Clinical trial NCT04401579
Conditions: COVID-19
Keywords: Adaptive COVID-19 Efficacy Multicenter novel coronavirus Safety
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2020-05-08; Completion date: 2020-07-31
Enrollment: 1033 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
ACTT-2 will evaluate the combination of baricitinib and remdesivir compared to remdesivir alone. 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 oropharyngeal (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 is conducted by phone. The primary outcome is time to recovery by Day 29.

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. New arms can be introduced according to scientific and public health needs. 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. This adaptive platform is used to rapidly evaluate different therapeutics in a population of those hospitalized with moderate to severe COVID-19. The platform will provide a common framework sharing a similar population, design, endpoints, and safety oversight. New stages with new therapeutics can be introduced. One independent Data and Safety Monitoring Board (DSMB) will actively monitor interim data in all stages to make recommendations about early study closure or changes to study arms.

ACTT-2 will evaluate the combination of baricitinib and remdesivir compared to remdesivir alone. 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 oropharyngeal (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 is 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. Each stage may prioritize different secondary endpoints for the purpose of multiple comparison analyses.

Contacts:

20-0006 Central Contact

Telephone: 1 (301) 7617948

Email: DMIDClinicalTrials@niaid.nih.gov

Arms: arm 1: 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-day total course and 4 mg (2 tablets of 2 mg) of Baricitinib administered orally daily for the duration of the hospitalization up to a 14-day total course. 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-day total course and 4 mg (2 tablets of 2 mg) of Baricitinib Placebo administered orally daily for the duration of the hospitalization up to a 14-day total course.
Interventions: intervention 1: Placebo intervention 2: Remdesivir intervention 3: Baricitinib
Intervention descriptions: intervention 1: The matching Baricitinib placebo contains lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The coating for the placebo tablet is identical to that of the corresponding active tablet. 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. intervention 3: Baricitinib is a Janus kinase (JAK) inhibitor with the chemical name \[1-(ethylsulfonyl)-3-(4-(7Hpyrrolo(2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl\]acetonitrile Each tablet contains 2 mg of baricitinib and the following inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, ferric oxide, lecithin (soya), polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.

Protocol documents:
ICF_001.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 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 1 of 18 
 
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 of the Safety 
and Efficacy of Investigational Therapeutics for the 
Treatment of COVID-19 in Hospitalized Adults” 
 
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: 
 
(301) 496-8029 (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. 
 
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. 
 


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 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 2 of 18 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
 
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. Early 
data from this study suggest a drug called remdesivir may help hospitalized patients with COVID-
19. This study will test remdesivir and another drug in adults that are hospitalized with COVID-
19. These drugs have been tested before in humans with other diseases. In this study, we would 
like to make sure that together they are safe for use in humans with COVID-19 and see if together 
they can improve patients’ health when they are sick with COVID-19. 
 
What drugs are 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. We are also studying a drug called baricitinib.  This drug has also 
been studied in animals and in people.  It is given as pills that you swallow. 
 
Remdesivir is given to all people who enroll in this study. Remdesivir can be given at some 
hospitals as an “emergency use” drug, which means you may be able to get this drug and not be 
in this study.  It is not available at every hospital because it is not a licensed drug in the United 
States. 
 
We want to compare the effect of giving remdesivir with and without baricitinib (the study drugs). 
We need to use a tablet that does not have the baricitinib 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.  
 
 


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 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 3 of 18 
 
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 remdesivir infusion with 
placebo tablets, and 1 will get remdesivir infusion and baricitinib tablets. You will have an equal 
chance of being in either of the study groups.  You and the study staff will not know what group 
you are in. When the study is over, we will learn if the study drugs are safe in combination and if 
the combination of drugs were more successful in treating people with COVID-19 than remdesivir 
alone.   
 
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) 
or the back of your nose (also known as an NP swab). If either of these methods cannot be 
performed, we may swab the inside lower portion of your nose (nasal swab). Only hospitalized 
adults 18 years old and older who are not pregnant and not breastfeeding and who test positive for 
COVID-19 can join this study. You may not be able to join this study if you have abnormal values 
for liver, kidney or immune system tests, are receiving a biologic therapy (including B-cell or T-
cell targeted therapies) or some cancer medicines (such as TNF inhibitors), have a recent history 
of  blood clots, are taking oral high dose corticosteroids such as prednisone, take a medicine for 
gout called probenecid, have received vaccines recently, or if you have tuberculosis, or another 
serious infection.  
 
If you qualify for this study and decide to join, you will get 1 infusion of study drug for 10 days 
and 1 or 2 pills of study drug or placebo every day for 14 days while you are a patient in the 
hospital. The number of pills you receive each day will depend upon your kidney function. You 
will not get infusions or pills after you are discharged from the hospital. The maximum number 
of infusions you will receive is 10 and the maximum number of pills will be 28 pills given over 
14 days.  If you are already discharged from the hospital, you will come back to the site for study 
visits on Days 15 and 29.  If you are unable to come back for study visits, we will call you. We 
will call you on Day 22 to ask you about your health and recovery and if you were readmitted to 
a hospital.  As long as you are hospitalized, visits will take place in the hospital. We will take 
one blood sample and one 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 in-person follow-up study visits on Days 15 and 29. 
We will use the blood and swab samples for research and safety tests. Your total amount of time 
on this study will be about 30 days. You will not be compensated taking part in the 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 4 of 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 4 of 18 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
What are the main study risks? 
The study drug remdesivir has been given to 138 healthy (not sick) people in four 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. Early data on over 400 hospitalized people in this study suggest that remdesivir may 
help hospitalized patients with COVID-19. 
 
The study drug baricitinib is licensed for use for rheumatoid arthritis in the United States. The side 
effects of taking this medication for rheumatoid arthritis and related conditions is fairly well 
understood.  A recent as yet unpublished case series showed positive results of using this drug for 
treatment of COVID-19 in 10 of the 11 people with severe disease who received the drug. 
Baricitinib blocks the effects of proteins in the body called Janus kinases. Blocking these proteins 
can affect the immune system. Drugs that affect the immune system can increase the risk of 
infection and cancer. This study drug may also reduce replication of the virus in the body.  Very 
common side effects of baricitinib included upper respiratory infections and higher amounts of 
cholesterol in the blood.  Common side effects included small increases in blood tests related to 
the liver, higher number of blood platelets (parts of the blood that aid in clotting), cold sores and 
shingles, upset stomach, rash, and headache.  
 
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. 
 
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 these are new 
drugs that we are still studying, they 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 drugs work and you received the study 
drug on this study, you may benefit by getting better sooner or having less severe disease. 


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 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 5 of 18 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
 
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. If 
you feel that you need medicines or herbal products, you should talk to a member of the study 
team first. 
You should not volunteer for another study that gives volunteers a new study drug for COVID-19 
for at least 30 days after you start receiving the study drug on Day 1.  If you want to be in another 
study that follows people who have or have had COVID-19, you should talk to a member of the 
study team first especially if this follow-up study will collect blood from you.  
 
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. Animal studies of baricitinib have shown harmful effects to both the mother 
and unborn babies, including a harmful effect on the bones of the babies. In one animal study, 
baricitinib was present in breast milk.  Women who are breastfeeding should not take baricitinib. 
 
If you can become pregnant, you must use an acceptable nonhormonal method of birth control, 
from screening until Day 29 of the study. 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.  
 
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 drugs. 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. 
 
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. 
 
 


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 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 6 of 18 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
 
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. We may 
need over 1,000 hospitalized adults with COVID-19 to participate in this study. 
 
We will ask you some questions about your health, including whether you have liver disease, 
kidney disease, problems with blood clotting, tuberculosis or other serious infections, take high 
dose steroids, medicine for gout, medicines for cancer, medicines to modify your immune 
system, have allergies to medications, have had a vaccine recently, and if you received any 
medications from your doctor during this illness. We will also perform a physical exam, measure 
your height and weight, get a swab sample to test for the virus, and take some of your blood to 
determine if your liver, kidneys, blood clotting, and immune system are working well. We may 
obtain some of this information from your inpatient hospital records. 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 for 10 days and 1 or 2 pills 
every day for 14 days while you are a patient in the hospital. The infusion will be study drug and 
the pills 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 or any more pills.   
 
We will take one blood sample and one 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 swab sample at Days 15 and 29.  
 
We will use the blood and swab samples for research and safety tests. Swab samples will be tested 
for presence of the virus that causes COVID-19. We will call you on Day 22 to ask you about your 
health and recovery and if you were readmitted to a hospital.  As long as you are hospitalized, 
visits will take place in the hospital.   


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 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 7 of 18 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
 
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 drugs work 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 30 days. 
 
3. 
What could be the side effects from the study drugs? 
 
The study drug remdesivir has been given to a 138 healthy (not sick) people in four 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. 
 


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 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 8 of 18 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
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 contains a compound that caused changes in the kidneys of animals but did not 
affect how well the kidneys worked. The animal’s 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. 
 
The study drug baricitinib is licensed for use for rheumatoid arthritis in the United States. The side 
effects of taking this medication for rheumatoid arthritis and related conditions is fairly well 
understood.  A recent as yet unpublished case series showed positive results of using this drug for 
treatment of COVID-19 in 10 of the 11 people with severe disease who received the drug. 
Baricitinib blocks the effects of proteins in the body called Janus kinases. Blocking these proteins 
can affect the immune system. Drugs that affect the immune system can increase the risk of 
infection and cancer. This study drug may also reduce replication of the virus in the body.   
 
The following table lists the risks and discomforts associated with baricitinib: 
Very Common (10% or 
greater [affects more than 1 
in 10 people]) 
Common (1- less than 10% 
[affects less than 1 in 10 
people])) 
Uncommon (0.1 to less than 1% 
[affects less than 1 in 100 
people]) 
• 
higher amounts of 
cholesterol in the blood 
• 
upper respiratory tract 
infections 
• 
small increases in blood tests 
related to the liver  
• 
higher number of blood 
platelets (parts of the blood 
that aid in clotting) 
• 
cold sores and shingles 
• 
upset stomach 
• 
rash 
• 
headache 
• 
changes in blood tests related to 
muscle* 
• 
acne* 
• 
lower number of white blood 
cells, including special types of 
white blood cells (blood cells 
that fight infections) 
• 
higher amounts of fat in the 
blood 
• 
blood clots in blood vessels 
• 
hives 
• 
swelling of the face 
• 
weight increase 
*In atopic dermatitis clinical trials, changes in blood tests related to muscle and acne were commonly reported. 
 
 


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 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 9 of 18 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
Infections 
Upper respiratory tract infections include symptoms similar to the common cold (cough, stuffy 
or runny nose, scratchy or sore throat, sneezing).  These have been very common during studies 
in people taking baricitinib.  Infections that were common include shingles and cold sores.  Some 
people with atopic dermatitis had other rashes caused by the cold sore virus.  
Serious infections requiring hospitalization have also occurred in people taking baricitinib.  
These were common during studies.   
Unusual infections can occur in people with weakened immune systems.  These infections 
include tuberculosis, invasive fungal infections, and some viruses.  These have been 
uncommonly reported in people taking baricitinib.   
Your study doctor will decide what treatment, if any, you may need for an infection. 
Blood Clots in the Blood Vessels 
Some people who received baricitinib developed blood clots in the blood vessels of their legs.  In 
addition, COVID-19 may increase the risk of developing blood clots in various places in the 
body. These clots may then dislodge and travel to the lungs.  Baricitinib should be used with 
caution in people who are at high risk for blood clots in their blood vessels.   
Tell your study doctor if you have had blood clots in the veins of your legs or lungs in the past or 
take a medicine for clots.  The study drug will be stopped if signs or symptoms of blood clots 
develop.  Your study doctor may advise that you take medications to reduce the risk of blood 
clots while you are hospitalized. 
Blood Tests 
Higher amounts of cholesterol in the blood (good and bad cholesterol) were very common in 
people who took baricitinib.  Higher amounts of fat in the blood were uncommon.  Taking 
baricitinib did not increase the chance of having heart related problems such as heart disease, 
heart attack, heart failure, or stroke. 
A higher number of parts of the blood that aid in clotting (blood platelets) were commonly 
reported in people taking baricitinib.  These increases have not been associated with an increased 
risk of stroke, heart attack, or blood clots. 
Small changes in blood tests related to muscle have been seen uncommonly in people treated 
with baricitinib.  In most people with these changes, the changes were temporary.  Although 
there was no clear link with any muscle problems, symptoms such as muscle aches and pain 
were reported by some people. In people with atopic dermatitis, small changes in blood tests 
related to muscle were seen commonly. 


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 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 10 of 18 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
Baricitinib affects your immune system.  It may decrease the number of parts of the blood that 
aid in fighting infections (white blood cells).  This decrease may increase your risk for 
infections.  Decreases in white blood cells have been uncommon with baricitinib. 
 
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 these are new drugs that we are still studying, they may cause other changes that could hurt 
or bother you that we do not know about and, these drugs have never been studied before in people 
receiving both study drugs. 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. 
 
Short-term medical care will be provided if there are side effects from the infusions or the pills 
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. 
 
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 remdesivir 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. 
 


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 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 11 of 18 
 
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 drugs work and you received them in 
this study, you may benefit by getting better sooner and/or getting less severe disease. If we find 
that the study drugs do work alone or in combination, they will continue to be tested in more study 
volunteers until they can be approved as a treatment for COVID-19. Your participation in this 
study is important to learn more about the study drugs, including if they are safe and work 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 COVID-19.  
 
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. 
 
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 and baricitinib 
work, 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.  
 


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 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 12 of 18 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH 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.  
 
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. 


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 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 13 of 18 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
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 will also be watching over this study and have the authority to stop the study at 
any time.   
 
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. 
• Qualified representatives from Eli Lilly and Company, the pharmaceutical company who 
produces baricitinib. 
 
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. 
 


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 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 14 of 18 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
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.   
 
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. 
 
 
 


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 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 15 of 18 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
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. 
 
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. 
 


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 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 16 of 18 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
Gilead Sciences, Inc., the company that makes remdesivir, is providing remdesivir for this 
study to NIH without charge. Eli Lilly and Company, the company that makes baricitinib, is 
providing baricitinib 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. 
 
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. 
 
 
 


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 17 of 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 17 of 18 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
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.  
 
A Declaration under the Public Readiness and Emergency Preparedness (PREP) Act was 
issued by the Secretary of the United States Department of Health and Human Services on 
March 10, 2020.  This Declaration limits the legal rights of a subject participating in clinical 
studies utilizing COVID-19 countermeasures, such as the remdesivir and baricitinib used in 
this study.  Because this study is covered by the PREP Act Declaration, covered persons, such 
as the manufacturers, study sponsor, researchers, healthcare providers and others have liability 
immunity (that is, they cannot be sued by you or your family under the laws of the United 
States). 
 
If you believe that you may have been harmed as a result of this research study, certain claims 
for serious injury or death caused by the countermeasure may be eligible for compensation 
through the Countermeasures Injury Compensation Program. This is a program set up by the 
United States Government.  
 
Information about this program can be found at https://www.hrsa.gov/cicp/about/index.html 
or by calling 1-855-266-2427. If you are eligible for this program, you must file a claim within 
one year of the administration or use of the covered countermeasure. 
 
 
 
 


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 18 of 18   
 
 
Richard Davey, Jr, MD 
Advarra IRB Approved Version 29 May 2020 
Revised 4 Jun 2020 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
 
File in Section 4: Protocol Consent (1) 
Version Date: 5/29/2020 
Page 18 of 18 
 
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 
 
Witness to the oral short-form consent process only:  
Witness: 
 
 
 
 
 
Signature of Witness* 
 
Print Name of Witness 
 
Date 
 
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER: 
 
 
An interpreter, or other individual, who speaks English and the participant’s preferred  
language facilitated the administration of informed consent and served as a witness. The investigator 
obtaining consent may not also serve as the witness. 
 
 
 
 
 
 
An interpreter, or other individual, who speaks English and the participant’s preferred  
language facilitated the administration of informed consent but did not serve as a witness. The name 
or ID code of the person providing interpretive support is:_________________________________. 
 

Prot_002.pdf: 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 1 of 146 
 
 
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: 6.0 
 
25 May 2020 
 
 
 
 


Protocol 20-0006 
Version 6.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
25 May 2020 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 2 of 146 
STATEMENT OF COMPLIANCE 
Each institution engaged in this research will hold a current Federalwide Assurance (FWA) 
issued by the Office of Human Research Protection (OHRP) for federally funded research. The 
Institutional Review Board (IRB)/Independent or Institutional Ethics Committee (IEC) must be 
registered with OHRP as applicable to the research.  
 
The study will be carried out in accordance with the following as applicable: 
• All National and Local Regulations and Guidance applicable at each site 
• The International Council for Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH) E6(R2) Good Clinical Practice, and the 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects 
of Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• United States (US) Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of 
Human Subjects 
• US Food and Drug Administration (FDA) Regulations: 21 CFR Part 50 (Protection of 
Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 
CFR Part 56 (IRBs), 21 CFR Part 11, and 21 CFR Part 312 (Investigational New Drug 
Application), and/or 21 CFR 812 (Investigational Device Exemptions) 
• The policies and procedures of National Institutes of Health (NIH) Office of Extramural 
Research and Division of Microbiology and Infectious Diseases (DMID) 
 
The signature below provides the necessary assurance that this study will be conducted 
according to all stipulations of the protocol including statements regarding confidentiality, and 
according to local legal and regulatory requirements, US federal regulations, and ICH E6(R2) 
GCP guidelines. 
 
Site Investigator Signature: 
 
 
Signed: 
 
Date: 
 
 
Name and Title 
 
 
 
 


Protocol 20-0006 
Version 6.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
25 May 2020 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 3 of 146 
TABLE OF CONTENTS 
 
STATEMENT OF COMPLIANCE ................................................................................................ 2 
TABLE OF CONTENTS ................................................................................................................ 3 
LIST OF TABLES .......................................................................................................................... 9 
LIST OF FIGURES ...................................................................................................................... 10 
1. 
OVERALL PROTOCOL SUMMARY ................................................................................ 11 
1.1 
Synopsis ........................................................................................................................ 11 
1.2 
Stages in the adaptive trial ............................................................................................ 16 
1.3 
Schedule of Assessments .............................................................................................. 16 
1.4 
Study Schema................................................................................................................ 17 
2. 
INTRODUCTION ................................................................................................................ 18 
2.1 
Study Rationale ............................................................................................................. 18 
2.2 
Background ................................................................................................................... 18 
 
Purpose of Study ................................................................................................... 18 
2.3 
Risk/Benefit Assessment .............................................................................................. 19 
3. 
OBJECTIVES AND ENDPOINTS ...................................................................................... 19 
4. 
STUDY DESIGN.................................................................................................................. 22 
4.1 
Overall Design .............................................................................................................. 22 
4.2 
Scientific Rationale for Study Design........................................................................... 23 
5. 
STUDY POPULATION ....................................................................................................... 23 
5.1 
Inclusion Criteria .......................................................................................................... 23 
5.2 
Exclusion Criteria ......................................................................................................... 24 
5.3 
Specific Populations...................................................................................................... 24 
5.4 
Strategies for Recruitment and Retention ..................................................................... 24 
 
Recruitment ........................................................................................................... 24 
 
Retention ............................................................................................................... 24 
 
Compensation Plan for Subjects ........................................................................... 24 
 
Costs ...................................................................................................................... 24 
6. 
STUDY PRODUCT.............................................................................................................. 25 
7. 
STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL..................................................................................... 25 
7.1 
Halting Criteria and Discontinuation of Study Intervention ......................................... 25 
 
Individual Study Product Halting ......................................................................... 25 
 
Study Halting ........................................................................................................ 25 
7.2 
Withdrawal from the Study ........................................................................................... 25 
7.3 
Lost to Follow-Up ......................................................................................................... 25 


Protocol 20-0006 
Version 6.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
25 May 2020 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 4 of 146 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 25 
8.1 
Screening and Efficacy Assessments ............................................................................ 25 
 
Screening Procedures ............................................................................................ 25 
 
Efficacy Assessments............................................................................................ 27 
 
Exploratory assessments ....................................................................................... 29 
8.2 
Safety and Other Assessments ...................................................................................... 30 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings .................................................................................................. 31 
 
Unscheduled Visits ............................................................................................... 31 
8.3 
Adverse Events and Serious Adverse Events ............................................................... 32 
 
Definition of Adverse Event (AE) ........................................................................ 32 
 
Definition of Serious Adverse Event (SAE) ......................................................... 32 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR).............................. 33 
 
Classification of an Adverse Event ....................................................................... 33 
 
Time Period and Frequency for Event Assessment and Follow-Up ..................... 34 
 
Serious Adverse Event Reporting ......................................................................... 34 
 
Reporting of Pregnancy ........................................................................................ 35 
8.4 
Unanticipated Problems ................................................................................................ 35 
 
Definition of Unanticipated Problems .................................................................. 35 
 
Unanticipated Problem Reporting......................................................................... 36 
9. 
STATISTICAL CONSIDERATIONS.................................................................................. 36 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....... 36 
10.1 
Regulatory, Ethical, and Study Oversight Considerations............................................ 36 
 
Informed Consent Process .................................................................................... 37 
 
Study Termination and Closure ............................................................................ 38 
 
Confidentiality and Privacy .................................................................................. 39 
 
Secondary Use of Stored Specimens and Data ..................................................... 39 
 
Key Roles and Study Governance ........................................................................ 40 
 
Safety Oversight.................................................................................................... 40 
 
Clinical Monitoring ............................................................................................... 41 
 
Data Handling and Record Keeping ..................................................................... 41 
 
Protocol Deviations ............................................................................................... 42 
 Publication and Data Sharing Policy .................................................................... 43 
 Human Data Sharing Plan ..................................................................................... 43 
 Publication ............................................................................................................ 43 
 Conflict of Interest Policy ..................................................................................... 43 
10.2 
Additional Considerations ............................................................................................ 43 
 
Research Related Injuries ..................................................................................... 43 
10.3 
Abbreviations ................................................................................................................ 44 
10.4 
Protocol Amendment History ....................................................................................... 45 
11. REFERENCES ..................................................................................................................... 50 
Appendix A - ACTT-1: Remdesivir vs Placebo ........................................................................... 54 
1. 
PROTOCOL SUMMARY .................................................................................................... 54 


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1.1 
Synopsis ........................................................................................................................ 54 
1.2 
Schedule of Assessments .............................................................................................. 61 
1.3 
Study Schema................................................................................................................ 62 
2. 
INTRODUCTION ................................................................................................................ 62 
2.1 
Study Rationale ............................................................................................................. 62 
2.2 
Background ................................................................................................................... 62 
 
Purpose of Study ................................................................................................... 62 
 
Potential Therapeutics ........................................................................................... 63 
2.3 
Risk/Benefit Assessment .............................................................................................. 63 
 
Known Potential Risks .......................................................................................... 63 
 
Potential Risks of Remdesivir ............................................................................... 64 
 
Known Potential Benefits ..................................................................................... 65 
 
Assessment of Potential Risks and Benefits ......................................................... 65 
3. 
OBJECTIVES AND ENDPOINTS ...................................................................................... 65 
4. 
STUDY DESIGN.................................................................................................................. 68 
4.1 
Overall Design .............................................................................................................. 68 
4.2 
Scientific Rationale for Study Design........................................................................... 70 
4.3 
Justification for Dose .................................................................................................... 70 
5. 
STUDY POPULATION ....................................................................................................... 70 
5.1 
Inclusion Criteria .......................................................................................................... 70 
5.2 
Exclusion Criteria ......................................................................................................... 71 
 
Exclusion of Specific Populations ........................................................................ 71 
5.3 
Inclusion of Vulnerable Subjects .................................................................................. 72 
5.4 
Lifestyle Considerations ............................................................................................... 72 
5.5 
Screen Failures .............................................................................................................. 72 
5.6 
Strategies for Recruitment and Retention ..................................................................... 73 
 
Recruitment ........................................................................................................... 73 
 
Retention ............................................................................................................... 73 
 
Compensation Plan for Subjects ........................................................................... 73 
 
Costs ...................................................................................................................... 73 
6. 
STUDY PRODUCT.............................................................................................................. 73 
6.1 
Study Product(s) and Administration – GS-5734 (Remdesivir) and placebo ............... 73 
 
Study Product Description .................................................................................... 74 
 
Dosing and Administration ................................................................................... 74 
 
Dose Escalation ..................................................................................................... 74 
 
Dose Modifications ............................................................................................... 74 
 
Overdosage ........................................................................................................... 74 
6.2 
Preparation/Handling/Storage/Accountability .............................................................. 75 
 
Acquisition and Accountability ............................................................................ 75 
 
Formulation, Appearance, Packaging, and Labeling ............................................ 75 
 
Product Storage and Stability................................................................................ 76 
 
