneous 
Abortion/ 
Miscarriage 
Elective 
Abortions 
Therapeutic 
Abortions 
Major 
Congenital 
Anomaly 
with 
Previous 
Pregnancy? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gravida includes the current pregnancy, para events do not. 
a Preterm Birth 
b Term Birth 
 


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Listing 16: 
Pregnancy Reports – Live Birth Outcomes 
Subject 
ID 
Pregnancy 
Number 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal 
Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Live 
Birth  
Size for 
Gestational 
Age 
Apgar 
Score, 1 
minute 
Apgar 
Score, 5 
minutes 
Cord pH 
Congenital 
Anomalies? 
Illnesses/ 
Hospitalizations 
within 1 Month of 
Birth? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Congenital Anomalies are included in the Adverse Event listing. 
 


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Listing 17: 
Pregnancy Reports – Still Birth Outcomes 
Subject 
ID 
Date of 
Initial 
Report 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Still 
Birth 
Size for 
Gestational 
Age 
Cord pH 
Congenital 
Anomalies? 
Autopsy 
Performed? 
If Autopsy, Etiology 
for Still Birth 
Identified? 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 18: 
Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion Outcomes 
Subject 
ID 
Date of Initial 
Report 
Fetus Number 
Pregnancy Outcome 
(for this Fetus) 
Gestational Age at 
Termination 
Abnormality in Product of Conception? 
Reason for Therapeutic 
Abortion 
 
 
 
 
 
 
 
 


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Listing 19: 
Clinical Laboratory Results 
Treatment Group 
Subject ID 
Planned 
Time Point  
Actual 
Study Day  
Sex  
Age (years) 
Laboratory 
Parameter (Units) 
Result (Toxicity 
Grade) 
Reference Range 
Low 
Reference Range 
High 
Remdesivir/Placebo 
xxx 
xx 
xx 
xx 
x 
xxx (xxx) 
xxx (xxxx) 
xxxx 
xxxx 
 


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Listing 20: 
Physical Exam Findings 
Treatment Group 
Subject ID 
Planned 
Study Day 
Actual Study 
Day 
Body System 
Abnormal Finding 
Reported as an AE? 
(AE Description; Number) 
Remdesivir/Placebo 
xxx 
xx 
xx 
xxxx 
xxxxxx 
Yes/No/NA 
 
Implementation Note: For respiratory findings denoted as 'Yes' on the Physical Exam CRF, denote the Body System as "Respiratory Finding' and denote 
the Abnormal Finding as the symptom name; e.g. if Wheezing is reported, the Abnormal Finding will be 'Wheezing'. The Reported as an AE cell will be 
denoted as 'NA' for respiratory findings. Each reported respiratory finding will appear in its own row. 
 
Sort order will be treatment group, subject ID, planned time point, and body system. 

Prot_001.pdf: 
 
 
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 
 
 
 
 


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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 


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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 


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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 


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LIST OF FIGURES 
No table of figures entries found. 
 


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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  
 


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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 


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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 
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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 
organizational meeting of the DSMB. The DSMB will review SAEs on a regular basis and ad 


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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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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.