Preparation ............................................................................................................ 76 


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6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................... 77 
6.4 
Study Intervention Compliance .................................................................................... 77 
6.5 
Concomitant Therapy.................................................................................................... 77 
 
Rescue Medicine ................................................................................................... 78 
 
Non-Research Standard of Care............................................................................ 78 
7. 
STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL..................................................................................... 78 
7.1 
Halting Criteria and Discontinuation of Study Intervention ......................................... 78 
 
Individual Infusion Halting ................................................................................... 78 
 
Study Halting ........................................................................................................ 79 
7.2 
Withdrawal from the Study ........................................................................................... 79 
7.3 
Lost to Follow-Up ......................................................................................................... 79 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 79 
8.1 
Screening and Efficacy Assessments ............................................................................ 79 
 
Screening Procedures ............................................................................................ 79 
 
Efficacy Assessments............................................................................................ 81 
 
Exploratory assessments ....................................................................................... 83 
8.2 
Safety and Other Assessments ...................................................................................... 84 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings .................................................................................................. 85 
 
Unscheduled Visits ............................................................................................... 85 
8.3 
Adverse Events and Serious Adverse Events ............................................................... 86 
 
Definition of Adverse Event (AE) ........................................................................ 86 
 
Definition of Serious Adverse Event (SAE) ......................................................... 86 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR).............................. 87 
 
Classification of an Adverse Event ....................................................................... 87 
 
Time Period and Frequency for Event Assessment and Follow-Up ..................... 88 
 
Serious Adverse Event Reporting ......................................................................... 88 
 
Reporting of Pregnancy ........................................................................................ 89 
8.4 
Unanticipated Problems ................................................................................................ 89 
 
Definition of Unanticipated Problems .................................................................. 89 
 
Unanticipated Problem Reporting......................................................................... 90 
9. 
STATISTICAL CONSIDERATIONS.................................................................................. 90 
9.1 
Statistical Hypotheses ................................................................................................... 90 
9.2 
Sample Size Determination........................................................................................... 91 
9.3 
Populations for Analyses .............................................................................................. 95 
9.4 
Statistical Analyses ....................................................................................................... 95 
 
General Approach ................................................................................................. 95 
 
Analysis of the Primary Efficacy Endpoint .......................................................... 95 
 
Analysis of the Secondary Endpoint(s)................................................................. 95 
 
Safety Analyses ..................................................................................................... 96 
 
Baseline Descriptive Statistics .............................................................................. 96 
 
Planned Interim and Early Analyses ..................................................................... 96 
 
Sub-Group Analyses ............................................................................................. 97 


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Exploratory Analyses ............................................................................................ 97 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....... 98 
Appendix B - ACTT-2: Baricitinib/Remdesivir Vs. Remdesivir Trial......................................... 99 
1. 
PROTOCOL SUMMARY .................................................................................................... 99 
1.1 
ACTT-2 – Synopsis ...................................................................................................... 99 
1.2 
Schedule of Assessments ............................................................................................ 102 
1.3 
Study Schema.............................................................................................................. 103 
2. 
INTRODUCTION .............................................................................................................. 103 
2.1 
Background ................................................................................................................. 103 
 
ACTT-2 – Baricitinib/Remdesivir vs. Remdesivir Trial .................................... 103 
2.2 
Risk/Benefit Assessment ............................................................................................ 104 
 
Known Potential Risks ........................................................................................ 104 
 
Remdesivir .......................................................................................................... 105 
 
Baricitinib ........................................................................................................... 107 
3. 
OBJECTIVES AND ENDPOINTS .................................................................................... 109 
4. 
STUDY DESIGN................................................................................................................ 112 
4.1 
Overall Design ............................................................................................................ 112 
4.2 
Scientific Rationale for Study Design......................................................................... 112 
4.3 
Justification for Dose .................................................................................................. 113 
 
Justification for Dose of Remdesivir .................................................................. 113 
 
Justification for Dose of Baricitinib .................................................................... 113 
5. 
STUDY POPULATION ..................................................................................................... 113 
5.1 
Inclusion Criteria ........................................................................................................ 113 
5.2 
Exclusion Criteria ....................................................................................................... 114 
 
Exclusion of Specific Populations ...................................................................... 115 
5.3 
Inclusion of Vulnerable Subjects ................................................................................ 116 
5.4 
Lifestyle Considerations ............................................................................................. 116 
5.5 
Screen Failures ............................................................................................................ 116 
5.6 
Strategies for Recruitment and Retention ................................................................... 117 
 
Recruitment ......................................................................................................... 117 
 
Retention ............................................................................................................. 117 
 
Compensation Plan for Subjects ......................................................................... 117 
 
Costs .................................................................................................................... 117 
6. 
STUDY PRODUCT............................................................................................................ 117 
6.1 
Study Product(s) and Administration.......................................................................... 117 
 
Study Product Description .................................................................................. 118 
 
Dosing and Administration ................................................................................. 118 
 
Dose Escalation ................................................................................................... 119 
 
Dose Modifications ............................................................................................. 119 
 
Overdosage ......................................................................................................... 120 
6.2 
Preparation/Handling/Storage/Accountability ............................................................ 120 


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Acquisition and Accountability .......................................................................... 120 
 
Formulation, Appearance, Packaging, and Labeling .......................................... 121 
 
Product Storage and Stability.............................................................................. 121 
 
Preparation .......................................................................................................... 122 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................ 122 
 
Randomization .................................................................................................... 122 
 
Blinding and Masking Procedures ...................................................................... 122 
6.4 
Study Intervention Compliance .................................................................................. 123 
6.5 
Concomitant Therapy.................................................................................................. 123 
 
Permitted Concomitant Therapy and Procedures ............................................... 123 
 
Prohibited Concomitant Therapy ........................................................................ 123 
 
Rescue Medicine ................................................................................................. 124 
 
Non-Research Standard of Care.......................................................................... 124 
7. 
STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL................................................................................... 124 
7.1 
Halting Criteria and Discontinuation of Study Intervention ....................................... 125 
 
Individual Study Product Halting ....................................................................... 125 
 
Study Halting ...................................................................................................... 125 
7.2 
Withdrawal from the Study ......................................................................................... 126 
7.3 
Lost to Follow-Up ....................................................................................................... 126 
7.4 
Readmission ................................................................................................................ 126 
8. 
STUDY ASSESSMENTS AND PROCEDURES .............................................................. 126 
8.1 
Screening and Efficacy Assessments .......................................................................... 126 
 
Screening Procedures .......................................................................................... 127 
 
Efficacy Assessments.......................................................................................... 128 
 
Exploratory assessments ..................................................................................... 131 
8.2 
Safety and Other Assessments .................................................................................... 132 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings ................................................................................................ 133 
 
Unscheduled Visits ............................................................................................. 134 
8.3 
Adverse Events and Serious Adverse Events ............................................................. 134 
 
Definition of Adverse Event (AE) ...................................................................... 134 
 
Definition of Serious Adverse Event (SAE) ....................................................... 135 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR)............................ 135 
 
Classification of an Adverse Event ..................................................................... 136 
 
Time Period and Frequency for Event Assessment and Follow-Up ................... 137 
 
Serious Adverse Event Reporting ....................................................................... 137 
 
Reporting of Pregnancy ...................................................................................... 138 
8.4 
Unanticipated Problems .............................................................................................. 138 
 
Definition of Unanticipated Problems ................................................................ 138 
 
Unanticipated Problem Reporting....................................................................... 138 
9. 
STATISTICAL CONSIDERATIONS................................................................................ 139 
9.1 
Statistical Hypotheses ................................................................................................. 139 
9.2 
Sample Size Determination......................................................................................... 139 


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9.3 
Populations for Analyses ............................................................................................ 143 
9.4 
Statistical Analyses ..................................................................................................... 143 
 
General Approach ............................................................................................... 143 
 
Analysis of the Primary Efficacy Endpoint ........................................................ 143 
 
Analysis of the Secondary Endpoint(s)............................................................... 143 
 
Safety Analyses ................................................................................................... 144 
 
Baseline Descriptive Statistics ............................................................................ 144 
 
Planned Interim and Early Analyses ................................................................... 144 
 
Sub-Group Analyses ........................................................................................... 145 
 
Exploratory Analyses .......................................................................................... 145 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS – ALL 
STAGES ..................................................................................................................................... 145 
Country specific appendix .......................................................................................................... 146 
 
LIST OF TABLES 
Table 1. Schedule of Assessments (SOA) .................................................................................. 16 
Table 2. National Early Warning Score (NEWS) .................................................................... 28 
Table 3. Venipuncture Volumes1 ............................................................................................... 31 
Table 1. Schedule of Assessments (SOA) .................................................................................... 61 
Table 2. National Early Warning Score (NEWS) .................................................................... 82 
Table 3. Venipuncture Volumes1 ............................................................................................... 85 
Table 4 Number of recoveries needed for 85% power assuming a type I error rate of 5% for 
various recovery ratios. ................................................................................................................. 91 
Table 5. Possible scenarios for the distribution of ordinal outcomes for the control arm at Day 15.
....................................................................................................................................................... 92 
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. .................................... 93 
Table 7. Treatment ordinal outcome proportions under an odds ratio of 1.75 for five scenarios in 
Table 6 at Day 15. ......................................................................................................................... 93 
Table 1. Schedule of Assessments (SOA) ................................................................................ 102 
Table 2. National Early Warning Score (NEWS) .................................................................. 130 
Table 3. Venipuncture Volumes1 ............................................................................................. 133 
Table 4. Hypothesis tests of interest for ACTT-1 and ACTT-2 ................................................. 139 
Table 5. Number of recoveries needed for 85% power assuming a type I error rate of 5% 
for various recovery ratios. ...................................................................................................... 140 
Table 6: Possible scenarios for the distribution of ordinal outcomes for the control arm at Day 
15................................................................................................................................................. 141 
Table 7: Sample size calculations for scenarios in Table 6 for a two-arm study assuming 85% 
power, a two-sided type I error rate of 5%, and various true odds ratios. .................................. 142 
Table 8. Treatment ordinal outcome proportions under an odds ratio of 1.75 for five 
scenarios in Table 5 at Day 15. ................................................................................................ 142 
 
 


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LIST OF FIGURES 
No table of figures entries found. 
 


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1. OVERALL 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 cases on January 5, 2020, 278 cases on 
January 20, 2020, 318,000 cases on March 22, 2020, and more than 1,800,000 cases and 113,000 
deaths as of April 12, 2020 according to various international health reporting agencies (1). 
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. New arms can 
be introduced according to scientific and public health needs. 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. This adaptive 
platform is used to rapidly evaluate different therapeutics in a population of those hospitalized 
with moderate to severe COVID-19. The platform will provide a common framework sharing a 
similar population, design, endpoints, and safety oversight. New stages with new therapeutics 
can be introduced and will be described in a stage-specific appendix. One independent Data and 
Safety Monitoring Board (DSMB) will actively monitor interim data in all stages to make 
recommendations about early study closure or changes to study arms.  
 
Subjects will be assessed daily while hospitalized. See section study specific Schedule of 
Assessment for details. All subjects will undergo a series of efficacy, safety, and laboratory 
assessments. See stage specific schedule of assessment for details.  
 
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. Each stage may prioritize different secondary endpoints for the purpose 
of multiple comparison analyses. 
 
Study Objectives  
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
Primary 
 
To evaluate the clinical efficacy, as assessed 
by time to recovery, of different 
Day of recovery is defined as the first day on 
which the subject satisfies one of the 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
investigational therapeutics as compared to 
the control arm. 
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. 
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. 
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. 
 
 
 
 
 
 
 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
 
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 (if the subject 
attends an in-person visit or still 
hospitalized) 
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 28-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. 
 
 
 
• SAEs 
• Grade 3 and 4 AEs  


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
• Cumulative incidence of Grade 3 and 4 
clinical and/or laboratory AEs through 
Day 29. 
• Discontinuation or temporary 
suspension of study product 
administrations (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 
reported as INR) over time (analysis of 
lab values in addition to AEs noted 
above). 
• WBC with differential, hemoglobin, 
platelets, creatinine, glucose, total 
bilirubin, ALT, AST, and PT/INR 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). 
 
Study Population 
This trial will study putative therapeutics in a hospitalized population with moderate to severe 
COVID-19. The platform trial will have common inclusion criteria but may be modified for each 
stage for the unique risk of the study product in that stage. Exclusion criteria are described in 
each stage specific appendix.  
 
Inclusion Criteria 
1. Admitted to a hospital with symptoms suggestive of COVID-19. 
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. 


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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 through 
Day 29. 
 
Exclusion Criteria 
Exclusion criteria are described in each stage specific appendix. 
 
 
Study Phase 
• Phase 3 
 
Study Population 
Hospitalized adults (≥18 years old) with COVID-19. 
 
Study Sites 
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 
Each stage specific appendix will detail the stage specific study intervention 
 
Study Duration 
The full adaptive 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 


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• 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/pooled data of Grade 3 and 4 
AE / SAE 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 in real time, will have formal 
safety/efficacy reviews after approximately every 200 subjects have met recovered status 
for each pairwise comparison. 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. 
  
1.2 
Stages in the adaptive trial 
Each new intervention represents a new stage in the adaptive design clinical trial. In order to 
clearly convey the protocol elements, interventions, objectives and endpoints for each stage, 
common elements are described in the main protocol document while each stage is noted in a 
stage specific appendix.  
 
The stages in the clinical trial include: 
ACTT-1: Remdesivir vs Placebo Trial 
ACTT-2: Baricitinib/Remdesivir vs. Remdesivir Trial 
 
 
1.3 
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 investigational 
agent 
 
Detailed in the stage specific 
appendix. 
 
 
 
 
 
 
 
 
 
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 


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Concomitant medication review 
 
X4 
Detailed in the stage 
specific appendix 
 
 
 
 
 
 
 
 
 
 
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. See stage-
specific appendix as additional screening laboratory tests may be added based on study product risk profile. 
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 study product administration. 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. See stage-specific appendix as additional safety laboratory tests may be added based on study product risk profile. 
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: collect clinical data (ordinal and 
NEWS), 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 or nasal swabs may be substituted.  
 
1.4 
Study Schema 
 


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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 
 
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) detected an outbreak 
of viral pneumonia cases of unknown cause. Coronavirus RNA was quickly identified in some 
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 (ARDS), kidney failure, 
and death. The first US COVID-19 death occurred on February 29, 2020. 
 
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 
Drug X 


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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.  
 
2.3 
Risk/Benefit Assessment 
Each stage will detail the stage and study specific risk/benefit assessment.  
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. 
 
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; 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
• 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. 
 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. 
• Days of non-invasive ventilation/high 
flow oxygen (if applicable) up to Day 29 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
 Incidence and duration of new non-
invasive ventilation or high flow 
oxygen use during the study. 
 
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 28-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 study product 
administrations (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: 
 
 
 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
• 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. New arms can 
be introduced according to scientific and public health needs. 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. This adaptive 
platform is used to rapidly evaluate different therapeutics in a population of those hospitalized 
with moderate to severe COVID-19. The platform will provide a common framework sharing a 
similar population, design, endpoints, and safety oversight. New stages with new therapeutics 
can be introduced and will be described in a stage-specific appendix. One independent Data and 
Safety Monitoring Board (DSMB) will actively monitor interim data in all stages to make 
recommendations about early study closure or changes to study arms.  
 
Subjects will be assessed daily while hospitalized. See section study specific Schedule of 
Assessment for details. All subjects will undergo a series of efficacy, safety, and laboratory 
assessments. See stage specific schedule of assessment for details.  
 
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. Each stage may prioritize different secondary endpoints for the purpose 
of multiple comparison analyses. 
 
The sample size will be described in each stage specific appendix.  
 


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4.2 
Scientific Rationale for Study Design 
This study utilizes an adaptive platform 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. 
 
5. STUDY POPULATION 
This trial will study putative therapeutics in a hospitalized population with moderate to severe 
COVID-19. The platform trial will have common inclusion criteria but may be modified in each 
stage-specific appendix for the unique risk associated with the study product used in that stage. 
Exclusion criteria are described in each stage specific appendix.  
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. 
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.  


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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 
Exclusion criteria are described in each stage specific appendix. 
5.3 
Specific Populations 
The inclusion of vulnerable subjects and exclusion of specific populations need to be customized 
according to each intervention, with the current understanding of epidemiology and clinical 
disease. Inclusion and exclusion of specific populations will be described for each stage in the 
stage-specific appendices. 
5.4 
Strategies for Recruitment and Retention 
 
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. 
 
 
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.  
 
 
Compensation Plan for Subjects  
Compensation, if any, will be determined locally and in accordance with local IRB requirements, 
and subject to local IRB approval.  
 
 
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. 


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6. STUDY PRODUCT 
Each stage in this platform trial may have different study products. Information about the study 
product(s) for a given stage can be found in the stage specific appendix.  
7. STUDY INTERVENTION DISCONTINUATION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Halting Criteria and Discontinuation of Study Intervention 
 
Individual Study Product Halting 
See the stage specific appendix for specific study product stopping rules.  
 
 
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 
 
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-study product administration baseline assessments, specimen collection and 


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the initial study product administration can occur on the same calendar day as the screening 
procedures.  
 
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. Additional information 
may be needed based on risk profile of the study product and the exclusion criteria (e.g., 
recent live vaccine history). Please consult stage-specific appendix. The minimum history 
includes:  
• 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. Additional screening laboratory evaluations may be added based on the 
risk profile of the study product for a given stage of the study. Please see stage specific 
appendix. The minimum screening laboratory evaluations include: 
 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). 


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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 
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 study product administration 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. 
 
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. 
 
 Measures of clinical support, limitations and infection control 
The subject’s clinical status will be captured on each study day while hospitalized up until and 
including Day 29. If a subject is discharged prior to Day 15, clinical status is captured on Day 15 
and 29 if the subject returns for an in-person clinic visit or by phone if an in-person visit is not 
possible. Clinical status 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 study product 
administration, 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. 
 
 Ordinal Scale 
The ordinal scale is the primary measure of clinical outcome.  


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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; 
• 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 
 
 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). ECMO and mechanically ventilated subjects should be assigned a score of 3 
for RR (RR <8) regardless of the ventilator setting. Subjects on ECMO should get a score of 3 
for heart rate since they are on cardiopulmonary bypass. 
 
Table 2. National Early Warning Score (NEWS) 


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  Level of consciousness = alert (A), and non-alert and arousable only to voice (V) or pain (P), and 
unresponsive (U).  
 
 
 Exploratory assessments 
 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) or nasal 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 1.3) 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, 


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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: 
 
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.  
 
8.2 
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 study product 
administration 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.  
 
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  
s 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.  


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Clinical laboratory evaluations: 
• Fasting is not required before collection of laboratory samples. 
• Blood will be collected at the time points indicated in the SOA.  
• Minimal 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/INR will be allowed to report an international normalized 
ratio (INR). Additional safety laboratory tests may be required for a given stage 
due to the study product risk profile. See safety laboratory in the stage-specific 
appendix. 
• Day 1 clinical laboratory evaluations are drawn prior to initial study product 
administration as a baseline and results do not need to be reviewed to determine if 
initial study product administration should be given. 
• Clinical laboratory testing will be performed at each clinical trial site in real time.  
 
 
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 1.3 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. 
 
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). 
 
 
Unscheduled Visits 


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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 
 
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. If multiple abnormalities are part 
of the same clinical syndrome, they can be reported together as one AE under a unifying clinical 
diagnosis. For example, the diagnosis of bacterial sepsis may include hypotension, positive blood 
culture, and increased white blood cell count. 
 
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 (baseline) 
medical condition increases above baseline to severity grade 3 or 4, it should be recorded as an 
AE. 
 
Given the nature of severity of the underlying illness, subjects will have many symptoms and 
abnormalities in vital signs and laboratory values. Only Grade 3 and 4 AEs will be captured in 
this trial. In addition, the following AEs will be reported: 
• Any Grade 2 or higher suspected drug-related hypersensitivity reactions associated with 
study product administration will be reported as an AE. 
 
Intermittent abnormal laboratory values or vital sign measurements common in the severely ill 
populations (such as electrolyte abnormalities, low blood pressure, hyperglycemia, etc.) that are 
part of the same clinical diagnosis (e.g., uncontrolled diabetic) can be recorded once with the 
worst grade for each adverse event (grade 3 and 4 only for this trial), with the start and stops 
dates of the intermittent syndrome. If there is clear resolution of the event, and then recurrence, it 
should be treated as a separate adverse event. Resolution is defined as return to baseline (either 
normal if was normal at Day 1, or baseline (Day 1) grade if already an abnormality on the 
toxicity table at Day 1) for > 48 hours.  
 
 
 
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 
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• 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. 
 
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. 
 
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. 
 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. 
 


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• 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). 
 
 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. 
 
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 
administration will be reported as an AE.  
 
 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. 
 
Serious Adverse Event Reporting 
 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 


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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. 
 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. 
 
Sites may have additional local reporting requirements (to the IRB and/or national regulatory 
authority).  
 
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 
 
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; 


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 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. 
 
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 is an adaptive platform study is intended to allow for several adaptations: 1) sample size re-
estimation and 2) addition of new experimental arm(s) into one stage, or 3) addition of separate 
study stages. A brief summary is provided the study specific appendix for each stage. Details 
will be described in the statistical analysis plan (SAP) for each stage.  
 
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 


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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. 
 
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. 
 
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 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. 
 
 Requirements for Permission by Parents/Guardians and Assent by Children (in 
case of a minor) 
Not Applicable 
 


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 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 
study is completed and documentation will be completed that outlines the reason for withdrawal 
of permission for secondary use of samples.  
 
 
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. 


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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. 
 
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. 
 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.  
 


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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. 
 
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. 
 
Safety Oversight 
 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.  
 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 
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: 
• Intermittent safety reviews at a frequency as determined by the DSMB. The DSMB will 
have access to safety data electronically in real time.  
• Formal safety/efficacy reviews after approximately every 200 subjects have met 
recovered status for each pairwise comparison 
• 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. 


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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. 
 
Data Handling and Record Keeping 
 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. 


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 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. 
 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.  
 
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. 
 
 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. 


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 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. 
  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. 
 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. 
 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 
 
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 


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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 
ARDS 
Acute Respiratory Distress Syndrome 
AST 
Aspartate Transaminase 
BP 
Blood Pressure 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
CMS 
Clinical Material Services 
Cr 
Creatinine 
CRF 
Case Report Form 
CROMS 
Clinical Research Operations and Management Support 
CSR 
Clinical Study Report 
CMP 
Clinical Monitoring Plan 
CQMP 
Clinical Quality Management Plan 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases 
EC 
Ethics Committee 
eGFR 
Estimated Glomerular Filtration Rate 
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 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 


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Abbreviation 
Definition 
JAK 
Janus kinase 
LAR 
Legally Authorized Representative 
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 
NP 
Nasopharyngeal 
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 
SBECD 
Sulfobutylether-beta-cyclodextrin 
SDCC 
Statistical and Data Coordinating Center 
SDSP 
Study Data Standardization Plan 
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 
TNF 
Tumor Necrosis Factor 
UP 
Unanticipated Problem 
US 
United States 
WBC 
White Blood Cell 
10.4 
Protocol Amendment History 


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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. 
 
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. 


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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 
follow-up due to infection control and restrictions on travel. 
Additionally, staff at some sites have limited ability to go 
into rooms due to limited 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. 


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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 increase in use of off label 
therapies for COVID-19, including many repurposed agents 
and therapies targeting immune 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. 


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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.  
4.0 
13APR2020 
Note – version 4 was submitted to the US FDA and some IRBs, but given  
the interim DSMB findings this version was never implemented.  
 
General, 
Appendix A, 
Appendix B 
As this is an adaptive study, an additional treatment stage 
“ACTT-2” was added. To allow better organization, the 
general protocol was separated from the study specific 
Appendix A (remdesivir vs placebo) and Appendix B (2x2 
study factorial design of +/- remdesivir and +/- baricitinib). 
 
Appendix B 
Appendix B is a new stage in the platform study that 
describes all study specifics of the 2x2 study factorial design 
of +/- remdesivir and +/- baricitinib 
Appendix B- 
1 
Synopsis 
A new synopsis for ACTT-2 was added. 
App B - 1.2 
SOA 
A revised SOA was added. This is similar to the ACTT-1 
SOA, but footnotes have been edited for clarity.  
App B - 2.2 
Risk 
Risk of baricitinib was added, along with prior language 
about the risk of remdesivir.  
App B - 3 
Objectives 
ACTT-2 will use the same objectives from ACTT-1. 
App B - 4 
Study Design 
The study design and justification for studying baricitinib in 
a factorial study was added.  
App B - 5 
Study 
Population 
ACTT-2 will use similar inclusion and exclusion criteria, 
with some additions unique to the risk or mechanism of 
action of baricitinib. 
App B - 6 
Study Product 
Information about baricitinib was added. 
App B - 9 
Statistical 
Consideration 
While similar to ACTT -1, additional information was added 
for how the factorial design would be analyzed, and how 
arms may be dropped based on ACTT-1 findings.  
5.0 
4MAY2020 
 
 
Appendix B - 
1 
Synopsis 
Information about the preliminary findings from ACTT-1 
was added. 
App B - 1 
Synopsis and 
throughout 
Descriptions of the study design was revised to reflect a 2 
arms study -  Baricitinib/Remdesivir Vs. Remdesivir 
App B – 1 
Synopsis and 
9.2 
A new sample size was calculated to reflect the 2 arm 
design, and the likely lower anticipated treatment effect of a 
second agent (i.e. the incremental value of no treatment to 1 
treatment is likely larger than from 1 treatment to a 
combination. 
App B – 1 
Synopsis and 
throughout 
Wording has been added to reflect that all subjects (both 
arms) will receive remdesivir.  


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11. REFERENCES 
1. 
JHU Coronavirus Resource Center. COVID-19 Dashboard by the Center for Systems 
Science and Engineering (CSSE) at Johns Hopkins University (JHU) 2020 [Available from: 
https://coronavirus.jhu.edu/map.html. 
App B – 
2.2.2.2 
Potential 
benefits 
Updated with the preliminary findings from ACTT-1. 
App B – 
2.2.3.1 
Potential Risks 
of Baricitinib 
Updated with additional language about drug-drug 
interactions as requested by the FDA.  
App B – 
6.1.1 
Study Product 
Description 
Additional wording was added to better describe the 
baricitinib placebo. 
App B – 
6.3.1 
Randomization Stratification was revised to match the ordinal scale 
categories rather than separate criteria.  
App B – 
6.3.2 
Blinding and 
masking 
This section was added to clearly describe the blinding of 
study product  (baricitinib only), and the unblinding process 
(both routine and unplanned for given subjects).  
App B – 
8.1.3.2 
Exploratory 
endpoints 
Exploratory endpoints were added for cytokine assessments 
to support the mechanism of action of the baricitinib arm.  
App B – 
8.3.5.1 
Reporting of 
AEs 
Added wording for better reporting of new infections, and 
requested by the FDA.  
App B – 
8.3.6.1 
Investigator 
reporting of 
SAEs 
Revised wording for SAE reporting.  All SAEs are saptured 
in the regular database.  Only those SAEs that are judged to 
be related to either study product are submitted on a larger 
SAE form.  
6.0 
21MAY2020 
 
 
Appendix B – 
1.1 
Exclusion 
Criteria 
Added exclusion for remdesivir use prior to study entry 
(exclusing 3 or more doses). 
Appendix B – 
1.1 
Exclusion 
Criteria 
Separated prior exclusion based on immunosuppressants into 
different categories with different time periods (based on 
FDA’s comments).  Small molecule exclusion shortened to 1 
week and some biologics increased to 3 months.   
Appendix B – 
1.1 
Exclusion 
Criteria 
Revised exclusion for corticosteroid use to permit larger 
amounts prior to enrollment (this is often used for 
syndromes related to COVID such as asthma exacerbation, 
and the prior wording was too restrictive).  
Appendix B – 
4.2 
Scientific 
Rationale for 
Study Design 
This section was blank before, so scientific rationale for 
ACTT-2 was added (scientific rational was previously 
conveyed in the background, but not this section). 
Appendix B – 
5.4 
Lifestyle 
Considerations 
Revised to be more precise regarding what types of studies 
subjects can be co-enrolled in (reflecting questions that have 
arisen during the study). 
Appendix B – 
6.5 
Concomitant 
Medications  
Rewritten extensively for clarity.  The one substantive 
change was to permit corticosteroids as needed for standard 
care for non-COVID-19 syndromes.  


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Tanaka Y, Emoto K, Cai Z, Aoki T, Schlichting D, Rooney T, et al. Efficacy and Safety 
of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis Receiving Background 
Methotrexate Therapy: A 12-week, Double-blind, Randomized Placebo-controlled Study. J 
Rheumatol. 2016;43(3):504-11. 


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32. 
Richardson P, Griffin I, Tucker C, Smith D, Oechsle O, Phelan A, et al. Baricitinib as 
potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020;395(10223):e30-e1. 
33. 
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected 
with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. 
34. 
Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to 
COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 
2020. 
35. 
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for 
mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. 
Lancet. 2020;395(10229):1054-62. 
36. 
Sanchez GAM, Reinhardt A, Ramsey S, Wittkowski H, Hashkes PJ, Berkun Y, et al. 
JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J 
Clin Invest. 2018;128(7):3041-52. 
37. 
Stebbing J, Phelan A, Griffin I, Tucker C, Oechsle O, Smith D, et al. COVID-19: 
combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 2020. 
38. 
Genovese MC, Smolen JS, Takeuchi T. THU0078 SAFETY PROFILE OF 
BARICITINIB FOR THE TREATMENT OF RHEUMATOID ARTHRITIS UP TO 7 YEARS: 
AN UPDATED INTEGRATED SAFETY ANALYSIS. Annals of the Rheumatic Diseases. 
2019;78:308-309. 
39. 
Favalli EG, Biggioggero M, Maioli G, Caporali R. Baricitinib for COVID-19: a suitable 
treatment? Lancet Infect Dis. 2020. 
40. 
Shi JG, Chen X, Lee F, Emm T, Scherle PA, Lo Y, et al. The pharmacokinetics, 
pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers. J 
Clin Pharmacol. 2014;54(12):1354-61. 
41. 
Winthrop KL, Bingham CO, 3rd, Komocsar WJ, Bradley J, Issa M, Klar R, et al. 
Evaluation of pneumococcal and tetanus vaccine responses in patients with rheumatoid arthritis 
receiving baricitinib: results from a long-term extension trial substudy. Arthritis Res Ther. 
2019;21(1):102. 


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APPENDIX A - ACTT-1: REMDESIVIR VS PLACEBO 
 
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 1000.  
 
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 


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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 (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; 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
• 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. 
 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 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
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 28-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 study product 
administrations (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.  
 
 
 
• 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 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
• 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. 
 
(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). 
 
 
Inclusion Criteria 
1. Admitted to a hospital with symptoms suggestive of COVID-19. 
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. 


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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 
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 


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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 in real time, will have formal 
safety/efficacy reviews after approximately every 200 subjects have met recovered status 
for each pairwise comparison. 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. 


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• 
If still hospitalized at Day 15 and 29 or returns to the site for an in-person visit: collect 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.  
 
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 
 
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 (2). 
The human disease caused by SARS-CoV-2 has been designated COVID-19. In most (~80%) 


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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 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 (3).  
 
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.  
 
 
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 (4-6). 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) (7). 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 (8). In mouse infection models, remdesivir had therapeutic efficacy 
against SARS-CoV and MERS-CoV (8, 9). 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 (10). 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 (11, 12). 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. 
2.3 
Risk/Benefit Assessment 
 
Known Potential Risks 


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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. 
 
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.  
 
 
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 


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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 
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. 
 
 
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.  
 
 
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 


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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. 
 
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 
 
 
 
• Clinical outcome assessed using ordinal 
scale daily while hospitalized and on Days 
15, 22, and 29. 
 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
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. 
 
 
 
 
 
 
 
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 
 
• Date and cause of death (if applicable) 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
o 28-day mortality 
 
 
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 study product 
administrations (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. 


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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.  
 
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. 


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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 
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 (13-25). 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 (26-28).  
 
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 


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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. 
 
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. 
 
 
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 


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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 
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 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.  


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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. 
 
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 
 
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. 
 
 
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.  
 
Compensation Plan for Subjects  
Compensation, if any, will be determined locally and in accordance with local IRB requirements, 
and subject to local IRB approval.  
 
 
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 


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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 
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. 
 
 
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.  
 
 
Dose Escalation 
Not Applicable 
 
 
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. 
 
 
Overdosage 


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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. 
 
6.2 
Preparation/Handling/Storage/Accountability 
 
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. 
 
 
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).  


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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: 
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.” 
 
 
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. 
 
 
Preparation 
Refer to the protocol-specific MOP for details about preparation.  
 


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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. 
 
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).  
 


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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 
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.  
 
 
 
Rescue Medicine 
Not Applicable 
 
 
Non-Research Standard of Care 
Not Applicable 
 
7. STUDY INTERVENTION DISCONTINUATION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Halting Criteria and Discontinuation of Study Intervention 
 
Individual Infusion Halting 


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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 
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. 
 
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 
 
Screening Procedures 


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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-study product administration baseline assessments, specimen collection and 
the initial study product administration can occur on the same calendar day as the screening 
procedures.  
 
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. 


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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 
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. 
 
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. 
 
 Measures of clinical support, limitations and infection control 
The subject’s clinical status will be captured on each study day while hospitalized up until and 
including Day 29. If a subject is discharged prior to Day 15, clinical status is captured on Day 15 
and 29 if the subject returns for an in-person clinic visit or by phone if an in-person visit is not 
possible. Clinical status 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 study product 
administration, 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. 
 
 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): 


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• 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; 
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). 
 
 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). ECMO and mechanically ventilated subjects should be assigned a score of 3 
for RR (RR <8) regardless of the ventilator setting. Subjects on ECMO should get a score of 3 
for heart rate since they are on cardiopulmonary bypass. 
 
Table 2. National Early Warning Score (NEWS) 


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  Level of consciousness = alert (A), and non-alert and arousable only to voice (V) or pain (P), and 
unresponsive (U).  
 
 
 Exploratory assessments 
 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, 


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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: 
 
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.  
 
8.2 
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.  
 
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 


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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.  
 
 
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. 
 
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). 
 
 
Unscheduled Visits 


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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 
 
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. If multiple abnormalities are part 
of the same clinical syndrome, they can be reported together as one AE under a unifying clinical 
diagnosis.  
 
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 (baseline) 
medical condition increases above baseline to severity grade 3 or 4, it should be recorded as an 
AE. 
 
Given the nature of severity of the underlying illness, subjects will have many symptoms and 
abnormalities in vital signs and laboratory values. Only Grade 3 and 4 AEs will be captured in 
this trial. In addition, the following AEs will be reported: 
• Any Grade 2 or higher suspected drug-related hypersensitivity reactions associated with 
study product administration will be reported as an AE. 
 
Intermittent abnormal laboratory values or vital sign measurements common in the severely ill 
populations (such as electrolyte abnormalities, low blood pressure, hyperglycemia, etc.) that are 
part of the same clinical diagnosis (e.g., uncontrolled diabetic) can be recorded once with the 
worst grade for each adverse event (grade 3 and 4 only for this trial), with the start and stops 
dates of the intermittent syndrome. If there is clear resolution of the event, and then recurrence, it 
should be treated as a separate adverse event. Resolution is defined as return to baseline (either 
normal if was normal at Day 1, or baseline (Day 1) grade if already an abnormality on the 
toxicity table at Day 1) for > 48 hours.  
 
 
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. 


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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. 
 
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. 
 
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. 
 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. 
 


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• 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). 
 
 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. 
 
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.  
 
 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. 
 
Serious Adverse Event Reporting 
 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) 


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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. 
 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. 
 
Sites may have additional local reporting requirements (to the IRB and/or national regulatory 
authority).  
 
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 
 
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 
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 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. 
 
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.  
 
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 (29).  
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. 
 


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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. 
 
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 


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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.  
 
 
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 


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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 
 
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 
10 
7.2 
9 
5.9 
10 
6.8 
20 
16.2 
25 
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longer requires ongoing 
medical care; 
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 
 
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.  
 
 
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. 
 
 
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. 
 
 
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.  
 
 
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).  
 
 
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.  
 
 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. The unblinded statistical 
team will prepare these reports for review by the DSMB.  
 
 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.  
 
 
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, baseline 
disease severity (stratification of mild/moderate and severe, as well as ordinal scale of 4/5 vs 6/7) 
age, race, 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. 
 
 
Exploratory Analyses 
An exploratory analysis will compare treatment efficacy estimates according to the various 
scales outlined in section 8.1.2. 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 
All supporting documentation and operational considerations are applicable to the entire 
platform trial and are not unique to the individual stages. These are therefore covered in the main 
protocol document.  


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APPENDIX B - ACTT-2: BARICITINIB/REMDESIVIR VS. REMDESIVIR 
TRIAL  
1. PROTOCOL SUMMARY 
1.1 
ACTT-2 – Synopsis 
Study overview 
The cause of ARDS is a hyperinflammatory state characterized by upregulation of multiple 
cytokines. Baricitinib, an orally administered, selective inhibitor of Janus kinase 1 (JAK1) and 
JAK2, could be a therapeutic option because of the potential to inhibit signaling from multiple 
cytokines in COVID-19 patients (30). Baricitinib treatment resulted in a reduction from baseline 
in serum IL-6 at Week 12 in patients with active RA in a Phase 2, randomized, placebo-
controlled study of baricitinib (31). In addition, baricitinib has recently been hypothesized (32) 
and shown (nonclinical data on file) to be a potent inhibitor of numb-associated kinases (NAKs), 
which play a critical role in the host epithelial cell’s ability to facilitate propagation of viruses. 
As these are unique mechanism of actions, the effects of combination therapy may exceed either 
component.  
 
A preliminary review of data from ACTT-1 occurring after 606 recoveries and 103 deaths 
(approximately 67% of the 1063 subjects enrolled) demonstrated that subjects that received 
remdesivir had a 31% faster time to recovery (11 vs 15 days, recovery rate ratio 1.312 (1.119, 
1.541), p<0.001), and a decrease in mortality ( 8.0% vs 11.6%, p = 0.059). The DSMB asked that 
the sponsor be unblinded early given public health implications and implications for ACTT-2. 
Given these findings, there will be no placebo arm in ACTT-2. We will instead investigate 
remdesivir and baricitinib in combination versus remdesivir alone.  
 
Enrollment Period:  
It is anticipated the enrollment may be completed in 2-3 months. 
 
General 
ACTT-2 will evaluate the combination of baricitinib and remdesivir compared to remdesivir 
alone. 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 is 
conducted by phone.  
 
We anticipate that this trial will require 732 recoveries. Assuming that 70% of subjects achieve 
recovery in 28 days, the total sample size is approximately 1032.  
 
Study Population 


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Hospitalized adults (≥18 years old) with COVID-19. 
 
Inclusion Criteria 
1. Admitted to a hospital with symptoms suggestive of COVID-19. 
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 adults ≥ 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 or ECMO. 
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 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 or patient is receiving 
hemodialysis or hemofiltration at time of screening. 
3. Neutropenia (absolute neutrophil count <1000 cells/μL) (<1.0 x 103/μL or <1.0 GI/L). 
4. Lymphopenia (absolute lymphocyte count <200 cells/μL) (<0.20 x 103/μL or <0.20 
GI/L) 
5. Pregnancy or breast feeding. 
6. Anticipated discharge from the hospital or transfer to another hospital which is not a 
study site within 72 hours. 
7. Allergy to any study medication. 
8. Received three or more doses of remdesivir including the loading dose, outside of the 
study under the EUA (or similar mechanism) for COVID-19.  
9. Received convalescent plasma or intravenous immunoglobulin [IVIg]) for COVID-19, 
the current illness for which they are being enrolled. 
10. Received small molecule tyrosine kinase inhibitors (e.g. baricitinib, imatibib, genfinitib), 
in the 1 week prior to screening.   


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11. Received monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-
interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab]), or T-cells (e.g., abatacept) in 
the 4 weeks prior to screening. 
12. Received monoclonal antibodies targeting B-cell (e.g., rituximab, and including any 
targeting multiple cell lines including B-cells) in the 3 months prior to screening. 
13. Received other immunosuppressants in the 4 weeks prior to screening and in the 
judgement of the investigator, the risk of immunosuppression with baricitinib is larger 
than the risk of COVID-19.  
14. Received ≥20 mg/day of prednisone or equivalent for ≥14 consecutive days in the 4 
weeks prior to screening.  
15. Use of probenecid that cannot be discontinued at study enrollment. 
16. Have diagnosis of current active tuberculosis (TB) or, if known, latent TB treated for less 
than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history 
only, no screening required). 
17. Suspected serious, active bacterial, fungal, viral, or other infection (besides COVID-19) 
that in the opinion of the investigator could constitute a risk when taking investigational 
product. 
18. Have received any live vaccine (that is, live attenuated) within 4 weeks before screening, 
or intend to receive a live vaccine (or live attenuated) during the study. Note: Use of non-
live (inactivated) vaccinations is allowed for all subjects.  
19. Have a history of VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) 
within 12 weeks prior to screening or have a history of recurrent (>1) VTE (DVT/PE). 
20. Immunocompromised patients, patients with a chronic medical condition, or those taking 
a medication that cannot be discontinued at enrollment, who, in the judgment of PI, are at 
increased risk for serious infections or other safety concerns given the study products. 
 
Study Intervention 
Subjects will be randomized into two arms (1:1). 
Baricitinib 
Placebo 
Remdesivir 
Arm 1 
Baricitinib tablets + 
remdesivir IV 
Arm 2 
Placebo tablets + 
remdesivir IV 
 
 
All subjects will receive remdesivir 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. See Section 6.1.4 for details of dosing and dose modification.   
 
For the baricitinib component, subjects will receive either active product or placebo as follows: 
• Baricitinib will be administered as a 4 mg* orally (po) (two 2mg tablets) or crushed for 
NG tube, daily for the duration of the hospitalization up to a 14-day total course. 
• A placebo will be given as two tablets* po or crushed for NG tube, daily for the duration 
of the hospitalization up to a 14-day total course 
* Patients with eGFR <60 mL/min will receive a dose of one tablet (2-mg or placebo) 
once daily. 


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Duration of therapy: 
• IV remdesivir – 10 days while hospitalized. 
• Oral (baricitinib or placebo) component – 14 days while hospitalized. 
• Both stop on discharge from hospital. 
 
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 
 
 
 
 
 
Review SARS-CoV-2 results 
X 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Administration of investigational 
agent 
 
• Remdesivir daily infusion until day 
10 or discharge.  
• Baricitinib or placebo: daily by 
mouth until day 14 or discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY PROCEDURES 
 
 
 
 
 
 
Targeted physical exam 
 
X 
 
 
 
 
Vital signs including SpO2 1 
 
X4 
Daily until discharge8 
X9 
 
X9 
Clinical data collection 2  
 
X4 
Daily until discharge8 
X9 
X9 
X9 
Adverse event evaluation 
 
X4 
Daily until discharge8 
X9 
X9 
X9 
Concomitant medication review 
 
X4 
From Day -7 to Day 15 
 
 
 
 
 
 
 
 
 
 
SAFETY LABORATORY 
 
 
 
 
 
 
Safety hematology, chemistry and 
liver tests 
X3 
X4,5,6,7 
Day 3, 5, 8, 11 (all ± 1 day) 
if hospitalized6,7 
X9 
 
X9 
Pregnancy test for females of 
childbearing potential 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH LABORATORY  
 
 
 
 
 
 
Blood for plasma to test for PCR 
SARS-CoV-2 
 
X4,6 
Day 3, 5, 8, 11 (all ± 1 day) 
if hospitalized 
 
 
 
Oropharyngeal swab 10 
 
X4,6 
Day 3, 5, 8, 11 (all ± 1 day) 
if hospitalized 
X9 
 
X9 
Blood for serum (secondary 
research) 
 
X4,6 
Day 3, 5, 8, 11 (all ± 1 day) 
if hospitalized 
X9 
 
X9 
Notes: 
1Vital signs include temperature, systolic blood pressure, heart rate, respiratory rate, O2 saturation and level of 
consciousness. Vital signs collected as part of standard care may be used.  
2 Refer to Section 8.1.2 of the protocol for details of clinical data to be collected including ordinal score, NEWS, oxygen 
requirement, mechanical ventilator requirement, etc. 
3 Screening laboratory tests include: CBC with differential (including absolute neutrophil count and absolute lymphocyte 
count), ALT, AST, creatinine (and calculate an estimated glomerular filtration rate (eGFR) the formula used is determined 


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by the sites, but should be consistent throughout the study), and pregnancy test. Laboratory tests performed in the 48 hours 
prior to enrollment will be accepted for determination of eligibility. 
4 Baseline assessments should be performed within 24 hours prior to first study product administration. Results of Day 1 
(baseline) laboratory assessment do not need to be reviewed to determine if initial study product should be given. 
5 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.  
6 Safety laboratory tests include WBC with differential, hemoglobin, platelets, creatinine, glucose, total bilirubin, ALT, AST, 
INR, d-dimer, and C-reactive protein (CRP). Note: D-dimer and CRP values may predict severity and support assessment 
of outcomes and unlike other safety laboratory values, D-dimer and CRP should not be graded.   
7 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. 
8 Daily until hospital discharge or end of study, whichever comes first.  
9 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 subject is still hospitalized during the follow-up 
period, they should get Day 15, 22 and 29 assessments along with the daily clinical data collection. 
• 
If still hospitalized at Day 15 and 29 or returns to the site for an in-person visit: collect 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. 
10 Oropharyngeal swabs are preferred, but if these are not obtainable, nasopharyngeal or nasal swabs may be substituted.  
  
1.3 
Study Schema 
 
 
 
2. INTRODUCTION 
2.1 
Background 
 
ACTT-2 – Baricitinib/Remdesivir vs. Remdesivir Trial 
A preliminary review of data from ACTT-1 occurring after 606 recoveries and 103 deaths 
(approximately 67% of the 1063 subjects enrolled) demonstrated that subjects that received 
remdesivir had a 31% faster time to recovery (11 vs 15 days, recovery rate ratio 1.312 (1.119, 
1.541), p<0.001), and a decrease in mortality ( 8.0% vs 11.6%, p = 0.059). The DSMB asked that 
the sponsor be unblinded early given public health implications and implications for ACTT-2. 
While an antiviral appears to have some efficacy in the treatment of COVID-19, the mortality 
rate is still high.  Infection by pathogenic coronaviruses (e.g. SARS and SARS-CoV–2) often 
results in excessive cytokine and chemokine action with the development of acute respiratory 
distress syndrome (ARDS) (33-35). It is postulated that this dysregulated inflammatory immune 
response is contributing to the excessive mortality, and targeting this response will further 
improve outcomes.  
 
Baricitinib, an orally administered, selective inhibitor of JAK1 and JAK2, could be a therapeutic 
option because of the potential to inhibit signaling from multiple cytokines in COVID-19 


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patients (30). Baricitinib inhibits signaling of cytokines implicated in COVID-19, including IL-2, 
IL-6, IL-10, IFN-γ, and G-CSF, with lower IC50 values translating to a greater overall inhibition 
of STAT signaling during the dosing interval (33). Baricitinib treatment resulted in a reduction 
from baseline in serum IL-6 at Week 12 in patients with active RA in a Phase 2, randomized, 
placebo-controlled study of baricitinib (data on file). The potent anti-inflammatory effects of 
baricitinib have also been demonstrated by the reduction of serum levels of IFN-γ, IP-10, GM-
CSF and MCP-1 in pediatric patients with steroid-dependent chronic inflammation, resulting in 
control of disease activity and the ability to wean or taper steroids (36).  
 
A recent comment by Richardson et al. published in the Lancet (32), suggested a potential role 
for baricitinib in the treatment of COVID-19. The authors hypothesize that baricitinib, a JAK1/2 
inhibitor, will directly mitigate the inflammatory response triggered by SARS-CoV-2 infection. 
In addition, baricitinib has been identified as a numb-associated kinase (NAK) inhibitor with 
high-affinity for AP2-associated protein kinase 1 (AAK1-8.2 nM, BIKE-20 nM and GAK-120 
nM). AAK1 and GAK were previously described as a crucial regulator of clathrin-mediated 
endocytosis and propagation of coronavirus and other viruses (37). In light of this, baricitinib 
may have an unappreciated antiviral effect by attenuating host-cell propagation of the virus in 
infected COVID-19 patients. 
 
Like all host directed therapeutics, the experience of baricitinib is limited to case series. At the 
Atlanta VA Medical Center to date, ten patients received baricitinib as treatment for COVID-19 
and have recovered (personal communications, Vince Marconi). An additional patient received 
only one day of baricitinib but was made DNR/DNI while on supplemental oxygen. This patient 
died the following day. An additional four patients have received treatment but are pending 
recovery. Of the eleven with complete data by recovery or death, six out of eleven patients met 
criteria for severe disease and required intensive care level management, with two of these 
requiring several days of mechanical ventilation. Initiation of therapy with baricitinib led to 
resolution of fever within 48 hours in 10/11 patients, a downward trend in most inflammation 
markers by the end of treatment, decreased oxygen requirements in 7/8 patients needing 
supplemental oxygen at the time of hospital admission. Complete recovery was observed in 
10/11 patients. Overall, the 10 patients who made a full recovery tolerated the short course of 
treatment with baricitinib and did not develop any secondary bacterial or viral infections during 
the follow-up period (6 to 15 days). 
 
Baricitinib is already approved for treatment of rheumatoid arthritis. It is administered orally 
once a day, with good oral bioavailability. It has a short half-life (approximately 12 hours in RA 
patients), so treatment can be interrupted or stopped if necessary. It has few drug-drug 
interactions (due to low CYP inhibitory activity) so it can be given concomitantly with 
background therapies. Baricitinib has a well-established safety profile, based on clinical trial data 
and post-marketing data in patients with RA. This profile, together with the observation that 
baricitinib is a potent AAK1/BIKE/GAK inhibitor with known anti-cytokine effects, provide the 
rationale to study baricitinib in the context of a randomized, controlled clinical trial in patients 
with COVID-19. 
2.2 
Risk/Benefit Assessment 
 
Known Potential Risks 


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Potential risks of participating in this trial are those associated with having blood drawn, the IV 
catheterization, possible reactions to the study interventions (as noted in Section 2.3.2), and 
breach of confidentiality. 
 
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.  
 
 
Remdesivir  
 Potential Risks of Remdesivir  
Remdesivir is an investigational therapeutic agent. 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.  
 


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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 
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. 
 
 Potential Benefits of Remdesivir 
A preliminary review of data from ACTT-1 occurring after 606 recoveries and 103 deaths 
(approximately 67% of the 1063 subjects enrolled) demonstrated that subjects that received 
remdesivir had a 31% faster time to recovery (11 vs 15 days, recovery rate ratio 1.312 (1.119, 
1.541), p<0.001), and a decrease in mortality ( 8.0% vs 11.6%, p = 0.059). The DSMB asked that 
the sponsor be unblinded early given public health implications and implications for ACTT-2. As 
a result, all subjects in ACTT-2 will be given remdesivir.  
 
This is a benefit to participation, though at some point this drug may be available outside of 
clinical trials. In addition, society may benefit from their participation in this study resulting 
from insights gained about the efficacy of remdesivir combined with baricitinib, a licensed, 
readily-available drug. Determining if additional clinical benefit can be realized by combining an 
antiviral with an anti-inflammatory medication for the treatment of COVID-19 may benefit 
society during this global COVID-19 pandemic.  
 
 Assessment of Potential Risks and Benefits of Remdesivir 
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 


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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 remdesivir is currently the only therapeutic agent likely to 
effective for COVID-19, there may not be benefits for an individual subject depending on timing 
of initial infusion relative to disease onset and presence of viral replication. However, we will try 
to mitigate this risk by assessing PCR positivity for eligibility and enrolling eligible subjects in a 
timely manner. The potential risks therefore are thought to be acceptable given the potential 
benefits.  
 
 
Baricitinib 
 Potential Risks of Baricitinib 
Baricitinib is a Janus kinase (JAK) inhibitor indicated for the treatment of adult patients with 
moderately to severely active rheumatoid arthritis who have had an inadequate response to one 
or more TNF antagonist therapies.  
 
The US product labeling indicates a boxed warning for the risk of serious infections, 
malignancies and thrombosis, while warnings and precautions include serious infections, 
thrombosis, gastrointestinal perforations, abnormal laboratory assessments (potential changes in 
lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids), and avoidance with the use of 
live vaccines.  
 
The Summary of Product Characteristics (SmPC) indicates as special warning and precautions 
for infections, including TB, hematological abnormalities, viral reactivation, use of live vaccines, 
increase in blood lipid parameters, increase in hepatic transaminase, malignancy, venous 
thromboembolism, hypersensitivity, and use of baricitinib with potent immunosuppressive 
medications.  
 
Baricitinib has an established safety profile with a positive benefit/risk profile in rheumatoid 
arthritis. An integrated analysis of patients with active RA exposed to baricitinib with 3770 
patients and 10,127 patient years for a maximum exposure of 7 years (as of February 2018) was 
recently published (38). No significant differences were seen for baricitinib 4-mg vs placebo in 
adverse events leading to permanent drug discontinuation, death, malignancy, serious infection, 
or major adverse cardiovascular events. Incidence rates for deep vein thrombosis/pulmonary 
embolism were numerically higher in baricitinib 4-mg vs placebo; Incidence rates were similar 
by dose in 2-mg/4-mg-extended dataset. Malignancy (excluding non-melanoma skin cancer) 
Incidence rates were 0.8 (2-mg) and 1.0 (4-mg; as-randomized analysis). Fewer than 1% of 
patients discontinued due to abnormal laboratory results. The frequency of Herpes zoster was 
higher for baricitinib 4-mg vs placebo (1.4 vs 0.4) baricitinib 4-mg vs 2-mg (1.4 vs 1.0).  
 
It is difficult to extrapolate the potential risks of baricitinib in rheumatoid arthritis to a COVID-
19 population. The duration of baricitinib treatment will be limited to up to 14 days in this study 
and the half-life is approximately 12 hours which will lead to a very short washout period once 
discontinued. JAK–STAT signal blocking by baricitinib produces an impairment of interferon 
responses. Interferons are important for the innate control of viral replication. Thus baricitinib 


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could potentially increase viral replication (39) though this has not been described in the cases 
series of baricitinib in COVID-19.  
 
Adverse drug reactions of baricitinib include venous thromboembolism (deep vein thrombosis 
/pulmonary embolism). Mitigating the risk of venous thromboembolism will be managed 
through adding appropriate exclusion and discontinuation criteria to the protocol to limit 
participation of patients who are at an increased risk of VTE. There is evidence to suggest that 
COVID-19 patients are at increased risk of thromboembolic events from infection with SARS-
CoV-2. The etiology this may be tissue injury from the SARS-CoV-2 or may be due to 
inflammation via pro-inflammatory cytokine upregulation of tissue factor. It is unknown if 
baricitinib would increase or decrease this risk. Investigators are recommended to add VTE 
prophylaxis in all hospitalized patients given the risk of VTE. As thrombocytopenia can be seen 
in COVID-19, the risk/benefit of VTE prophylaxis should be made by the treating clinician. 
 
Baricitinib is not recommended in patients taking strong Organic Anion Transporter 3 (OAT3) 
inhibitors (probenecid in the main clinically relevant medication). Patients who take probenecid 
and are unable to discontinue it at study entry will not be eligible for the study.  
 
While baricitinib does inhibit OAT1, OAT2, OAT3, organic cation transporter (OCT) 1, OCT2, 
OATP1B3, BCRP, MATE1 and MATE2-K in vitro, clinically meaningful changes in the PK of 
drugs that are substrates for these transporters are unlikely. In vitro, baricitinib did not inhibit the 
transporters Pgp or organic anion transporting polypeptide (OATP) 1B1. Clinical drug-drug 
interaction studies showed no clinically meaningful effects on the PK of digoxin (Pgp substrate) 
or methotrexate (substrate of several transporters) when co-administered with baricitinib. 
 
Drug-drug interactions with concomitantly administered baricitinib and remdesivir are unlikely. 
In vitro, baricitinib is a substrate of cytochrome P450 (CYP) 3A and the following transporters: 
organic anion transporter (OAT) 3, P-glycoprotein (Pgp), breast cancer resistance protein 
(BCRP), and multidrug and toxic extrusion protein (MATE) 2-K. However, in vivo, baricitinib is 
primarily eliminated by the kidneys, with minimal hepatic clearance. The only clinically relevant 
drug-drug interaction observed with baricitinib is with concomitant administration of strong 
inhibitors of OAT3, such as probenecid. Available data for remdesivir does not suggest that 
remdesivir is an OAT3 inhibitor. Therefore, the potential for remdesivir to affect the 
pharmacokinetics (PK) of baricitinib is not likely.  
  
Baricitinib is also unlikely to affect the PK of other drugs, including remdesivir. Available data 
for remdesivir suggests that it is a substrate for CYP2C8, CYP2D6, CYP3A4, OATP1B1, and 
Pgp (EMA 2020). In vitro, baricitinib did not significantly inhibit or induce the activity of CYPs 
3A, 1A2, 2B6, 2C9, 2C19, and 2D6. Additionally, no clinically meaningful changes in the PK of 
several CYP3A substrates were observed when co-administered with baricitinib. Since 
baricitinib does not inhibit these particular CYPs, and transporters, a drug-drug interaction 
between baricitinib and remdesivir is unlikely.   
 
More detailed information about the known risks and reasonably expected adverse events of 
baricitinib may be found in the Investigator’s Brochure (IB).  
 


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 Potential Benefits of Baricitinib 
Baricitinib 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 agents 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 another safe, efficacious therapeutic agent can be identified during this 
global COVID-19 pandemic.  
 
 Assessment of Potential Risks and Benefits of Baricitinib 
In the context of the cumulative knowledge for baricitinib regarding the safety profile, the potential 
to mitigate the hyperinflammatory state and cytokine release syndrome (CRS) associated with 
SARS-CoV-2 and the lack of an established effective treatment for the life-threatening 
complications of COVID-19 due to CRS, the benefit/risk balance for this study is assessed to be 
favorable. 
 
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. 
 
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; 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
• 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  
 
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. 
• Days of non-invasive ventilation/high 
flow oxygen (if applicable) up to Day 29 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
 Incidence and duration of new non-
invasive ventilation or high flow 
oxygen use during the study. 
 
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 28-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 study product 
administrations (for any reason) 
• Changes in white blood cell (WBC) 
count with differential, hemoglobin, 
platelets, creatinine, glucose, total 
bilirubin, alanine aminotransferase 
(ALT), aspartate aminotransferase 
(AST), prothrombin time (PT reported 
as INR), d-dimer, and C-reactive protein 
(CRP) 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, INR, d-dimer, CRP 
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: 
 
 
 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
• 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 
ACTT-2 will evaluate the combination of baricitinib and remdesivir compared to remdesivir 
alone. 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 is 
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.  
4.2 
Scientific Rationale for Study Design 
This study utilizes an adaptive platform 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. 


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The ACTT-2 design will specifically evaluate the contributions of blocking inflammatory 
pathways (with the JAK inhibitor) while all subjects receive the antiviral remdesivir.   
 
4.3 
Justification for Dose 
 
Justification for Dose of Remdesivir 
The dose of remdesivir used in this study will be the same dose that was used in the Ebola 
clinical trials and the same dose that was used in the initial stage of this trial (ACTT-1).  
 
 
Justification for Dose of Baricitinib 
The 4-mg QD dose of baricitinib selected for this study in a patient population with COVID-19 
is based on clinical data showing an effect of baricitinib on inhibition of cytokine signaling. In 
patients with rheumatoid arthritis, the 4-mg dose of baricitinib (but not lower doses) was shown 
to significantly reduce IL-6 levels, assessed after 12 weeks of treatment. In a compassionate use 
program in pediatric patients with chronic atypical neutrophilic dermatosis with lipodystrophy 
and elevated temperature (CANDLE) syndrome, patients on a mean dose of baricitinib 6-mg QD 
showed a striking reduction in cytokine signaling. In healthy volunteers, exposures observed at 
the baricitinib 4 mg (or higher) doses are associated with reduction of IL-6 induced ex vivo 
pSTAT3 activation (40).  
 
In a vaccine response study, individuals treated with 4 mg baricitinib can mount an appropriate 
immune response to a pneumococcal vaccine, suggesting that transient exposure to baricitinib 
will not result in clinically meaningful changes to adaptive immunity (41). In addition, the choice 
of the 4-mg dose is supported by PK, safety, and efficacy data for baricitinib in Phase 2 and 
Phase 3 RA studies. The 4-mg dose of baricitinib is approved in multiple regions globally for the 
treatment of RA. In summary, the potential benefit of the 4-mg dose in reducing the 
hyperinflammatory state caused by COVID-19, and the short duration of treatment with this dose 
with a well-established safety profile, provides the rationale for the assessment of the benefit/risk 
profile of the 4-mg dose of baricitinib in the setting of a randomized, controlled clinical trial in a 
hospital setting. 
5. 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. 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 


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1. Admitted to a hospital with symptoms suggestive of COVID-19. 
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 adults ≥ 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 or ECMO. 
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 through 
Day 29. 
 
5.2 
Exclusion Criteria 
1. ALT or AST > 5 times the upper limit of normal. 
2. Estimated glomerular filtration rate (eGFR) < 30 ml/min or patient is receiving 
hemodialysis or hemofiltration at time of screening. 
3. Neutropenia (absolute neutrophil count <1000 cells/μL) (<1.0 x 103/μL or <1.0 GI/L). 
4. Lymphopenia (absolute lymphocyte count <200 cells/μL) (<0.20 x 103/μL or <0.20 
GI/L) 
5. Pregnancy or breast feeding. 
6. Anticipated discharge from the hospital or transfer to another hospital which is not a 
study site within 72 hours. 
7. Allergy to any study medication. 
8. Received three or more doses of remdesivir, including the loading dose, outside of the 
study under the EUA (or similar mechanism) for COVID-19.  
9. Received convalescent plasma or intravenous immunoglobulin [IVIg]) for COVID-19, 
the current illness for which they are being enrolled. 
10. Received small molecule tyrosine kinase inhibitors (e.g. baricitinib, imatibib, genfinitib), 
in the 1 week prior to screening  


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11. Received monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-
interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab]), or T-cells (e.g., abatacept) in 
the 4 weeks prior to screening. 
12. Received monoclonal antibodies targeting B-cell (e.g., rituximab, and including any 
targeting multiple cell lines including B-cells) in the 3 months prior to screening. 
13. Received other immunosuppressants in the 4 weeks prior to screening and in the 
judgement of the investigator, the risk of immunosuppression with baricitinib is larger 
than the risk of COVID-19.  
14. Received ≥20 mg/day of prednisone or equivalent for ≥14 consecutive days in the 4 
weeks prior to screening.  
15. Use of probenecid that cannot be discontinued at study enrollment. 
16. Have diagnosis of current active tuberculosis (TB) or, if known, latent TB treated for less 
than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history 
only, no screening required). 
17. Suspected serious, active bacterial, fungal, viral, or other infection (besides COVID-19) 
that in the opinion of the investigator could constitute a risk when taking investigational 
product. 
18. Have received any live vaccine (that is, live attenuated) within 4 weeks before screening, 
or intend to receive a live vaccine (or live attenuated) during the study. Note: Use of non-
live (inactivated) vaccinations is allowed for all subjects.  
19. Have a history of VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) 
within 12 weeks prior to screening or have a history of recurrent (>1) VTE (DVT/PE). 
20. Immunocompromised patients, patients with a chronic medical condition, or those taking 
a medication that cannot be discontinued at enrollment, who, in the judgment of PI, are at 
increased risk for serious infections or other safety concerns given the study products. 
 
 
 
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. Baricitinib has been used extensively in 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, and that neither drug has demonstrated efficacy in COVID-19, this 
research is not known to have the prospect of direct benefit to individual child participants, and 
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 
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. While baricitinib 
is a licensed drug with a known safety profile, the limited human data on use of baricitinib in 
pregnant women are not sufficient to inform a drug-associated risk for major birth defects or 
miscarriage. Because the effects on the fetus and the pregnant woman are not fully known, 
pregnant women will not be eligible for the trial.  
 


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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. 
 
There is no information available on the presence of baricitinib in human milk or the effects of 
the drug on the breastfed infant. Baricitinib is present in the milk of lactating rats. However, the 
clinical relevance of these data is not clear. Because of the potential for serious adverse reactions 
in nursing infants, 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 getting pregnant during the study from Day 1 through Day 29. 
• Agreed not to participate in another clinical trial for the treatment of COVID-19 or 
SARS-CoV-2. This includes interventional trials that evaluate treatment of SARS-CoV-2 
infection as well as the disease pathogenesis (e.g., experimental treatment trials for the 
COVID-19-related thrombo-occlusive disease respiratory complications and dysregulated 
immune response to the virus). Co-enrollment for natural history studies of COVID-19, 
studies of SARS-CoV-2 diagnostics, or strategy trials comparing different standards of 
care for non-COVID treatment (i.e. comparing two VTE prophylaxis regimens) is 
permitted; however, participation in both ACTT and these 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.  


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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. 
 
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 
 
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. 
 
 
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.  
 
 
Compensation Plan for Subjects  
Compensation, if any, will be determined locally and in accordance with local IRB requirements, 
and subject to local IRB approval.  
 
 
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  


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Subjects will be randomized into one of two arms (1:1). 
Baricitinib 
Placebo 
Remdesivir 
Arm 1 
Baricitinib tablets + 
remdesivir IV 
Arm 2 
Placebo tablets + 
remdesivir IV 
 
 
 
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 
ingredient, the lyophilized formulation of remdesivir contains the following inactive ingredients: 
water for injection, SBECD, and hydrochloric acid and/or sodium hydroxide. 
 
Baricitinib is a Janus kinase (JAK) inhibitor with the chemical name [1-(ethylsulfonyl)-3-(4-
(7Hpyrrolo(2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile and will be supplied 
in 36 count bottles. The treatment will be allocated as one bottle per subject, with some overage 
per bottle. Each tablet contains 2 mg of baricitinib and the following inactive ingredients: 
croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, ferric oxide, 
lecithin (soya), polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. 
 
Placebo tablets also manufactured by Eli Lilly and Company USA, and they contain lactose 
monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The 
coating for the placebo tablet is identical to that of the corresponding active tablet listed above. 
However, there is no lactose monohydrate in baricitinib, the active oral product. 
 
Baricitinib and placebo tablets will be supplied in 36 count bottles. The treatment will be 
allocated as one bottle per subject, with some overage per bottle.  
 
 
Dosing and Administration 
All subjects will receive remdesivir 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.  
 
If subjects already received the loading dose as under the EUA or similar mechanism, then start 
at 100 mg/day.  Any doses of remdesivir under an EUA (or similar mechanism) prior to 
enrollment will be counted, so the total duration of remdesivir (i.e. EUA + on this trial) is 10 
days (i.e., a maximum of 10 total infusions). If one or two doses of remdesivir were administered 
(under EUA or similar mechanism) prior to study enrollment, this should be documented in 
eClinical as a concomitant medication given prior to Day 1. 
 
For the baricitinib component, subjects will receive either active product or placebo as follows: 
• Baricitinib will be administered as a 4 mg orally (po) (two 2mg tablets) or crushed for 
NG tube, daily for the duration of the hospitalization up to a 14-day total course. 


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• A placebo will be given as two tablets po or crushed for NG tube, daily for the duration 
of the hospitalization up to a 14-day total course.  
 
See Section 6.1.4 for dosing modifications for renal failure. 
 
Dosing of the two medications does not need to occur at the same. 
 
Any dose that is delayed may be given later that calendar day. Any dose that is missed during the 
study due to any reason (not given that calendar day) is not made up. The treatment course 
continues as described above even if the subject becomes PCR negative.  
 
Duration of therapy: 
• IV remdesivir – 10 days while hospitalized (i.e., maximum of 10 total infusions pre-
enrollment and during study). 
• Oral (baricitinib or placebo) component – 14 days while hospitalized (i.e., maximum of 
14 total doses). 
• Both stop on discharge from hospital. If readmitted after discharge, see Section 7.4. 
 
 
Dose Escalation 
Not Applicable 
 
 
Dose Modifications 
The site should use all available laboratory values to evaluate for potential dose modifications.  
These laboratory values may be drawn as part of standard of care or protocol-required safety 
laboratories done as per the SOA.  The protocol-required safety laboratories (per the SOA) are 
anticipated to be sufficient for evaluating for most dose modifications, but if other laboratory 
data obtained as part of standard care are available, these should be also be used in the 
evaluation.  
 
 
Remdesivir component: 
If the eGFR decreases to an eGFR < 25 ml/min, the remdesivir 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, 
remdesivir will be discontinued. 
 
If the ALT and/or AST increases to > 5 times upper limits of normal, the remdesivir infusion 
should be held and not be restarted until the ALT and AST ≤ 5 times upper limits of normal. 
 
Baricitinib/Oral Placebo component: 
Dose of oral study product will be decreased based on eGFR. Specifically, subjects with eGFR 
<60 mL/min will receive a dose of one tablet (2-mg or placebo) once daily. 
 
Oral study product should be temporarily interrupted if the subject develops any of the following 
during the study but may resume when that criteria is no longer fulfilled: 


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• Total white blood cells (WBC) <1000 cells/μL  
• Absolute neutrophil count (ANC) <500 cells/μL  
• Absolute lymphocyte count (ALC) <200 cells/μL  
• ALT or AST >5 times ULN  
• Infection that, in the opinion of the investigator, merits study drug being withheld 
• eGFR < 30 mL/min, resume when eGFR returns to ≥ 30 mL/min.  
o If subject’s renal function worsens to the point that they require hemodialysis or 
hemofiltration, oral study product and remdesivir as discussed above will be 
discontinued. 
 
For laboratory values that meet permanent discontinuation thresholds, study product should be 
discontinued. However, if in the opinion of the investigator, the laboratory abnormality is due to 
intercurrent illness or another identified factor, laboratory tests may be repeated.  
 
 
Overdosage 
There is no known antidote for baricitinib. Overdose is not anticipated in the context of a clinical 
trial.  However, if a site inadvertently gives a subject 4 mg of oral study product when they 
should be receiving 2 mg because of a eGFR <60 mg/mL, the site should contact the Sponsor. 
The subject should receive supportive therapy based on the subject´s signs and symptoms. 
 
6.2 
Preparation/Handling/Storage/Accountability 
 
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) or pharmacy manual. Drug preparation will be 
performed by the participating site’s unblinded 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 investigational products.  
 
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 
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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 product can be 
destroyed on-site following applicable site procedures with a second staff member observing and 
verifying the destruction.  
Unused product at the end of the study should be saved until instructed by the Sponsor. 
 
 
Formulation, Appearance, Packaging, and Labeling 
Remdesivir component 
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: 
water for injection, SBECD, hydrochloric acid, and/or sodium hydroxide. For more information, 
refer to the MOP. 
 
Remdesivir will be labeled according to manufacturer specifications and include the statement 
“Caution: New Drug Limited by Federal (USA) Law to Investigational Use.” 
 
Baricitinib component 
According to the package insert, baricitinib tablets are available for oral administration as film-
coated, immediate-release tablets. The 2 mg tablet is light pink and oblong. Each tablet contains 
2 mg of baricitinib and the following inactive ingredients: croscarmellose sodium, magnesium 
stearate, mannitol, microcrystalline cellulose, ferric oxide, lecithin (soya), polyethylene glycol, 
polyvinyl alcohol, talc and titanium dioxide. 
 
Oral placebo component 
Placebo tablets match the active product in appearance. The placebo tablets contain lactose 
monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The 
coating for the placebo tablet is identical to that of the corresponding active tablet listed above. 
Placebo is supplied as 2 mg film-coated, in 36 count bottles, open label.  
 
Study interventions (baricitinib and placebo) will be supplied by the sponsor or its designee in 
accordance with current Good Manufacturing Practice (cGMP). 
 
 
Product Storage and Stability 


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The Pharmacy Manual provides instructions for the preparation, handling, and storage of baricitinib 
drug product and placebo, and describes site responsibility and accountability for the administered 
products.  
 
Preparation 
Refer to the protocol-specific MOP for details about preparation.  
 
Remdesivir is not considered a hazardous drug 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. Baricitinib is a “Hazardous Chemical" as defined by the 
OSHA Hazard Communication Standard, 29 CFR 1910.1200. 
 
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 
 
Randomization  
Randomization will be stratified by: 
• Site 
• Severity of illness at enrollment (by ordinal scale) 
o Severe disease:  
 Hospitalized, on invasive mechanical ventilation or ECMO, or 
 Hospitalized, on non-invasive ventilation or high flow oxygen devices. 
o Moderate disease:  
 Hospitalized, requiring supplemental oxygen, or 
 Hospitalized, not requiring supplemental oxygen. 
 
The randomization procedure will be described in the MOP.  
 
 
Blinding and Masking Procedures 
As both arms are receiving remdesivir, the remdesivir product is not blinded and study infusions 
can be labeled accordingly.  
 
The baricitinib/placebo component is blinded. Baricitinib and placebo tablets are identical in 
appearance. 
 
Unblinding of the study will occur after all subjects enrolled have reached the end of study, and 
these visits are monitored and data is cleaned, or if the DSMB recommends unblinding.  
 
If AEs occur and investigators are concerned about the treatment allocation, the treatment can be 
discontinued. If a Serious Adverse Event occurs, that is thought to be related to the study drug, 
and the treating clinician believes that knowledge of the treatment arm may change the therapy 
provided to the patient, the individual subject can be unblinded. The procedure for unblinding 
will be further detailed in the Manual of Operations. 
 


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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 
 
Permitted Concomitant Therapy and Procedures 
Receipt of any exclusionary treatments or medications prior to screening will be assessed to 
determine eligibility as described in the exclusion criteria. This includes use of strong inhibitors 
of organic anion transporter 3 (OAT3) such as probenecid which are prohibited during the study. 
 
For patients that are eligible for the study, other therapy received 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 administration of study products. However, 
these prior treatments and their end date should be documented on the Concomitant Medication 
(CCM) form in the Advantage eClinical system.  
 
There are two scenarios in which outpatient experimental treatment or off-label use of marketed 
medications that are intended as specific treatment for COVID-19 do not need to be 
discontinued. First, subjects who are taking another antiviral for a concurrent infection (e.g. 
oseltamivir for an influenza virus, lopinavir/ritonavir for HIV, etc.) or another existing medical 
condition (e.g. hydroxychloroquine for lupus, etc.) may continue with the treatment. Note that 
these treatments may be thought of as an off-label medication for COVID-19, however, because 
they were being used prior to study enrollment for another indication, they are allowable.  
Second, if there is a written policy or guideline for the local standard of care and treatment of 
COVID-19 patients or SARS-CoV-2 infection (i.e., not just an individual clinician decision), 
continuation of these outpatient medications are permitted. This could include lopinavir/ritonavir 
(Kaletra), hydroxychloroquine or other agents. There should be plans on how the concomitant 
drugs are stopped in case of additive toxicities. 
 
VTE prophylaxis is recommended for all patients unless there is a major contraindication such as 
active bleeding events or history of heparin-induced thrombosis. 
 
 
Prohibited Concomitant Therapy 
A subject cannot participate in another clinical trial for the treatment of COVID-19 until after Day 
29 (see exclusion criteria).  
 
If there are NO written policies or guidelines for local standard of care and treatment of COVID-
19 patients or SARS-CoV-2 infection, concomitant use of any other experimental treatment or 


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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. 
 
Once enrolled, use of any biologic therapy outside of local written standards of care are 
prohibited. This includes monoclonal antibodies targeting cytokines (e.g., TNF inhibitors; 
interleukin-1[IL-1], IL-6 [tocilizumab or sarilumab]), or T-cells (e.g., abatacept); monoclonal 
antibodies targeting B-cells (e.g., rituximab, and including any targeting multiple cell lines 
including B-cells); JAK inhibitor(s) other than baricitinib (e.g., imatibib, genfinitib); and 
interferon, plasma, or immunoglobulin (IgG) therapies for COVID-19.  
 
Strong inhibitors of organic anion transporter 3 (OAT3) such as probenecid are prohibited during 
the study. 
 
Corticosteroids for the treatment of COVID-19 are prohibited.  Several treatment guidelines for 
COVID-19 recommend against the routine use of systemic corticosteroids for the treatment of 
COVID-19 in hospitalized, non-critically ill patients. However, corticosteroids are permitted for 
other standard indications including asthma exacerbation, ARDS, COPD, laryngeal edema, 
adrenal insufficiency, shock, etc.   
 
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 15 or 
upon discharge, whichever comes first. Report all prescription medications taken during this time 
period. Record medications once regardless of the number of times it was given during the time 
period. For example, vasopressors or insulin should be recorded when first started (the start date) 
and end date if ended before Day 15 or discharge. Dose of medication is not recorded in 
Advantage eClinical. 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. Do not report medications that the 
subject did not actually receive during study (e.g., prn medications that were never given).  
 
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. See the MOP for more information about recording concomitant medications. 
 
 
Rescue Medicine 
Not Applicable 
 
 
Non-Research Standard of Care 
Not Applicable 
 
7. STUDY INTERVENTION DISCONTINUATION AND 


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SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Halting Criteria and Discontinuation of Study Intervention 
 
Individual Study Product Halting  
Study product administration for 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. 
For an individual subject, study product must be stopped if they have a suspected drug-related 
event of hypersensitivity (Grade 2 or higher) during or shortly after receiving the IP. While there 
are no criteria 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 the study product stopped for a safety related issues will not continue with 
dosing. In addition, subjects who have an allergic reaction that is temporally associated with study 
product administration and the PI believes it to be related to study product will not receive any 
more study product. 
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. 
 
 Remdesivir Halting 
See Section 6.1.4. for information about dosing modifications due to laboratory abnormalities. 
 
 Oral Study Product Halting 
See Section 6.1.4. for information about dosing modifications due to laboratory abnormalities. 
 
The subject should not receive any additional oral study product if they develop any of the 
following conditions during the study:  
• Active TB infection or evidence of latent TB (though testing is not required per 
protocol). 
• VTE (DVT/PE). 
• Suspected drug-induced liver injury with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
• New malignancy (except for successfully treated basal or squamous cell skin carcinoma) 
• ALT or AST >8 times ULN  
 
 
Study Halting 


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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.  
 
7.4 
Readmission  
If a subject is discharged from the hospital and then readmitted prior to Day 14, they may be 
given the remainder of the study product (i.e., infusion until Day 10 and oral product until Day 
14). If the subject did not withdrawal his/her consent to participate in the study, there is no need 
to reconsent upon readmission to the study hospital. However, the site will need to inform them 
that since he/she was readmitted, study product administration will resume and confirm that they 
still agree to receive study product. If the subject is re-admitted with diminished mental capacity, 
the site should discuss continued study participation with a LAR.  
 
The study team will need to notify the study pharmacist of the readmission. The subject will not 
get the doses that they missed after being discharged. Upon readmission, the subject will get 
maintenance doses of infusion only since they already received the loading dose of the study 
product infusion on Day 1. No study product infusions should be given past Day 10 and no oral 
study product should be given past Day 14.  
 
The site should not complete the Discontinuation of Treatment form in Advantage eClinical 
since the subject came back to the study hospital to be readmitted. For all data collection 
procedures required for those readmitted, please see the MOP.  
 
8. STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Screening and Efficacy Assessments 


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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-study product administration baseline assessments, specimen collection and 
the initial study product administration can occur on the same calendar day as the screening 
procedures.  
 
After the informed consent, the following assessments are performed to determine eligibility: 
• 
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 vaccinations within 4 weeks before screening and planned vaccinations.  
• Exclusionary vaccine history includes: 
o Has received any live vaccine (that is, live attenuated) within 4 weeks 
before screening, or intend to receive a live vaccine (or live attenuated) 
during the study. Note: Use of non-live (inactivated) vaccinations is 
allowed for all subjects.  
 
• History of chronic medical conditions, including chronic oxygen requirement, prior to 
onset of COVID-19. See conditions included in exclusion criteria (Section 5.2) and 
on the Medical History (CMX) data collection form. 
 
• History of medication allergies. 
 
• Medications and therapies for this current illness taken in the 7 days prior to Day 1, 
and history of any medication listed in the exclusion criteria. 
 
• Ask if they are participating in another clinical trial or plan to enroll in another 
clinical trial in the next 28 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. 


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• 
Blood for screening laboratory evaluations if not done as part of routine clinical care in the 
preceding 48 hours: 
 CBC with differential  
• Evaluate if subject is neutropenic (absolute neutrophil count <1000 cells/μL) 
(<1.0 x 103/μL or <1.0 GI/L) and/or lymphopenic (absolute lymphocyte count 
<200 cells/μL) (<0.20 x 103/μL or <0.20 GI/L) 
 ALT and AST 
• Assess if ALT or AST > 5 times the upper limit of normal. 
 Creatinine (and calculate eGFR).  
• Determine if eGFR < 30 ml/min as these subjects are not eligible. Also, subject 
receiving hemodialysis or hemofiltration are not eligible. 
• 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. The 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 ordinal scale and the NEWS should be done at the time 
of randomization; the site will need this data to randomize the subject in eClinical. The study 
team has 24 hours to complete other Day 1 baseline assessments prior to the first study product 
administration including the collection of OP swab and blood and completing or recording a 
baseline physical examination that was done. 
 
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. 
 
 Measures of clinical support, limitations and infection control 
The subject’s clinical status will be captured on each study day while hospitalized through Day 29 
or day after death whichever comes first. See more information about capturing death below. If a 
subject is discharged prior to Day 15, clinical status is collected on Day 15 and 29 if the subject 
returns for an in-person clinic visit or by phone if an in-person visit is not possible. Clinical status 
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 


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phone if the discharged subject is unable to return for visits on Day 15 and 29 as well as on Day 
22.  
 
Except for on Day 1, when the ordinal scale and the NEWS is captured at the time of 
randomization, a site should try to complete the ordinal scale and the NEWS at approximately the 
same time each day. Ideally, complete the ordinal scale concurrently with NEWS just prior to 
study product administration, 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. 
 
 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; 
• 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. As there should be <24 hours between randomization and infusion, the 
ordinal scale at done at randomization suffices as the Day 1 ordinal scale.  After Day 1, collect 
the ordinal scale daily while hospitalized from Day 2 through Day 29 by providing the worst 
clinical assessment for the previous day (i.e., midnight to midnight; 00:00 – 23:59 (24-hr clock)).  
For those who are discharged prior to Day 15, collect ordinal scale on follow-up Days 15, 22 and 
29 by providing 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 


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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).  
 
It is important to capture all deaths that occur during the study as this is one of the outcomes of 
the study. Death is a category on the ordinal scale.  If a subject dies during the study, the site will 
need to complete an ordinal scale assessment for the day after death. If a subject dies within the 
window of the final study visit (i.e., Day 29 ± 3 days), complete an ordinal scale assessment on 
the day after death.  
 
For more information about the data collected for the ordinal scale, see the MOP. 
 National Early Warning Score (NEWS) 
Vital signs and other clinical assessments are collected for the calculation of the NEWS, and 
include temperature, systolic blood pressure, heart rate, respiratory rate, O2 saturation and level 
of consciousness. Vital signs collected per standard of care can be used. 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 (including parameters collected prior to the time of consent) 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). ECMO and mechanically 
ventilated subjects should be assigned a score of 3 for RR (RR <8) regardless of the ventilator 
setting. Subjects on ECMO should get a score of 3 for heart rate since they are on 
cardiopulmonary bypass. 
 
Table 2. National Early Warning Score (NEWS) 


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 Level of consciousness = alert (A), and non-alert and arousable only to voice (V) or pain (P), and unresponsive 
(U).  
If the subject is on ECMO or invasive mechanical ventilation, they will be given score of 3 (≤8 RR) for 
respiratory rate regardless of ventilator setting. For subjects on ECMO, they will also receive a score of 3 
(≤40 HR) for heart rate. 
 
 
 Exploratory assessments 
 Viral Load and/or Shedding 
As outlined on the SOA, OP samples (collected by swab) 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 samples are preferred, but if these are not obtainable, nasopharyngeal (NP) samples 
(collected by NP swab) or nasal swab 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. 


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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: 
 
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 or Nasopharyngeal/nasal specimen 
• 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.  
 Cytokine Assessments 
To assess the impact of baricitinib on serum cytokine levels, blood samples will be assessed 
using a multiplex assay that is less sensitive to variability in sample integrity due to sample 
processing limitations during the pandemic. Cytokines to be tested may include (but not be 
limited to) IL-2, IL-19, IL-4, IL-10, IL-8, G-CSF, GM-CSF, MCP-1, MIP1α, IL-7, IL-13, IL-31, 
IL-15, IL-6, IFNα, IFNγ and TNFα. The list of cytokines tested is subject to change as new 
information about the pro-inflammatory state of COVID-19 is known. Given the challenges of 
obtaining samples and evolving knowledge about COVID-19, these will be considered 
exploratory endpoints. The description of the final methodology utilized, and the assay 
performance characteristics will be included in the final study report.  
8.2 
Safety and Other Assessments 


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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 study product 
administration on Day 1. The baseline physical examination can be one that is conducted from 
screening to Day 1. No routine physical exam is needed for study visits after Day 1.  
 
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, INR, d-dimer, and C-reactive protein.  
• Day 1 clinical laboratory evaluations are drawn prior to initial study product 
administration as a baseline and results do not need to be reviewed to determine if 
initial study product administration should be given. 
• Clinical laboratory testing will be performed at each clinical trial site in real time.  
 
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. 
 
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 


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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). 
 
 
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 
 
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. If multiple abnormalities are part 
of the same clinical syndrome, they can be reported together as one AE under a unifying clinical 
diagnosis.  
 
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 (baseline) 
medical condition increases above baseline to severity grade 3 or 4, it should be recorded as an 
AE. 
 
Given the nature of severity of the underlying illness, subjects will have many symptoms and 
abnormalities in vital signs and laboratory values. Only Grade 3 and 4 AEs will be captured in 
this trial. In addition, the following AEs will be reported: 
• Any Grade 2 or higher suspected drug-related hypersensitivity reactions associated with 
study product administration will be reported as an AE. 
• Any venous thromboembolism at any time during the study. 
 
Unsolicited laboratory values collected as part of standard of care, will need to be reported only 
if Grade 3 or above and only if clinically significant and/or part of a diagnosis or a clinical 
syndrome.  In this case, if laboratory and vital sign abnormalities are part of the clinical 
syndrome, they should be reported as one AE under one clinical diagnosis or 
syndrome.  Example: Low oxygen level/arterial blood gases could be part of respiratory failure 
diagnosis. 
 
Intermittent abnormal laboratory values or vital sign measurements common in the severely ill 
populations (such as electrolyte abnormalities, low blood pressure, hyperglycemia, etc.) that are 
part of the same clinical diagnosis (e.g., uncontrolled diabetic) can be recorded once with the 
worst grade for each adverse event (grade 3 and 4 only for this trial), with the start and stops 
dates of the intermittent syndrome. If there is clear resolution of the event, and then recurrence, it 
should be treated as a separate adverse event. Resolution is defined as return to baseline (either 


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normal if was normal at Day 1, or baseline (Day 1) grade if already an abnormality on the 
toxicity table at Day 1) for > 48 hours. 
 
D-dimer and CRP should not be graded. There are collected on the same schedule as the safety 
laboratory tests (see SOA). However, they will be used in the assessment of study outcomes.   
 
 
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. 
 
Grade 4 AEs (potentially life-threatening events) are not always SAEs unless they are 
imminently life threatening.  
 
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 AE CRF and reported to DMID (see Section 8.3.6). 
 
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. 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 


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A SUSAR is any SAE where a causal relationship with the study product is at least reasonably 
possible but is not listed in the Investigator Brochure (IB), Package Insert, and/or Summary of 
Product Characteristics. 
 
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. 
 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. 
 
• Potentially life-threatening event (Grade 4): Events that are potentially life threatening. 
 
 
• Deaths (Grade 5): All deaths related to an AE are classified as grade 5 (per DAIDS 
Table). 
 
 
 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. 
 


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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. 
 
 Investigator Reporting of AEs 
Information on 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. 
Any new infection that occurs on study, regardless of infecting agent (i.e., viral or non-viral) 
will be captured if it is a Grade 3 or 4 AE or SAE. Completion of the Infection Follow-up eCRF 
page is required for each infection reported as an adverse event or SAE with site of infection 
and source of culture provided, if available. The purpose is to document the occurrence of new 
infections by type of infection and not the duration of the new infections. Therefore, capture the 
first positive result(s) for the new infection (e.g., blood or urine culture, molecular diagnostic 
test result, etc.); there is no need to capture repeatedly positive results unless there is a new 
pathogen identified from the same site (e.g., blood) during the infection event. The sponsor will 
identify infections considered to be opportunistic based on Winthrop et al. 2015. 
 
Serious Adverse Event Reporting 
 Investigators Reporting of SAEs 
Any AE that meets a protocol-defined criterion as an SAE that is judged to be related to either 
study product 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. 
 
SAEs that that are judged to be not related to study product are still captured on the AE case 
report form, but do not require separate reporting to the DMID Pharmacovigilance Group. 


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 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 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. 
 
Sites may have additional local reporting requirements (to the IRB and/or national regulatory 
authority).  
 
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 
 
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. 
 
Unanticipated Problem Reporting 
To satisfy the requirement for prompt reporting, all Ups will be reported using the following 
timeline: 


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 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 
9.1 
Statistical Hypotheses 
The primary null hypothesis tests whether the time-to-recovery differs between the experimental 
and control arms.  
 
Table 4. Hypothesis tests of interest for ACTT-1 and ACTT-2 
R=remdesivir, B=baricitinib and C=placebo 
 
ACTT-1 
Primary hypothesis 
R vs C 
ACTT-2  
Primary hypothesis 
R+B vs R 
  
 
A key secondary hypothesis tests the null distribution of a similar distribution of 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 control 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. 


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The force of recovery (sometimes loosely referred to as the “recovery ratio”) is the analogue of 
the hazard ratio and the term “recovery rate ratio” is the analogue of the hazard ratio in this 
setting. A recovery rate ratio of 1.31 was 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 
preliminary review of data from ACTT-1 demonstrated a recovery rate ratio 1.312. It is unlikely 
the second component of treatment will have a similar effect size. Therefore a recovery ratio of 
1.25 is assumed for this trial. A total of 723 recoveries are needed for a recovery ratio of 1.25 
with 85% power. Table 5 provides power for various recovery rate ratios. The study will accrue 
until approximately 723 recoveries have been achieved. The date of study closure will be 
estimated based on enrollment rate and recovery/enrollment percentages.  If approximately 70% 
of participants recover, the total sample size will be 1032. 
 
Table 5. Number of recoveries needed for 85% power assuming a type I error rate of 5% 
for various recovery ratios. 
 
Recovery rate 
ratio 
(θ) 
Number of recoveries 
needed for 85% 
power 
1.20 
1080 
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 control arm and the odds ratio representing clinical improvement. The odds ratio represents 
the odds of improvement in the ordinal scale for combination treatment relative to the control 
arm [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 6 displays five scenarios considered for outcome probabilities in the control arm for 
sample size determination. There is significant uncertainty with these assumptions given the 
limited data available. Table 6 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 8 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; 


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• 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.  
 
Table 6: 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 7: Sample size calculations for scenarios in Table 6 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 8. 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 


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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. 
 
Other key secondaries for testing combination therapy compared to control will be detailed in an 
addendum SAP 
 
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 dose of any investigational product.  
 
9.4 
Statistical Analyses 
 
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.  
 
 
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 as never recovering and censored at Day 29. In ACTT2, the analyses conducted will 
depend on the results from ACTT1 according to Table 4. 
 
 
Analysis of the Secondary Endpoint(s) 
 
7) 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.  
 
8) 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% 


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confidence bounds. The same procedure will be used to compare time to at least a two-
category improvement. 
 
9) 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). 
10) Duration of event (e.g., duration of mechanical ventilation) will be summarized according 
to median days with quartiles. 
11) 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. 
12) 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. 
 
 
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 AEs will be presented 
either in a table or a listing.  
 
 
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).  
 
 
Planned Interim and Early 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 
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.  
 
 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). The unblinded statistical team will prepare these reports for 
review by the DSMB.  
 


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 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 at approximately 33%, 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.  
 
 
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, baseline 
disease severity (stratification variable of mild/moderate and severe, as well as ordinal scale of 
4/5 vs 6/7) age, race, 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. 
 
Exploratory Analyses 
An exploratory analysis will compare treatment efficacy estimates according to the various 
scales outlined in section 8.1.2. Specifically, the probability of falling into category “i” or better 
will be compared between arms for each i.  
 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS – ALL STAGES 
All supporting documentation and operational considerations are applicable to the entire 
platform trial and are not unique to the individual stages. These are therefore covered in the main 
protocol document.  
 


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COUNTRY SPECIFIC APPENDIX 
The following language applies only to Clinical Research Sites located in the United States. 
 
Public Readiness and Emergency Preparedness Act 
The drugs remdesivir and baricitinib 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 and baricitinib. 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. 

SAP_003.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 
(ACTT-2) 
 
NC04280705 
 
ACTT-2 Version 3.0 
 
DATE: 20-AUG-2020 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL  
 
 


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STUDY TITLE 
Protocol Number Code: 
DMID Protocol: 20-0006 (ACTT-2) 
Development Phase: 
Phase 3 
Products: 
Baricitinib + Remdesivir 
Remdesivir 
Form/Route: 
IV (Remdesivir) and PO (Baricitinib/Placebo) 
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: 
May 8, 2020 
Clinical Trial Completion Date: 
Trial Ongoing 
Date of the Analysis Plan: 
August 20, 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. 
 


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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 ................................................................................13 
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 Invasive Mechanical Ventilation/ECMO ......................................................15 
3.3.8. 
Days of Oxygen ..........................................................................................................15 
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 
Product Administrations .............................................................................................16 
4. 
INVESTIGATIONAL PLAN .....................................................................................17 
4.1. 
Overall Study Design and Plan ...................................................................................17 
4.2. 
Selection of Study Population ....................................................................................17 
4.2.1. 
Treatments Administered ............................................................................................17 
4.2.2. 
Identity of Investigational Product(s) .........................................................................17 
4.2.3. 
Method of Assigning Subjects to Treatment Groups (Randomization) .....................17 
4.2.4. 
Selection of Doses in the Study ..................................................................................18 
4.2.5. 
Selection and Timing of Dose for Each Subject .........................................................18 
4.2.6. 
Blinding ......................................................................................................................18 


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4.2.7. 
Prior and Concomitant Therapy ..................................................................................18 
4.2.8. 
Treatment Compliance ................................................................................................18 
4.3. 
Efficacy and Safety Variables ....................................................................................18 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................21 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................22 
6.1. 
General Principles .......................................................................................................22 
6.2. 
Timing of Analyses .....................................................................................................23 
6.2.1. 
Early Sample Size Reassessment ................................................................................23 
6.2.2. 
Interim analyses ..........................................................................................................23 
6.2.3. 
Final Analyses ............................................................................................................23 
6.3. 
Analysis Populations ..................................................................................................23 
6.3.1. 
Intention-to-Treat (ITT) and As Treated Populations ................................................23 
6.4. 
Covariates and Subgroups ..........................................................................................24 
6.5. 
Missing Data ...............................................................................................................26 
6.6. 
Interim Analyses and Data Monitoring ......................................................................27 
6.6.1. 
Interim Safety Analyses ..............................................................................................27 
6.6.2. 
Interim Efficacy Review .............................................................................................27 
6.7. 
Multicenter Studies .....................................................................................................28 
6.8. 
Multiple Comparisons/Multiplicity ............................................................................28 
7. 
STUDY SUBJECTS ...................................................................................................29 
7.1. 
Disposition of Subjects ...............................................................................................29 
7.2. 
Protocol Deviations ....................................................................................................29 
8. 
EFFICACY EVALUATION ......................................................................................30 
8.1. 
Primary Efficacy Analysis ..........................................................................................30 
8.1.1. 
Primary Analyses ........................................................................................................30 
8.1.2. 
Supplemental and Sensitivity Analyses ......................................................................31 
8.2. 
Secondary Efficacy Analyses .....................................................................................32 
8.2.1. 
Ordinal Scale Outcomes (Key Secondary Outcome Measure) ...................................32 
8.2.2. 
NEWS .........................................................................................................................33 
8.2.3. 
Days of Oxygenation ..................................................................................................33 
8.2.4. 
Incidence of New Oxygen use ....................................................................................34 


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8.2.5. 
Days of Non-Invasive Ventilation/High-Flow Oxygen ..............................................34 
8.2.6. 
Incidence of New Non-Invasive Ventilation/High-Flow Oxygen ..............................34 
8.2.7. 
Days of Invasive Mechanical Ventilation/ECMO ......................................................34 
8.2.8. 
Incidence of New Invasive Mechanical Ventilation/ECMO ......................................34 
8.2.9. 
Days of Hospitalization ..............................................................................................34 
8.3. 
Exploratory Efficacy Analyses ...................................................................................34 
9. 
SAFETY EVALUATION ..........................................................................................35 
9.1. 
Demographic and Other Baseline Characteristics ......................................................35 
9.1.1. 
Prior and Concurrent Medical Conditions ..................................................................35 
9.1.2. 
Prior and Concomitant Medications ...........................................................................35 
9.2. 
Measurements of Treatment Compliance ...................................................................36 
9.3. 
Adverse Events ...........................................................................................................36 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ....................36 
9.5. 
Pregnancies .................................................................................................................37 
9.6. 
Clinical Laboratory Evaluations .................................................................................38 
9.7. 
Vital Signs and Physical Evaluations .........................................................................38 
9.8. 
Concomitant Medications ...........................................................................................38 
9.9. 
Other Safety Measures ................................................................................................38 
10. 
PHARMACOKINETICS ...........................................................................................39 
11. 
IMMUNOGENICITY ................................................................................................40 
12. 
OTHER ANALYSES .................................................................................................41 
13. 
REPORTING CONVENTIONS ................................................................................42 
14. 
TECHNICAL DETAILS ............................................................................................43 
15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ............................................................................................44 
16. 
REFERENCES ...........................................................................................................48 
17. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..............................................49 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................50 
APPENDIX 2. FIGURE MOCK-UPS ......................................................................................101 
APPENDIX 3. LISTINGS MOCK-UPS ...................................................................................124 
 


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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  
RDV 
Remdesivir 


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RNA 
Ribonucleic Acid 
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 
 


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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 the study’s 2nd stage 
“ACTT-2”: Baricitinib + Remdesivir vs. Remdesivir. 
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 Food and Drug 
Administration (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. 
 


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2. 
INTRODUCTION 
A preliminary review of data from ACTT-1 occurring after 606 recoveries and 103 deaths 
(approximately 67% of the 1063 subjects enrolled) demonstrated that subjects that received 
remdesivir had a 31% faster time to recovery (11 vs 15 days, recovery rate ratio 1.312 (1.119, 
1.541), p<0.001), and a decrease in mortality (8.0% vs 11.6%, p = 0.059). The Data and Safety 
Monitoring Board (DSMB) asked that the sponsor be unblinded early given public health 
implications and implications for ACTT-2. While an antiviral appears to have some efficacy in 
the treatment of COVID-19, the mortality rate is still high. Infection by pathogenic coronaviruses 
(e.g. SARS and SARS-CoV–2) often results in excessive cytokine and chemokine action with 
the development of acute respiratory distress syndrome (ARDS). It is postulated that this 
dysregulated inflammatory immune response is contributing to the excessive mortality and 
targeting this response will further improve outcomes.  
Baricitinib, an orally administered, selective inhibitor of Janus Kinase (JAK)1 and JAK2, could 
be a therapeutic option because of the potential to inhibit signaling from multiple cytokines in 
COVID-19 patients. Baricitinib inhibits signaling of cytokines implicated in COVID-19, 
including interleukin (IL) IL-2, IL-6, IL-10, Interferon gamma (IFN-γ), and Granulocyte colony-
stimulating factor (G-CSF), with lower IC50 values translating to a greater overall inhibition of 
STAT signaling during the dosing interval. Baricitinib treatment resulted in a reduction from 
baseline in serum IL-6 at Week 12 in patients with active rheumatoid arthritis (RA) in a Phase 2, 
randomized, placebo-controlled study of baricitinib (data on file). The potent anti-inflammatory 
effects of baricitinib have also been demonstrated by the reduction of serum levels of IFN-γ, IP-
10, Granulocyte-macrophage colony-stimulating factor (GM-CSF) and monocyte 
chemoattractant protein (MCP-1) in pediatric patients with steroid-dependent chronic 
inflammation, resulting in control of disease activity and the ability to wean or taper steroids.  
Baricitinib is already approved for treatment of rheumatoid arthritis. It is administered orally 
once a day, with good oral bioavailability. It has a short half-life (approximately 12 hours in RA 
patients), so treatment can be interrupted or stopped if necessary. It has few drug-drug 
interactions (due to low CYP inhibitory activity) so it can be given concomitantly with 
background therapies. Baricitinib has a well-established safety profile, based on clinical trial data 
and post-marketing data in patients with RA. This profile, together with the observation that 
baricitinib is a potent AAK1/BIKE/GAK inhibitor with known anti-cytokine effects, provide the 
rationale to study baricitinib in the context of a randomized, controlled clinical trial in patients 
with COVID-19. 
2.1. 
Purpose of the Analyses 
This SAP encompasses all interim analyses and the final analysis of primary and secondary 
outcome measures. These analyses will assess the efficacy and safety of baricitinib + remdesivir 
in comparison with remdesivir 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 33% 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 


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to recommend whether the current study arm should proceed or to stop early for benefit or 
futility. 
This SAP describes the planned analysis to be conducted by the Investigational New Drug (IND) 
sponsor NIAID. Additionally, there will be a separate analysis by the Manufacturer, Lilly USA, 
in which Lilly will: 
• Define key secondary endpoints that will be tested with adjustments for multiple 
comparison.  The adjustment is through a graphical testing scheme that controls for 
family-wise type I error;  
• Pre-specify details of handling of intercurrent events including imputation procedures; 
• Define additional analysis of time-to-event data that account for competing risk; 
• Define additional safety analysis will also be pre-specified in the Addendum SAP 
These analyses are useful to the manufacturer for regulatory purposes and will be pre-specified 
in an Addendum to this SAP.   


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
Primary Objective 
To evaluate the clinical efficacy, as assessed by time to recovery, of different investigational 
therapeutics as compared to the control arm. 
Secondary Objectives 
The key secondary objective is 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 clinical 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: 
 Oxygenation use up to Day 29. 
 Incidence and duration of new oxygen use through 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 
through 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 through Day 
29.  


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• 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 study product administrations (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 reported as INR), d-dimer, and C-reactive protein 
(CRP) 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; 
4. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 


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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 differentials, hemoglobin, platelets, creatinine, glucose, total bilirubin, ALT, 
AST, INR, d-dimer, and CRP 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 on trial. 
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 


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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. Such cases will be reviewed by the NIAID Medical 
Officer to make the determination of whether the subject should be considered recovered in 
analyses. Subject data to be reviewed as part of this determination will include the reported 
clinical status scores while hospitalized, where the subject was discharged to (e.g. private 
residence, rehabilitation facility, long-term care/nursing home), and any information regarding 
readmittance.  
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 for COVID-19 will not be considered a recovery 
but will instead be censored at 28 days.  
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. 
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 
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 


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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. 
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 Post-Discharge Supplemental Oxygen 
CRF questions regarding days of non-invasive ventilation or high-flow oxygen 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 Invasive Mechanical Ventilation/ECMO 
Invasive Mechanical Ventilator / ECMO days will be defined as the number of days where the 
clinical status score is equal to 7. After discharge, the Post-Discharge Supplemental Oxygen 
CRF questions regarding days of ECMO or invasive 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. 
3.3.8. 
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 Post-Discharge Supplemental Oxygen CRF question regarding days 
of oxygenation (including ECMO, invasive ventilation, non-invasive ventilation, high-flow 
oxygen devices, and all other oxygen delivery devices) 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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3.3.9. 
Days of Hospitalization 
Duration (in days) of hospitalization will be defined as the number of days subject is hospitalized 
for COVID-19-related reasons starting from the date of randomization. It will be calculated as 
the total number of days hospitalized, including readmissions for COVID-19-related reason. 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. 
3.3.11. 
Composite Endpoint of Death, SAEs, Severe AEs, Discontinuation of Study 
Product Administrations 
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 29 visit.  


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
ACTT-2 will evaluate the combination of baricitinib and remdesivir compared to remdesivir 
alone. 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 is 
conducted by phone. 
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.  
See Section 5.1 and 5.2 of Appendix B of the study protocol for the full list of inclusion and 
exclusion criteria. 
4.2.1. 
Treatments Administered  
All subjects will receive remdesivir 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.  
For the baricitinib component, subjects will receive either active product or placebo as follows: 
• Baricitinib will be administered as a 4 mg orally (po) (two 2mg tablets) or crushed for 
NG tube, daily for the duration of the hospitalization up to a 14-day total course. 
• A placebo will be given as two tablets po or crushed for NG tube, daily for the duration 
of the hospitalization up to a 14-day total course. 
4.2.2. 
Identity of Investigational Product(s) 
See Section 6.1.1 of Appendix B of the study protocol. 
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 baricitinib + remdesivir 
or remdesivir, with stratification by site and disease severity by ordinal scale (Moderate disease 
[4 or 5 on the ordinal scale] or Severe disease [6 or 7 on the ordinal scale]). 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. 


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4.2.4. 
Selection of Doses in the Study 
The dose of remdesivir used in this study will be the same dose that has been used in the human 
Ebola clinical trials.  
4.2.5. 
Selection and Timing of Dose for Each Subject 
See Sections 6.1.2 through 6.1.5 of Appendix B of the study protocol. 
4.2.6. 
Blinding 
As both arms are receiving remdesivir, the remdesivir product is not blinded and study infusions 
can be labeled accordingly.  
The baricitinib/placebo component is blinded. Baricitinib and placebo tablets are identical in 
appearance. 
Unblinding of the study will occur after all subjects enrolled have reached the end of study, and 
these visits are monitored and data is cleaned, or if the DSMB recommends unblinding.  
If AEs occur and investigators are concerned about the treatment allocation, the treatment can be 
discontinued. If a Serious Adverse Event occurs, that is thought to be related to the study drug, 
and the treating clinician believes that knowledge of the treatment arm may change the therapy 
provided to the patient, the individual subject can be unblinded. The procedure for unblinding 
will be further detailed in the Manual of Procedures (MOP). 
4.2.7. 
Prior and Concomitant Therapy  
See Section 6.5.1 of Appendix B of the study protocol for permitted concomitant therapy and 
procedures. See Section 6.5.2 of Appendix B of the study protocol for prohibited concomitant 
therapies. 
4.2.8. 
Treatment Compliance 
See Section 6.1.4 of Appendix B of the study protocol for details on dose modifications. 
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). 
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 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; 


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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; 
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 Section 8.1.2.3 in Appendix B of the study protocol). 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. 
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 study product administration (for any reason) 


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• Changes in white cell count, absolute neutrophil count, hemoglobin, platelets, creatinine, 
glucose, total bilirubin, ALT, AST, and INR, d-dimer, C-reactive protein 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). 
To assess the impact of baricitinib on serum cytokine levels, blood samples will be assessed 
using a multiplex assay that is less sensitive to variability in sample integrity due to sample 
processing limitations during the pandemic. Cytokines to be tested may include (but not be 
limited to) IL-2, IL-19, IL-4, IL-10, IL-8, G-CSF, GM-CSF, MCP-1, MIP1α, IL-7, IL-13, IL-31, 
IL-15, IL-6, IFNα, IFNγ and TNFα. The list of cytokines tested is subject to change as new 
information about the pro-inflammatory state of COVID-19 is known. Given the challenges of 
obtaining samples and evolving knowledge about COVID-19, these will be considered 
exploratory endpoints. The description of the final methodology utilized, and the assay 
performance characteristics will be included in the final study report. 
The schedule of study procedures is provided in Section 1.2 of Appendix B of the study protocol. 


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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. 
The force of recovery (sometimes loosely referred to as the “recovery ratio”) is the analogue of 
the hazard ratio and the term “recovery rate ratio” is the analogue of the hazard ratio in this 
setting. A recovery rate ratio of 1.31 was 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 
preliminary review of data from ACTT-1 demonstrated a recovery rate ratio 1.312. It is unlikely 
the second component of treatment will have a similar effect size. Therefore, a recovery ratio of 
1.25 is assumed for this trial. A total of 723 recoveries are needed for a recovery ratio of 1.25 
with 85% power. The study will accrue until approximately 723 recoveries have been achieved. 
The date of study closure will be estimated based on enrollment rate and recovery/enrollment 
percentages. If approximately 70% of participants recover, the total sample size will be 1032. 
See Section 9.2 of Appendix B of the study protocol for discussions on the sample size 
calculations for the key secondary outcome.  


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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 remdesivir+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=RemdesivirLabel); 
   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=ModerateLabel)  
   TreatmentVariable(param=ref ref=RemdesivirLabel); 
   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. The summaries to be generated for the interim analysis are provided in 
the separate DSMB shell report. 
6.2.3. 
Final Analyses 
The final analyses of all outcomes and planned summaries/listings will be performed on the final 
full locked database and provided in the final report. 
6.3. 
Analysis Populations 
Summaries and analysis of safety data will be presented for the As Treated Population. 
Summaries and analysis of efficacy data will be presented for the intent-to-treat (ITT) population 
and As Treated population.  
6.3.1. 
Intention-to-Treat (ITT) and As Treated Populations 
The intent-to-treat (ITT) population includes all subjects who were randomized. For ITT 
analyses, subjects will be classified by their randomized treatment assignment and randomized 
disease severity stratum. 
The As Treated population includes all randomized subjects who received the baricitinib/placebo 
study product, even if only one tablet was administered. 
For As Treated analyses of efficacy outcomes, subjects will be classified by their actual 
treatment assignment and randomized disease severity stratum. Note that if no subjects are 


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administered the incorrect treatment, the As Treated efficacy analysis will not be performed as 
they will be identical to the ITT analyses.   
For As Treated analyses of safety outcomes, concomitant medications, and medical history, 
subjects will be classified by their actual treatment assignment and actual disease severity 
stratum.   
Note that per Section 6.4, subgroup analyses of outcomes will classify subjects by randomized 
(for safety outcomes) and actual (for efficacy outcomes) severity strata. 
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),  
• Severity of disease  
o Randomization stratification: Moderate (ordinal 4/5); Severe (ordinal 6/7).  
o Actual disease severity at baseline: Moderate (ordinal 4/5); Severe (ordinal 6/7) 
Note these analyses will only be performed if at least one subject is erroneously 
randomized into the incorrect disease severity stratum. 
o Baseline ordinal scale category: 4; 5; 6; 7 
Additionally, main analyses of all secondary efficacy outcomes will evaluate the treatment effect 
across the following subgroups: 
• Duration of symptoms prior to enrollment (<= Median; > Median) 
• Severity of disease  


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o Randomization stratification: Moderate (ordinal 4/5); Severe (ordinal 6/7).  
o Actual disease severity at baseline: Moderate (ordinal 4/5); Severe (ordinal 6/7) 
Note these analyses will only be performed if at least one subject is erroneously 
randomized into the incorrect disease severity stratum. 
o Baseline ordinal scale category: 4; 5; 6; 7 
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. A blinded review of the concomitant medication data will be performed 
by the medical monitor to identify medications that fall into any of the following categories of 
“Medications of Interest”: 
• Antivirals 
o Protease inhibitors 
o Polymerase inhibitors 
• Potential Treatments for COVID-19 
o Hydroxychloroquine/Chloroquine 
o Other 
• Corticosteroids 
• Other anti-inflammatory drugs 
o Monoclonal Antibodies Targeting Cytokines 
o Other Biologic Therapies 
Summaries of subjects who report use of the categories and subcategories of therapies/treatments 
will be provided.  Note that after the blinded review of the medications, additional 
categories/sub-categories may be defined and/or categories/sub-categories may be combined. 
In addition, the sensitivity analyses will consider the following categories (individually): 
• Any Medication of Interest 
• Hydroxychloroquine/Chloroquine 
• Corticosteroids 
• Other Anti-Inflammatory Drugs 
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. 


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In addition, the effect of treatment on the primary and key secondary efficacy outcomes will be 
explored via regression modeling controlling for age, duration of symptoms prior to enrollment, 
baseline d-dimer, and baseline CRP values 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. If a 
subject terminates early from the study while they are hospitalized or completes the study while 
still hospitalized, the last observed clinical score assessment will be used as their final 
assessment. 
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 
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. 


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• 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 
An interim efficacy analysis will be conducted after approximately 33% of total information has 
been reached. The information fraction at an interim analysis will be computed as 𝑡𝑡= 𝑟𝑟/723 
where 𝑟𝑟 is the number of recoveries by the time of the data freeze date for the interim analysis. 
The Lan-DeMets spending function analog of the O’Brien-Fleming boundary will be used to 
monitor the 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. 


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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 session 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 may be provided to the DSMB prior to interim analyses.  
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 1). 
The composition of analysis populations, including reasons for subject exclusion will be 
summarized by treatment group and disease severity (Table 2). A subject listing of analysis 
population eligibilities will be generated (Listing 1). 
The disposition of subjects will be tabulated by treatment group and disease severity (Table 3). 
Study milestones included in the table will include, but not limited to: the total number of 
subjects that were randomized, completed expected blood draws, completed Study Day 15 visit, 
completed Study Day 22 visit, and completed Study Day 29 visit. For the calculation of 
percentages, subjects who die will not be included in the denominators for visits/assessments 
beyond their death.   
Treatment compliance will be summarized by treatment group (Table 4). Summaries of prior 
Remdesivir treatment by treatment group will also be provided (Table 5 and Table 6) 
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.  
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) geographic region for all 
subjects (Table 7 and Table 8). Supplementary protocol deviation summaries will also be 
generated (e.g. major deviations, non-subject specific deviations). 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 
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 
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 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 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 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 analysis. 
For the final analysis, 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 analysis. 
 
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 
             infoadj=prop 
             boundaryscale=score 
             ; 


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   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 final analysis. 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 15). 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 may or may not 
be reported, and 95% confidence levels will be used for confidence interval estimates.  
The primary analysis will be repeated in the As Treated analysis population where subjects who 
are not treated will be censored at enrollment. The tabular and graphical summaries described in 
the previous section will be replicated for this As 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 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. As 
requested by the DSMB, a restricted mean survival time analysis will be performed as an 
exploratory analysis. The restricted mean recovery time estimates will be provided for each 
treatment group and randomized disease severity stratum as well as the difference in restricted 
mean recovery time between treatment groups within each of the severity strata (Table 18). Time 
to recovery will also be explored within prior Remdesivir treatment subgroups (Any Treatment 
vs. No Treatment) (Table 19). 
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 


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and duration of symptoms as continuous covariates and baseline d-dimer and CRP values 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 (Table 20 and Table 21). These 
analyses will be performed in the ITT and As Treated populations.  
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.  
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 24). 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. As 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 
with the p-value (Table 25). The Study Visit Day 15 clinical status score will be depicted 
graphically using shifted bar plots; the outcomes will be presented by baseline ordinal score and 
treatment group (Figure 13). In addition to the subgroup analyses, the main analysis will be 


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repeated including a treatment * disease severity interaction term, where the interaction term p-
value will be reported for the interaction model. 
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 27). Differences in time-to-event endpoints by treatment arm will be summarized with 
Kaplan-Meier curves (Figure 16). 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. 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. 
The above analyses will be repeated with the modification to the ordinal scale described in 
Section 4.3 (Table 28). 
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 33). Change from baseline will also be summarized at Days 3, 5, 7, 
11, 15, 22, and 29 (Table 35). A figure will present stacked bar charts by day with side by side 
bars for each treatment arm (Figure 25). Histograms will be generated to display the ordinal scale 
value distributions over time in each treatment group (Figure 26). 
8.2.2. 
NEWS 
The median time to discharge or to a NEWS of ≤ 2 and CI will be summarized by treatment 
group (Table 37). 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 27).  
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 40). A figure with mean and 
SD over time will also be presented by treatment arm (Figure 32). 
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 42). This will only include subjects in category 5, 6, or 7 at randomization. 
Analyses will be performed in the ITT and As Treated populations. Bee swarm plots of oxygen 
days by treatment arm will be generated, where subjects whose days are imputed to the 
maximum of 28 days due to death are grouped separately from subjects who do not die 
(Figure 33). 


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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 randomization. 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 at 
randomization. Analyses will be performed in the ITT and As Treated populations. Bee swarm 
plots of non-invasive ventilation/high flow oxygen days by treatment arm will be generated, 
where subjects 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 randomization. 
New use will be identified by a post-enrollment score of 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 
randomization. Analyses will be performed in the ITT and As Treated populations. Bee swarm 
plots of invasive Mechanical Ventilation/ECMO days, and days hospitalized by treatment arm 
will be generated, where subjects 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 Invasive Mechanical Ventilation/ECMO 
The incidence and duration of new Invasive Mechanical Ventilation/ECMO use will be analyzed 
by treatment arm. This will only include subjects in category 4, 5, or 6 at randomization. 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. Incidence of readmittance will also be summarized (Table 48). Analyses will be 
performed in the ITT and As Treated population. Bee swarm plots of days hospitalized by 
treatment arm will be generated, where subjects 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, comorbidities, duration of symptoms prior to enrollment, and 
disease severity (Table 50 and Table 51). 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.  
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: 
• History of chronic medical conditions related to inclusion and exclusion criteria 
• Review medications and therapies for this current illness. 
Medical history is limited to the following conditions: asthma, cancer, cardiac valvular disease, 
chronic kidney disease, chronic liver disease, chronic oxygen requirement, chronic respiratory 
disease, coagulopathy, congestive heart failure, coronary artery disease, current nicotine 
consumption, diabetes I and II, hypertension, immune deficiency, obesity, and risk for deep vein 
thrombosis (DVT) or pulmonary embolism (PE). All current illnesses and past pre-existing 
medical conditions will be MedDRA® coded using MedDRA dictionary version 23.0 or higher. 
Summaries of subjects’ pre-existing medical conditions will be presented by treatment group 
(Table 52). 
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 15 or early 
termination (if Day 15), whichever occurs first.  
Summaries of medications that were started prior to dosing and continued at the time of dosing 
or started after dosing while on study will be presented by WHO Drug Level 1 and 2 Codes, 
disease severity, and treatment group (Table 53). Summaries of overall use of prohibited 
medications/therapies listed in Section 6.4 that were started prior to dosing and continued at the 
time of dosing or started after dosing while on study as well as use by select study days will also 
be generated (Table 54 and Table 55). 
Individual subject listings will be presented for all concomitant medications (Listing 9). 


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9.2. 
Measurements of Treatment Compliance 
Table 4 will provide summaries of key treatment compliance milestones/variables. 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, but not limited to: 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 56 and 
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: 
• Treatment-emergent renal adverse events by preferred term (Table 61); 
• Treatment-emergent hepatic adverse events by preferred term (Table 62); 
• Related adverse events by MedDRA system organ class and preferred term (Table 63); 
• 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 37); 
• Bar chart of non-serious related adverse events by maximum severity and MedDRA 
system organ class (Figure 40); 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse 
Events 
Listings of death and other serious adverse events will be presented, including Subject ID, 
treatment group, Adverse Event Description, Number of Days Post Dose (Duration), Number of 
Days Post Dose the Event Became Serious, Reason Reported as an SAE, Severity, Relationship 


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to Treatment, Alternate Etiology if not Related, Action Taken with Study Treatment, Subject 
Discontinuation, Outcome, MedDRA SOC, and MedDRA PT (Listing 14 and Listing 16).  
The number of subjects who die by Day 15 and Day 29 will be presented by treatment arm. The 
14- and 28-day mortality rate, which will use Kaplan-Meier estimator, will be presented 
(Table 64).  
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 66). Differences in time-to-event endpoints by treatment will be summarized with 
Kaplan-Meier curves (Figure 44). Analyses of mortality will be performed in the ITT and the 
Treated analysis populations. As a supplemental analysis, a Cox model will be fit with binary 
indicators for treatment group and disease severity as well as a treatment * disease severity 
interaction term. The model will be fit in the ITT and Treated analysis populations. The 
treatment group hazard ratios and CIs and the interaction term p-value will be reported. Finally, 
the results of the sensitivity time-to event analysis described in Section 6.4 will be presented in a 
table; the same summaries as in Table 66 will be provided. As requested by the DSMB, a 
restricted mean survival time analysis of mortality will be performed as an exploratory analysis.  
The restricted mean mortality time estimates will be provided for each treatment group and 
randomized disease severity stratum as well as the difference in restricted mean recovery time 
between treatment groups within each of the severity strata (Table 72). 
Rates of Grade 3 and 4 AE occurrence will be compared between treatment arms using 
Barnard’s exact test and presented. 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 73). Differences in time-to-event endpoints by treatment will be summarized with 
Kaplan-Meier curves. 
A summary of the infections reported on the AE CRF will be summarized by treatment group 
and disease severity (Table 74 ). The anatomical location(s) of the infection and causative 
pathogen(s) determined by culture will be summarized. Infections considered to be opportunistic, 
as identified by the sponsor, will also be included in the summaries. 
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, and Listing 18). 


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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, INR, d-dimer, and CRP. 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 80). 
Treatment-emergent laboratory abnormalities will be summarized by parameter and grade 
(Table 83). 
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 84). 
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 53).  
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 9). The use of concomitant medications during the study (regardless of whether the 
medications were started prior to enrollment or after enrollment) will be summarized by ATC1, 
ATC2 code, disease severity and treatment group for the Treated population (Table 53).  
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, median, IQR, and other statistics will be reported to 1 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. hazard ratios and 
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 below summarizes the changes made to the SAP from version 2.0 to version 3.0: 
In performing the final analyses of the ACTT-1 data, multiple tabular and graphical output 
required modifications from the shells provided in the ACTT-1 SAP to fixes errors, make 
clarifications, and provide additional supplementary information.  After review of the analyses 
for ACTT-1, multiple ad-hoc analyses were also performed as requested by the sponsor, 
manufacturer, and FDA. In addition, exploratory analyses of the primary outcome were 
requested by the ACTT-2 DSMB. The modifications to the ACTT-1 shells as well as the 
additional analyses requested for ACTT-1 has been added to this version of the ACTT-2 SAP. 
The additional analyses are all supplemental exploratory analyses and were not driven by review 
of the ACTT-2 data but were added to provide consistent analyses and summaries across the 
individual ACTTs. 
The additional summaries were added to the TFL appendices of this SAP; general updates were 
made to the corresponding text within the body of the document, however granular details of 
each new output were not necessarily added.  Note that in adding the additional TFLs, a large 
number of the existing TFLs were renumbered to conform to eCTD guidelines. 
Throughout the document: 
• Typos and errors introduced via copying/pasting language from other sections were 
corrected. 
• The Treated Population was renamed as the “As Treated Population”. 
• It was clarified that analyses that explore and/or incorporate readmittance will only 
consider readmittances for COVID-19 reasons. 
Section 6.3.1: 
• The definitions of the analysis populations were clarified to explicitly denote when the 
randomized treatment assignment or disease severity stratum would be used versus the 
actual treatment group or disease severity. TFL shells were updated to explicitly state 
whether randomized or actual group/severity will be used. 
Section 6.4: 
• The process for identifying the medications of interest and the categories of medications 
were updated to match what was used for ACTT-1. Corresponding TFLs were updated 
accordingly. 
Appendices: 
• Multiple TFLs were updated to fix omissions/errors and provide additional programming 
notes. 
• The formatting of multiple TFLs was updated to provide better organized and/or more 
clear displays of the content. 


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Table 3: 
• Included summaries and format was updated to match those used for the corresponding 
final ACTT-1 table. 
Table 4: 
• Replaced the term “Completed” with “Received” for infusion summaries throughout. 
• Summaries of prior RDV treatment were added. 
Table 5 and Table 6: 
• Multiple additional protocol deviation tables were added to match those generated for 
ACTT-1. 
Table 16 and Table 17: 
• Ad-hoc Fine-Gray, Covariate-Adjusted, and Interaction Modeling analyses of time to 
recovery were added to match those performed for ACTT-1. 
Table 18: 
• Restricted Mean Survival Time analysis of time to recovery was added per request by the 
ACTT-2 DSMB. 
Table 19: 
• Ad-hoc analysis of time to recovery by prior RDV treatment was added. 
Table 35 and Table 36: 
• Summaries of clinical status score at individual time points was added to match those 
generated for ACTT-1. 
Table 42, Table 43, Table 44, Table 45, Table 46, Table 47: 
• Tables were updated to provide additional summaries which were provided in the ACTT-
1 final analyses. 
Table 51: 
• IQR was added to match the addition to the corresponding table in ACTT-1. 
Table 56 and Table 57: 
• Additional key safety event categories were added to the table as was requested for 
ACTT-1. In addition, a table summarizing the risk difference of a subset of these events 
(difference between treatment groups) was added per request for ACTT-1. 
Table 61, Table 62, Table 63: 
• Additional summaries of adverse event data were added to match the additions to the 
ACTT-1 final analyses, including renal AEs, hepatic AEs, and related AEs. 
Table 64, Table 65, Table 66, Table 67: 
• Disease Severity was added to the tabular summaries. 


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Table 71: 
• Restricted Mean Survival Time analysis of time to death was added per request by the 
ACTT-2 DSMB. 
Table 75, Table 77, Table 79 : 
• Opportunistic infection summaries were added; shells were erroneously omitted from 
previous versions of the SAP. 
Table 80, Table 81, Table 82, Table 83: 
• A column for Grade 3 or 4 was added as the column was added to the corresponding 
ACTT-1 table. In addition, disease severity-specific summaries and summaries of 
treatment-emergent laboratory abnormalities were added, as similar summaries were 
generated for ACTT-1. 
Table 85 and Table 86:  
• Disease severity-specific summaries were added. 
Figure 6, Figure 7, Figure 8, Figure 9: 
• Figures displaying time to recovery Kaplan-Meier curves within subgroups defined by 
baseline ordinal score were added to match the figures generated for ACTT-1. 
Figure 12: 
• Forest plot of the hazard ratios of time to recovery by comorbidity was added to match 
the figure generated for ACTT-1. 
Figure 17, Figure 18, Figure 19, Figure 20, Figure 21, Figure 22, Figure 23, Figure 24: 
• Figures displaying time to improvement Kaplan-Meier curves within subgroups defined 
by baseline ordinal score were added to match the figures generated for ACTT-1. 
Figure 28, Figure 29, Figure 30, Figure 31: 
• Figures displaying time to discharge or NEWS <=2 Kaplan-Meier curves within 
subgroups defined by baseline ordinal score were added to match the figures generated 
for ACTT-1. 
Figure 44 and Figure 46: 
• Figures displaying time to death Kaplan-Meier curves within subgroups defined by 
disease severity and baseline ordinal score were added to match the figures generated for 
ACTT-1. 
Figure 47, Figure 48, Figure 49, Figure 50: 
• Figure displaying time to death Kaplan-Meier curves within subgroups defined by 
disease severity was added. 


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The below summarizes the changes made to the SAP from version 1.0 to version 2.0: 
Throughout the document: 
• Typos and errors introduced via copying/pasting language from other sections were 
corrected. 
Section 3.3.2: 
• Language was added to the definition of recovery to note that subjects who are 
discharged to another hospital, hospice, or similar health care institution will not be 
considered recovered. 
Section 6.4: 
• The Prohibited Medications that are being explored in sensitivity analyses were renamed 
“Medications of Interest”.  Corresponding tables and listings were updated accordingly. 
Section 6.5: 
• Language was added to the imputation rules for clinical scores to note that if a subject 
terminates early from the study while they are hospitalized or completes the study while 
still hospitalized without a reported clinical score on the day of discharge, the last 
observed clinical score assessment will be used as their final assessment. 
Section 9.4: 
• A supplemental analysis of the time to death outcome was added to explore the 
interaction between treatment and baseline disease severity with respect to the effect of 
treatment on the outcome. 
Appendices: 
• Multiple tables and listings were updated to fix omissions/errors and provide additional 
programming notes. 


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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: 
Ineligibility Summary of Screen Failures ...................................................................55 
Table 2: 
Analysis Population Eligibilities by Treatment Group and Randomized 
Disease Severity ..........................................................................................................56 
Table 3: 
Subject Disposition by Treatment Group and Randomized Disease Severity 
– ITT Population .........................................................................................................57 
Table 4: 
Treatment Compliance by Treatment Group ..............................................................58 
Table 5: 
Subjects Reporting Prior Remdesivir Treatment by Randomized Disease 
Severity and Treatment Group – ITT Population .......................................................60 
Table 6: 
Subjects Reporting Prior Remdesivir Treatment by Actual Disease Severity 
and Treatment Group – As Treated Population ..........................................................60 
Table 7: 
Distribution of Subject Specific Protocol Deviations by Category, Type, 
Treatment Group, and Randomized Disease Severity ................................................61 
Table 8: 
Distribution of Subject Specific Protocol Deviations by Category, Type, and 
Geographic Region .....................................................................................................63 
Table 9: 
Distribution of Major Subject Specific Protocol Deviations by Category, 
Type, Treatment Group, and Randomized Disease Severity ......................................63 
Table 10: Distribution of Major Subject Specific Protocol Deviations by Category, 
Type, and Geographic Region ....................................................................................63 
Table 11: Distribution of Non-Subject Specific Protocol Deviations by Category and 
Type ............................................................................................................................63 
Table 12: Distribution of Non-Subject Specific Protocol Deviations by Category, 
Type, and Geographic Region ....................................................................................63 
Table 13: Distribution of Major Non-Subject Specific Protocol Deviations by Category 
and Type .....................................................................................................................63 
Table 14: Distribution of Major Non-Subject Specific Protocol Deviations by 
Category, Type, and Geographic Region ...................................................................63 
Table 15: Time to Recovery by Treatment Group and Randomized Disease Severity ..............64 
Table 16: Time to Recovery by Treatment Group and Randomized Disease Severity: 
Fine-Gray, Covariate-Adjusted, and Interaction Modeling ........................................64 
Table 17: Time to Recovery by Treatment Group and Baseline Ordinal Score: Fine-
Gray and Interaction Modeling ...................................................................................64 
Table 18: Time to Recovery by Treatment Group and Disease Severity: Restricted 
Mean Survival Time Analysis – ITT Population ........................................................65 


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Table 19: Time to Recovery by Treatment Group within Prior RDV Treatment 
Subgroups ...................................................................................................................65 
Table 20: Time to Recovery by Treatment Group within Subgroups – ITT Population ............66 
Table 21: Time to Recovery by Treatment Group within Subgroups – As Treated 
Population ...................................................................................................................66 
Table 22: Time to Recovery by Treatment Group and Randomized Disease Severity: 
Readmittance Sensitivity Analysis – ITT Population .................................................66 
Table 23: Time to Recovery by Treatment Group and Randomized Disease Severity: 
Medications of Interest Sensitivity Analysis – ITT Population ..................................66 
Table 24: Summary of Recoveries and Deaths by Day 29 – ITT Population .............................67 
Table 25: Odds Ratio for Better (Lower) Clinical Status Score at Study Visit Day 15 
by Treatment Using a Proportional Odds Model, Baricitinib + RDV Relative 
to Placebo + RDV – ITT Population ..........................................................................68 
Table 26: Odds Ratio for Better (Lower) Clinical Status Score at Study Visit Day 15 
by Treatment Using a Proportional Odds Model, Baricitinib + RDV Relative 
to Placebo + RDV – As Treated Population ...............................................................69 
Table 27: Time to Improvement on the 8-Point Ordinal Scale by Treatment Group .................70 
Table 28: Time to Improvement on the 8-Point Ordinal Scale by Treatment Group: 
Modified Ordinal Scale ...............................................................................................70 
Table 29: Time to Improvement by at least One Clinical Status Category on the 8-
Point Ordinal Scale by Treatment Group within Subgroups – ITT Population .........70 
Table 30: Time to Improvement by at least One Clinical Status Category on the 8-
Point Ordinal Scale by Treatment Group within Subgroups – As Treated 
Population ...................................................................................................................70 
Table 31: Time to Improvement by at least Two Clinical Status Categories on the 8-
Point Ordinal Scale by Treatment Group within Subgroups – ITT Population .........70 
Table 32: Time to Improvement by at least Two Clinical Status Categories on the 8-
Point Ordinal Scale by Treatment Group within Subgroups – As Treated 
Population ...................................................................................................................70 
Table 33: Clinical Status Scores by Treatment Group and Study Visit – ITT Population .........71 
Table 34: Clinical Status Scores by Treatment Group and Study Visit – As Treated 
Population ...................................................................................................................71 
Table 35: Summary of Clinical Status Score by Treatment Group and Study Visit – 
ITT Population ............................................................................................................72 
Table 36: Summary of Clinical Status Score by Treatment Group and Study Visit – As 
Treated Population ......................................................................................................72 
Table 37: Time to Discharge or to a NEWS of ≤ 2 by Treatment Group ...................................73 


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Table 38: Time to Discharge or to a NEWS of ≤ 2 by Treatment Group within 
Subgroups – ITT Population .......................................................................................73 
Table 39: Time to Discharge or to a NEWS of ≤ 2 by Treatment Group within 
Subgroups – As Treated Population ...........................................................................73 
Table 40: Summary of NEWS by Treatment Group and Study Visit – ITT Population ............74 
Table 41: Summary of NEWS by Treatment Group and Study Visit – As Treated 
Population ...................................................................................................................74 
Table 42: Oxygen Use by Treatment Group ...............................................................................75 
Table 43: Oxygen Use by Treatment Group within Subgroups .................................................76 
Table 44: Non-invasive Ventilation/High-Flow Oxygen Use by Treatment Group ...................76 
Table 45: Non-invasive Ventilation/High-Flow Oxygen Use by Treatment Group 
within Subgroups ........................................................................................................76 
Table 46: Ventilation/ECMO Use by Treatment Group .............................................................76 
Table 47: Ventilation/ECMO Use by Treatment Group within Subgroups ...............................76 
Table 48: Hospitalization by Treatment Group ..........................................................................77 
Table 49: Hospitalization by Treatment Group within Subgroups .............................................77 
Table 50: Categorical Demographic and Baseline Characteristics by Randomized 
Disease Severity and Treatment Group – ITT Population ..........................................78 
Table 51: Continuous Demographic and Baseline Characteristics by Randomized 
Disease Severity and Treatment Group – ITT Population ..........................................80 
Table 52: Summary of Subjects with Pre-Existing Medical Conditions Treatment 
Group - As Treated Population ...................................................................................82 
Table 53: Number and Percentage of Subjects with Prior and Concurrent Medications 
by WHO Drug Classification, Actual Disease Severity, and Treatment 
Group – As Treated Population ..................................................................................83 
Table 54: Number and Percentage of Subjects Reporting Use of Medications of 
Interest by Actual Disease Severity, and Treatment Group – As Treated 
Population ...................................................................................................................84 
Table 55: Use of Medications of Interest by Study Day, Actual Disease Severity, and 
Treatment Group – As Treated Population .................................................................85 
Table 56: Overall Summary of Adverse Events – As Treated Population .................................86 
Table 57: Subject-Level Rates of Adverse Events and Differences between Treatment 
Groups – As Treated Population.................................................................................88 
Table 58: Adverse Events Occurring in 5% of Subjects in Any Treatment Group by 
MedDRA System Organ Class and Preferred Term, and Treatment Group - 
As Treated Population ................................................................................................89 


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Table 59: Adverse Events Occurring in 5% of Subjects in Any Treatment Group by 
MedDRA System Organ Class and Preferred Term, and Treatment Group – 
Moderate Disease Severity, As Treated Population ...................................................89 
Table 60: Adverse Events Occurring in 5% of Subjects in Any Treatment Group by 
MedDRA System Organ Class and Preferred Term, and Treatment Group – 
Severe Disease Severity, As Treated Population ........................................................89 
Table 61: Treatment-Emergent Renal Adverse Events by Preferred Term and 
Treatment Group – As Treated Population .................................................................90 
Table 62: Treatment-Emergent Hepatic Adverse Events by Preferred Term and 
Treatment Group – As Treated Population .................................................................90 
Table 63: Related Adverse Events by MedDRA System Organ Class and Preferred 
Term, and Treatment Group - As Treated Population ................................................90 
Table 64: Deaths by Day 15 or Day 29 by Treatment Group and Randomized Disease 
Severity – ITT Population ..........................................................................................91 
Table 65: Deaths by Day 15 or Day 29 by Treatment Group and Actual Disease 
Severity – As Treated Population ...............................................................................91 
Table 66: Time to Death through Day 15 and 29 by Treatment Group and Randomized 
Disease Severity – ITT Population .............................................................................92 
Table 67: Time to Death through Day 15 and 29 by Treatment Group and Actual 
Disease Severity – As Treated Population ..................................................................92 
Table 68: Time to Death through Day 15 and 29 by Treatment Group within 
Subgroups – ITT Population .......................................................................................92 
Table 69: Time to Death through Day 15 and 29 by Treatment Group: Medications of 
Interest Sensitivity Analysis – ITT Population ...........................................................92 
Table 70: Time to Death through Day 15 and 29 by Treatment Group: Interaction 
Modeling – ITT Population ........................................................................................92 
Table 71: Time to Death through Day 15 and 29 by Treatment Group: Restricted Mean 
Survival Time Analysis – ITT Population ..................................................................94 
Table 72: Subjects Experiencing Grade 3 or 4 AEs and SAEs through Day 29 by 
Treatment Group and Actual Disease Severity – As Treated Population ..................95 
Table 73: Analysis of Time to Death, SAEs, or Grade 3 or 4 AEs by Treatment Group 
– As Treated Population .............................................................................................96 
Table 74: Infections by Treatment Group – As Treated Population, Moderate Disease 
Severity .......................................................................................................................97 
Table 75: Opportunistic Infections by Treatment Group – As Treated Population, 
Moderate Disease Severity .........................................................................................97 
Table 76: Infections by Treatment Group – As Treated Population, Severe Disease 
Severity .......................................................................................................................97 


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Table 77: Opportunistic Infections by Treatment Group – As Treated Population, 
Severe Disease Severity ..............................................................................................97 
Table 78: Infections by Treatment Group – As Treated Population, All Subjects .....................97 
Table 79: Opportunistic Infections by Treatment Group – As Treated Population, All 
Subjects .......................................................................................................................97 
Table 80: Abnormal Laboratory Results of Grade 3 or 4 by Parameter, Maximum 
Severity, Time Point, and Treatment Group – As Treated Population .......................98 
Table 81: Abnormal Laboratory Results of Grade 3 or 4 by Parameter, Maximum 
Severity, Time Point, and Treatment Group – Moderate Disease Severity, As 
Treated Population ......................................................................................................99 
Table 82: Abnormal Laboratory Results of Grade 3 or 4 by Parameter, Maximum 
Severity, Time Point, and Treatment Group – Severe Disease Severity, As 
Treated Population ......................................................................................................99 
Table 83: Treatment-Emergent Laboratory Abnormalities - As Treated Population .................99 
Table 84: Summary Statistics of Laboratory Results by Parameter, Study Visit Day, 
and Treatment Group – As Treated Population ........................................................100 
Table 85: Summary Statistics of Laboratory Results by Parameter, Study Visit Day, 
and Treatment Group – Moderate Disease Severity, As Treated Population ...........100 
Table 86: Summary Statistics of Laboratory Results by Parameter, Study Visit Day, 
and Treatment Group – Severe Disease Severity, As Treated Population ...............100 
 
 


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Table 1: 
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 Note: 
Subjects who are eligible but not enrolled will be counted in the denominator. 
 


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Table 2: 
Analysis Population Eligibilities by Treatment Group and Randomized Disease Severity 
 
 
Baricitinib + RDV 
Placebo + RDV 
All Subjects 
Analysis 
Population 
Inclusion / Reason for Exclusion 
Moderate 
Severe 
Moderate 
Severe 
Moderate 
Severe 
n 
n 
n 
n 
n 
n 
Intention-to-Treat 
Population 
Included in Population1 
x 
x 
x 
x 
x 
x 
As Treated 
Population  
Included in Population2 
x 
x 
x 
x 
x 
x 
Excluded from Population1 
x 
x 
x 
x 
x 
x 
Did Not Receive Dose of 
Baricitinib/Placebo1 
x 
x 
x 
x 
x 
x 
1 Counts are the numbers of subjects randomized to the specified treatment group and randomized disease severity stratum. 
2 Counts are the numbers of subjects in the randomized disease severity stratum who received the specified treatment. 
 
Programming Notes:  
If at least one subject received the incorrect treatment, then a footnote will be added which reads “XX 
subject[s] [was/were] randomized to [insert randomized treatment] but was administered [insert actual 
treatment]. In addition, a row under “Included in Population” and “Excluded from Population” will be added 
for the As Treated Population section with the label “Randomized to [insert randomized treatment] but 
administered [insert actual treatment].” 
If at least one subject was randomized to the incorrect disease severity stratum then a separate table will be 
generated which classifies subjects by their actual disease severity. The title of the table will be: “Analysis 
Population Eligibilities by Treatment Group and Actual Disease Severity”. If needed, the table format used 
for ACTT-1 will be used. 
 


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Table 3: 
Subject Disposition by Treatment Group and Randomized Disease Severity – ITT 
Population 
Subject Disposition  
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
All Subjects 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
Randomized 
x/x 
100 
x/x 
100 
x/x 
100 
x/x 
100 
x/x 
100 
x/x 
100 
Completed Follow-up (Study Day 1) – 
Hospitalized Subjects in Study 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
Ordinal Scale Data Available 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
NEWS Data Scale Data Available 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
Safety Laboratory Blood Draw 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
OP Swab Collection 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
PCR Assays Blood Draw 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
Secondary Research Blood Draw 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
Continue for Days 3, 5, 8, 11 for hospitalized subjects. 
Completed Follow-up (Study Day 15) – All 
Subjects in Study 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
Ordinal Scale Data Available 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
NEWS Data Scale Data Available 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
Safety Laboratory Blood Draw 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
OP Swab Collection 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
Secondary Research Blood Draw 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
Completed Follow-up (Study Day 22) – All 
Subjects in Study 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
Ordinal Scale Data Available 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
NEWS Data Scale Data Available (Inpatient 
Subjects Only) 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
Completed Follow-up (Study Day 29) – All 
Subjects in Study 
x/x 
xx 
x/x 
Xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
Ordinal Scale Data Available 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
NEWS Data Scale Data Available 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
Safety Laboratory Blood Draw 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
OP Swab Collection 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
Secondary Research Blood Draw 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
N = Number of subjects enrolled and in study for visits 1, 15, 22 and 29 and the number of subjects hospitalized and in study for 
visits 3, 5, 8 and 11. Subjects that died or terminated from the study on or prior to the study visit are not included in the 
denominators. 
 


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Table 4: 
Treatment Compliance by Treatment Group 
Disposition 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
All Subjects 
(N=X) 
Proportion 
Difference 
n 
% 
95%CIa 
n 
% 
95%CI 
n 
% 
95%CI 
% 
95%CI 
Received Remdesivir Prior to 
Enrollment 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x.x, x.x 
Received First On-Study Dose 
of Remdesivir 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x.x, x.x 
Received at least one Oral 
Dose of Baricitinib/Placebo 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x.x, x.x 
Received all 10 Infusions of 
Remdesivir 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x.x, x.x 
Received all 14 Oral Doses of 
Barcitinib/Placebo 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x.x, x.x 
Received less than 10 Infusions 
of Remdesivir 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 
Received less than 10 Infusions 
of Remdesivir 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 
Received less than 14 doses of 
Baricitinib/Placebo 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 
Received less than 14 doses of 
Baricitinib/Placebo 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 of 
Remdesivir 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 
Had Any Oral Doses of 
Baricitinib/Placebo Modified 
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 
of Remdesivir 
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 Oral Dose of 
Baricitinib/Placebo 
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 
95% CI for proportions obtained by Clopper-Pearson 
95% CI for difference in proportions obtained by the exact method 
 
Programming Notes: 
Received On-Study Dose: Subjects received the first treatment: EC.ECTPT = DOSE 1. 
Infusions/doses are counted as “Received” even if they are halted/slowed/modified. 
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: 


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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 5: 
Subjects Reporting Prior Remdesivir Treatment by Randomized Disease Severity and 
Treatment Group – ITT Population 
Prior RDV Treatment Summary 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
All Subjects 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
Received RDV Treatment Prior to Enrollment 
– n (%) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Number of Doses of RDV Received Prior to 
Enrollment 
 
 
 
 
 
 
Number of Subjects with Data 
x 
x 
x 
x 
x 
x 
Mean (STD) 
x.x (x.x) 
x.x (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 
IQR 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
Range (Min, Max) 
x.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 subjects in the ITT Population.  
 
Table with similar format: 
Table 6: 
Subjects Reporting Prior Remdesivir Treatment by Actual Disease Severity and 
Treatment Group – As Treated Population 
 


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Table 7: 
Distribution of Subject Specific Protocol Deviations by Category, Type, Treatment Group, and Randomized Disease Severity 
Category 
Deviation Type 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
All Subjects 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
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 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
All Subjects 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
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 
 
Stratification error 
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: 


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Table 8: 
Distribution of Subject Specific Protocol Deviations by Category, Type, and Geographic Region  
Table 9: 
Distribution of Major Subject Specific Protocol Deviations by Category, Type, Treatment Group, and Randomized Disease 
Severity 
Table 10: 
Distribution of Major Subject Specific Protocol Deviations by Category, Type, and Geographic Region 
Table 11: 
Distribution of Non-Subject Specific Protocol Deviations by Category and Type 
Table 12: 
Distribution of Non-Subject Specific Protocol Deviations by Category, Type, and Geographic Region 
Table 13: 
Distribution of Major Non-Subject Specific Protocol Deviations by Category and Type 
Table 14: 
Distribution of Major Non-Subject Specific Protocol Deviations by Category, Type, and Geographic Region 
 
Programming Notes for Tables 8, Table 10, Table 12, and Table 14: 
Geographic Region will be North America vs. Europe vs. Asia. 
 


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Table 15: 
Time to Recovery by Treatment Group and Randomized Disease Severity 
Analysis 
Population 
Treatment Group 
Disease Severity 
n 
Median Time to Recovery 
HR 
P-value 
Estimate 
95% CI 
Estimate 
95% CI 
ITT Population Baricitinib + RDV (N=X) 
Moderate 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, 
x.xx 
-- 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Baricitinib + RDV (N=X) 
Severe 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, 
x.xx 
-- 
Plaecbo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Baricitinib + RDV (N=X) 
Any Severity  
x 
x.x 
x.x, x.x 
x.xx 
x.xx, 
x.xx 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Repeat for the As Treated Population. 
N= Number of subjects in the specified treatment group, disease severity, and analysis population.  
n = Number of recovered subjects.  
HR is the ratio of the hazard of recovery in each treatment group estimated from the Cox model. The ratio is Baricitinib + RDV to Placebo + 
RDV. 
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 16: 
Time to Recovery by Treatment Group and Randomized Disease Severity: Fine-Gray, 
Covariate-Adjusted, and Interaction Modeling 
Table 17: 
Time to Recovery by Treatment Group and Baseline Ordinal Score: Fine-Gray and 
Interaction Modeling 
Programming Notes for Table 16 and Table 17: 
For both tables, the median time columns will be excluded.   
The “Analysis Population” column will be replaced by a “Model” column.  For the Fine-Gray estimates, the 
column will display “Fine-Gray”, for the covariate-adjusted model, the column will display “Covariate-
Adjusted”, and for the interaction models (Table 16), the columns will display, respectively, for the three 
models to be run: 
• “Treatment-Severity Interaction (Randomized Severity)” 
• “Treatment-Severity Interaction (Actual Severity)”   
For the interaction models, the p-value for the interaction term will be provided in a footnote reading “The p-
value for the treatment by [randomized/actual] disease severity interaction term was 0.xxxx.”. 
For the covariate-adjusted model, a cox model will be run with age, duration of symptoms prior to enrollment, 
baseline d-dimer, and baseline CRP values included as continuous covariates. 
For Table 17, the interaction model column will display “Baseline Ordinal Score Interaction”. For the 
interaction models, the p-value for the interaction term will be provided in a footnote reading “The p-value for 
the treatment by baseline ordinal score interaction term was 0.xxxx.”. 


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Table 18: 
Time to Recovery by Treatment Group and Disease Severity: Restricted Mean Survival 
Time Analysis – ITT Population 
Analysis 
Population 
Treatment Group 
Randomized 
Disease Severity 
n 
Restricted Mean Recovery 
Time 
Difference 
Estimate 
95% CI 
Estimate 
95% CI 
ITT Population 
Baricitinib + RDV (N=X) 
Moderate 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, 
x.xx 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Baricitinib + RDV (N=X) 
Severe 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, 
x.xx 
Plaecbo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Baricitinib + RDV (N=X) 
Any Severity  
x 
x.x 
x.x, x.x 
x.xx 
x.xx, 
x.xx 
Plaecbo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Repeat for the As Treated Population. 
N= Number of subjects in the specified treatment group, disease severity, and analysis population.  
n = Number of recovered subjects.  
Difference is the difference in the restricted mean recovery time between Baricitinib + RDV and Placebo + RDV.   
Programming Notes: 
Within a severity stratum: 
 
proc lifetest data=enrevent plots=(rmst) method=breslow rmst(cl); 
by stratum; 
time evntday * Censor(1); 
strata trtcode /diff=all; 
ods output  rmst=rmst; 
run; 
 
Stratified by disease severity (“Any Severity” row). 
 
proc lifetest data=enrevent plots=(rmst) method=breslow rmst(cl); 
time evntday * Censor(1); 
strata trtcode CRSEVERE /diff=all; 
ods output  rmst=rmst; 
run; 
 
Table 19: 
Time to Recovery by Treatment Group within Prior RDV Treatment Subgroups 
Analysis 
Population 
Treatment Group 
Prior RDV 
Treatment 
Subgroup 
n 
Median Time to Recovery 
HR 
Estimate 
95% CI 
Estimate 
95% CI 
ITT Population 
Baricitinib + RDV (N=X) 
No Prior 
Treatment 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, 
x.xx 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Baricitinib + RDV (N=X) 
Any Prior 
Treatment 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, 
x.xx 
Plaecbo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Repeat for the As Treated Population. 
N= Number of subjects in the specified treatment group, disease severity, and analysis population.  
n = Number of recovered subjects. 
HR is the ratio of the hazard of recovery in each treatment group estimated from the Cox model. The ratio is Baricitinib + RDV to Placebo + 
RDV. 


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Additional tables with similar format as Table 15: 
Table 20: 
Time to Recovery by Treatment Group within Subgroups – ITT Population 
Table 21: 
Time to Recovery by Treatment Group within Subgroups – As Treated Population 
Table 22: 
Time to Recovery by Treatment Group and Randomized Disease Severity: Readmittance 
Sensitivity Analysis – ITT Population 
Table 23: 
Time to Recovery by Treatment Group and Randomized Disease Severity: Medications 
of Interest Sensitivity Analysis – ITT Population 
Programming Notes for Tables 20 and 21: 
The “Disease Severity” and “Analysis Population” columns will be removed.  A “Subgroup” column will be 
inserted to the left of the “Treatment Group” column. These tables will not display the “Any…” rows. For the 
analysis controlling for age, symptom duration, d-dimer, and CRP values as continuous covariates, the 
elements for the “Subgroup” column will state “Baseline Predictors as Continuous Covariates”. The elements 
for the “n” and “Median Time to Recovery” columns will display “-“.  P-values will not be included in these 
tables. 
Programming Notes for Tables 22 and 23: 
P-values will not be included in these tables. 
Table 22 will include a column to the left of the “n” column titled “m”. The corresponding footnote will read 
“m = Number of subjects readmitted for COVID-19.”  Table 11 will include the following footnote: “In this 
analysis, subjects that recover and are subsequently readmitted for COVID-19 are censored at 28 days”.   
Table 23 will include a column to the left of the “n” column titled “m”. The corresponding footnote will read 
“m = Number of subjects reporting use of the medication of interest.” For Table 12, the “Analysis Population” 
column will be replaced by a column labeled “Medication of Interest”.  Separate models will be fit for the 
following categories of medications (see Section 6.4): 
• Any Medication of Interest 
• Hydroxychloroquine/Chloroquine  
• Corticosteroids 
• Anti-Inflammatory Drugs 
The table will include the following footnote: “In this analysis, subjects that reported use of the specified 
medications of interest (Section 6.4 of the SAP) are censored at time of medication receipt.”   
 


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Table 24: 
Summary of Recoveries and Deaths by Day 29 – ITT Population  
Grouping 
Variable 
Subgroup 
Treatment Group 
Recovered 
Did Not Recover 
Deaths 
Not Recovered or 
Died 
n 
% 
n 
% 
n 
% 
n 
% 
Disease 
Severity 
Moderate 
Baricitinib + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
Placebo + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
Baricitinib + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
Placebo + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
Any Severity  
Baricitinib + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
Placebo + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
Repeat for duration of symptoms categories in Section 6.4 
N= Number of subjects in the ITT Population.  
 
Programming Note: For the categories of “Recovered”, “Did Not Recover” and “Deaths”, subjects who 
recover but subsequently die will be classified under “Recovered” and “Deaths”. If there are cases of this, a 
footnote will be added that states “Counts of recoveries and deaths include X subjects who recovered but 
subsequently died.” 
 


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Table 25: 
Odds Ratio for Better (Lower) Clinical Status Score at Study Visit Day 15 by Treatment 
Using a Proportional Odds Model, Baricitinib + RDV Relative to Placebo + RDV – ITT 
Population 
Analysis/Subgroup 
Treatment Group 
Odds Ratio 
P-value 
Estimate 
95% CI 
Main Analysis of Key Secondary Endpoint 
Analysis of Key Secondary Endpoint1 
Baricitinib + RDV (N=X) 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo + RDV (N=X) 
Subgroup Analyses of Key Secondary Endpoint 
[Repeat for each Section 6.4 
subgroups] 
Baricitinib + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
Placebo + RDV (N=X) 
Medications of Interest Sensitivity Analyses 
Any Medication of Interest 
Baricitinib + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
Placebo + RDV (N=X) 
Hydroxychloroquine/Chloroquine 
Baricitinib + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
Placebo + RDV (N=X) 
Corticosteroids 
Baricitinib + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
Placebo + RDV (N=X) 
Anti-Inflammatory Drugs 
Baricitinib + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
Placebo + RDV (N=X) 
Covariate-Adjusted Model 
Covariate-Adjusted  
Baricitinib + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
Placebo + RDV (N=X) 
Interaction Models 
Treatment-Severity Interaction 
Baricitinib + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
Placebo + RDV (N=X) 
Treatment-Baseline Ordinal Score 
Interaction 
Baricitinib + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
Placebo + RDV (N=X) 
1Analysis of key secondary endpoint using the full As Treated Population with disease severity as a model covariate. 
 
Programming Note:  P-value of treatment comparison will only be displayed for the main analysis. For the 
interaction models, the p-value for the interaction term will be provided in a footnote reading “The p-value for 
the treatment by disease severity interaction term was 0.xxxx.”. 
For the covariate-adjusted model, the model will be run with age, duration of symptoms prior to enrollment, 
baseline d-dimer, and baseline CRP values included as continuous covariates. 
 


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Table with similar format: 
Table 26: 
Odds Ratio for Better (Lower) Clinical Status Score at Study Visit Day 15 by Treatment 
Using a Proportional Odds Model, Baricitinib + RDV Relative to Placebo + RDV – As 
Treated Population 
 
Programming Note: P-value of treatment comparison will only be displayed for the main analysis. For the 
interaction models, the p-value for the interaction term will be provided in a footnote reading “The p-value for 
the treatment by disease severity interaction term was 0.xxxx.”. 
 


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Table 27: 
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 
Baricitinib + RDV (N=X) 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
x.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
As Treated 
Population 
Baricitinib + RDV (N=X) 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
x.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Improvement by at least Two Categories 
ITT Population 
Baricitinib + RDV (N=X) 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
x.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
As Treated 
Population 
Baricitinib + RDV (N=X) 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
x.xxx 
Placebo + RDV (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 ratio of the hazard of improvement in each treatment group estimated from the Cox model. The ratio is Baricitinib + RDV to Placebo + 
RDV.  
P-value calculated using the Log-rank test  
 
Tables with similar format: 
Table 28: 
Time to Improvement on the 8-Point Ordinal Scale by Treatment Group: Modified 
Ordinal Scale 
Table 29: 
Time to Improvement by at least One Clinical Status Category on the 8-Point Ordinal 
Scale by Treatment Group within Subgroups – ITT Population 
Table 30: 
Time to Improvement by at least One Clinical Status Category on the 8-Point Ordinal 
Scale by Treatment Group within Subgroups – As Treated Population 
Table 31: 
Time to Improvement by at least Two Clinical Status Categories on the 8-Point Ordinal 
Scale by Treatment Group within Subgroups – ITT Population 
Table 32: 
Time to Improvement by at least Two Clinical Status Categories on the 8-Point Ordinal 
Scale by Treatment Group within Subgroups – As Treated Population 
 
Programming notes for Table 28: 
The table will include the footnote: This analysis used the modified version of the ordinal scale where the 
categories “Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care” and 
“Not hospitalized, no limitations on activities” were classified together and given a score of 2 while the 
category “Not hospitalized, limitation on activities” was given the score 3.” 
Programming notes for Tables 29, Table 30, Table 31, Table 32:  Instead of the “Analysis Population” 
column, columns titled “Subgroup Category” and “Subgroup” will be to the left of Treatment Group.  Rows 
will be generated for each subgroup. Since the One and Two Category improvement outcomes are presented 
separately in these tables, the spanned row of "Improvement by at least XXX" will not be displayed in these 
tables. 


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Table 33: 
Clinical Status Scores by Treatment Group and Study Visit – ITT Population 
Study Visit 
Ordinal Scale Measure 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(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:  
If necessary, a row for “No clinical status score reported – Completed study without reporting score” will be added as the last row for each day. 
 
Table with similar format: 
Table 34: 
Clinical Status Scores by Treatment Group and Study Visit – As Treated Population 
 


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Table 35: 
Summary of Clinical Status Score by Treatment Group and Study Visit – ITT Population 
Study Visit 
Statistic 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
All Subjects 
(N=C) 
Baseline 
Number of reported clinical scores 
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 
Day 3 
Number of reported clinical scores 
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) 
Continue for Days 5, 8, 11, 15, 22, 29 
N = Number of subjects in the ITT Population. 
SD = Standard deviation. 
Missing values were imputed using Last Observation Carried Forward.  Clinical scores of 8 were carried forward from the date of death for subjects who died. 
 
Table with similar format: 
 
Table 36: 
Summary of Clinical Status Score by Treatment Group and Study Visit – As Treated Population 
 


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Table 37: 
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 
Baricitinib + RDV (N=X) 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
x.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
As Treated 
Population 
Baricitinib + RDV (N=X) 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
x.xxx 
Placebo + RDV (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 ratio of the hazard of discharge or NEWS of ≤ 2 in each treatment group estimated from the Cox model. The ratio is Baricitinib + RDV 
to Placebo + RDV. P-value calculated using the Log-rank test 
 
Tables with similar format: 
Table 38: 
Time to Discharge or to a NEWS of ≤ 2 by Treatment Group within Subgroups – ITT 
Population 
Table 39: 
Time to Discharge or to a NEWS of ≤ 2 by Treatment Group within Subgroups – As 
Treated Population 
Programming notes for Tables 38 – 39: “Subgroup Category” and “Subgroup” columns will replace the 
“Analysis Population” column to the left of “Treatment Group”. Rows will be repeated for each subgroup. P-
values will not be displayed in these tables. 
 


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Table 40: 
Summary of NEWS by Treatment Group and Study Visit – ITT Population 
Study 
Visit 
Statistic 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
All Subjects 
(N = X) 
Baseline 
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 
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 
na 
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. 
na = Number of subjects with an assessment at both baseline and the time point being summarized. 
SD = Standard deviation. 
 
Table with similar format: 
Table 41: 
Summary of NEWS by Treatment Group and Study Visit – As Treated Population 
 


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Table 42: 
Oxygen Use by Treatment Group 
Analysis Population 
Oxygen Use 
Statistic 
Treatment Group 
Baricitinib + RDV 
Placebo + RDV 
ITT Population 
On Oxygen at Baseline (N = x) 
Days on Oxygen (Including 
imputations for subjects who died) 
N 
x 
x 
Q1 
x.x 
x.x 
Median 
x.x 
x.x 
Q3 
x.x 
x.x 
Days of Oxygen (Among subjects 
who did not die) 
N 
x 
x 
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 
n 
x 
x 
Incidence Rate 
x.x 
x.x 
Incidence Rate CI 
x.x, x.x 
x.x, x.x 
Days on Oxygen (Including 
imputations for subjects who died) 
N 
x 
x 
Q1 
x.x 
x.x 
Median 
x.x 
x.x 
Q3 
x.x 
x.x 
Days of Oxygen (Among subjects 
who did not die) 
N 
x 
x 
Q1 
x.x 
x.x 
Median 
x.x 
x.x 
Q3 
x.x 
x.x 
Continue for As 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. 
 
Programming Notes: 
For the “Days on Oxygen” statistics within the “Not on Oxygen at Baseline” subgroup, only summarize days 
for subjects who reported new use. 
 


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Tables with similar format: 
Table 43: 
Oxygen Use by Treatment Group within Subgroups 
Table 44: 
Non-invasive Ventilation/High-Flow Oxygen Use by Treatment Group  
Table 45: 
Non-invasive Ventilation/High-Flow Oxygen Use by Treatment Group within Subgroups 
Table 46: 
Ventilation/ECMO Use by Treatment Group  
Table 47: 
Ventilation/ECMO Use by Treatment Group within Subgroups 
 
Programming notes for Table 43, Table 45, Table 47: “Analysis Population” will be replaced by “Grouping 
Variable” column. Summaries will only be generated for ITT population. 


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Table 48: 
Hospitalization by Treatment Group  
Analysis Population 
Summary 
Statistic 
Treatment Group 
Baricitinib + RDV 
Placebo + RDV 
ITT Population 
Number of Subjects 
N 
x 
x 
Days of Hospitalization 
Q1 
x.x 
x.x 
Median 
x.x 
x.x 
Q3 
x.x 
x.x 
Incidence of Readmittance 
N 
x 
x 
Percentage 
x 
x 
Percentage CI 
x.x, x.x 
x.x, x.x 
Continue for As 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 49: 
Hospitalization by Treatment Group within Subgroups 
Programming notes for Table 49: “Analysis Population” will be replaced by “Grouping Variable” column. 
Summaries will only be generated for ITT population 
 


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Table 50: 
Categorical Demographic and Baseline Characteristics by Randomized Disease Severity and Treatment Group – ITT Population 
Demographic Category 
Characteristic 
Baricitinib + RDV 
Placebo + RDV 
All Subjects 
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
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 


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Demographic Category 
Characteristic 
Baricitinib + RDV 
Placebo + RDV 
All Subjects 
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
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 
Comorbidity 1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Comorbidity 2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
…Continue for all 
comorbidities 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Comorbidities Group X 
…Continue for all 
comorbidity categorizations 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
N = Number of subjects enrolled.  
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-2) 
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Table 51: 
Continuous Demographic and Baseline Characteristics by Randomized Disease Severity and Treatment Group – ITT Population 
Variable 
Statistic 
Baricitinib + RDV  
Placebo + RDV 
All Subjects 
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
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 
 
IQR 
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 
 
IQR 
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 
 
IQR 
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 
 
IQR 
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 


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Variable 
Statistic 
Baricitinib + RDV  
Placebo + RDV 
All Subjects 
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
All Subjects 
(N=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 
 
IQR 
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 
IQR is the inter-quartile range. 
 


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Table 52: 
Summary of Subjects with Pre-Existing Medical Conditions Treatment Group - As 
Treated Population 
Condition 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(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 As Treated Population; 
n = Number of subjects reporting the condition. Subjects who report ‘unknown’ for a condition are assumed to not have the condition. 
 
Programming Note:  “None” and “Any Condition” will be the first two rows.  The remainder of the rows will 
be sorted in order of prevalence, with the condition most reported among All Subjects being displayed first. 
 


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Table 53: 
Number and Percentage of Subjects with Prior and Concurrent Medications by WHO Drug Classification, Actual Disease 
Severity, and Treatment Group – As Treated Population 
WHO Drug Code 
Level 1, Anatomic 
Group 
WHO Drug Code 
Level 2, Therapeutic 
Subgroup 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
All Subjects 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
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 As Treated Population.  
n=Number of subjects reporting taking at least one medication in the specific WHO Drug Class. 
 
Programming Note: Only include medications with missing end dates (i.e. ongoing) or end dates on or after the enrollment date. 
 


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Table 54: 
Number and Percentage of Subjects Reporting Use of Medications of Interest by Actual Disease Severity, and Treatment Group – 
As Treated Population 
Medication/Therapies 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
All Subjects 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
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 
Potential Treatments for COVID-19 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
   Chloroquine/Hydroxychloroquine 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
   Other 
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 
  Monoclonal Antibodies Targeting 
Cytokines 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
  Other Biologic Therapies 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
N = Number of subjects in the As Treated Population.  
n=Number of subjects reporting taking at least one medication in the specified category. 
 
Programming Note: only include medications where the end date is missing (i.e. ongoing) or end date is on or after enrollment date 
 


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Table 55: 
Use of Medications of Interest by Study Day, Actual Disease Severity, and Treatment Group – As Treated Population 
Study Day 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
All Subjects 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any Medication of Interest 
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 
…Repeat for all categories and sub-categories of the medications in Section 6.4 
N = Number of subjects in the As Treated Population.  
n=Number of subjects reporting taking at least one prohibited medication by the specified study day. 
 
Programming Note: 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 56: 
Overall Summary of Adverse Events – As Treated Population 
Subjectsa with 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
All Subjects 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
Any Severity 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
Any Severity 
(N=X) 
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 Severe or Life-threatening (Grade 3 or 
4) 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 
Severe or Life-Threatening (Grade 3 or 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 not 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 serious adverse event with fatal 
outcome 
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 related serious adverse event with fatal 
outcome 
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 study drug 
discontinuation 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
At least one related adverse event leading to study 
drug discontinuation 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 


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Subjectsa with 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
All Subjects 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
Any Severity 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
Any Severity 
(N=X) 
Moderate 
(N=X) 
Severe 
(N=X) 
Any Severity 
(N=X) 
N 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
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 actual disease severity stratum and As 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. 
 
Programming Note:  Use actual severity 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-2) 
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Table 57: 
Subject-Level Rates of Adverse Events and Differences between Treatment Groups – As 
Treated Population 
Subjectsa with at least one: 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
Risk Difference (95% CI) 
n 
% 
n 
% 
AE 
x 
x 
x 
x 
x.x (x.x, x.x) 
Related AE 
x 
x 
x 
x 
x.x (x.x, x.x) 
Grade 3-4 AE 
x 
x 
x 
x 
x.x (x.x, x.x) 
Grade 3-4 Related AE 
x 
x 
x 
x 
x.x (x.x, x.x) 
SAE 
x 
x 
x 
x 
x.x (x.x, x.x) 
Related SAE 
x 
x 
x 
x 
x.x (x.x, x.x) 
SAE with fatal outcome 
x 
x 
x 
x 
x.x (x.x, x.x) 
Related SAE with fatal outcome 
x 
x 
x 
x 
x.x (x.x, x.x) 
AE leading to discontinuation of study drug 
x 
x 
x 
x 
x.x (x.x, x.x) 
Related AE leading to discontinuation of 
study drug 
x 
x 
x 
x 
x.x (x.x, x.x) 
N = Number of subjects in the As Treated Population. 
aSubjects are counted once for each category regardless of the number of events. 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-2) 
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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 - As Treated Population 
Preferred Term 
MedDRA System 
Organ Class 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
All Subjects 
(N=X) 
 
 
n 
% 
Events 
n 
% 
Events 
n 
% 
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 As 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. 
 
Tables with similar format: 
Table 59: 
Adverse Events Occurring in 5% of Subjects in Any Treatment Group by MedDRA 
System Organ Class and Preferred Term, and Treatment Group – Moderate Disease 
Severity, As Treated Population 
Table 60: 
Adverse Events Occurring in 5% of Subjects in Any Treatment Group by MedDRA 
System Organ Class and Preferred Term, and Treatment Group – Severe Disease 
Severity, As Treated Population 
Programming Notes for Tables 59 and 60: Actual disease severity will be used. 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-2) 
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Table 61: 
Treatment-Emergent Renal Adverse Events by Preferred Term and Treatment Group – 
As Treated Population 
Preferred Term 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
All Subjects 
(N=X) 
 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
Any treatment-emergent hepatic adverse 
event 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Glomerular filtration rate decreased 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Blood creatinine increased 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Acute kidney injury 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Creatinine renal clearance decreased 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Renal failure 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Renal impairment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Proteinuria 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Renal tubular necrosis 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Blood creatinine abnormal 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Continuous haemodiafiltration 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Glomerular filtration rate abnormal 
x 
x 
x 
x 
x 
x 
x 
x 
x 
N = Number of subjects in the As Treated Population. 
n = Number of subjects reporting event. 
Events = Total frequency of events reported. 
 
Table with similar format: 
Table 62: 
Treatment-Emergent Hepatic Adverse Events by Preferred Term and Treatment Group 
– As Treated Population 
Table 63: 
Related Adverse Events by MedDRA System Organ Class and Preferred Term, and 
Treatment Group - As Treated Population 
MedDRA System Organ Class 
Preferred Term 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
All Subjects 
(N=X) 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
Any SOC 
Any PT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SOC1 
Any PT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Etc. 
Etc. 
… 
… 
… 
… 
… 
… 
… 
… 
… 
N = number of subjects in the As Treated Population (number of subjects at risk).  
n = number of subjects reporting event.  
Events = total frequency of events reported. 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-2) 
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Table 64: 
Deaths by Day 15 or Day 29 by Treatment Group and Randomized Disease Severity – ITT Population 
Study Day 
Randomized Disease 
Severity 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
n 
Mortality Ratea 
Rate 95% CI 
n 
Mortality Ratea 
Rate 95% CI 
Day 15 
Moderate 
X 
x.x 
x.x, x.x 
x 
x.x 
x.x, x.x 
Severe 
X 
x.x 
x.x, x.x 
x 
x.x 
x.x, x.x 
Any Severity 
X 
x.x 
x.x, x.x 
x 
x.x 
x.x, x.x 
Day 29 
Moderate 
X 
x.x 
x.x, x.x 
x 
x.x 
x.x, x.x 
Severe 
X 
x.x 
x.x, x.x 
x 
x.x 
x.x, x.x 
Any Severity 
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 
a Mortality Rate is the Kaplan-Meier estimate. 
 
Tables with similar format: 
Table 65: 
Deaths by Day 15 or Day 29 by Treatment Group and Actual Disease Severity – As Treated Population 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-2) 
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Table 66: 
Time to Death through Day 15 and 29 by Treatment Group and Randomized Disease Severity – ITT Population 
Study Day 
Treatment Group 
Randomized Disease Severity 
n 
Median Time 
HR 
P-value 
Estimate 
95% CI 
Estimate 
95% CI 
Day 15 
Baricitinib + RDV (N=X) 
Moderate 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Baricitinib + RDV (N=X) 
Severe 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Baricitinib + RDV (N=X) 
Any Severity 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
x.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Day 29 
Baricitinib + RDV (N=X) 
Moderate 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Baricitinib + RDV (N=X) 
Severe 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Baricitinib + RDV (N=X) 
Any Severity 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
x.xxx 
Placebo + RDV (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 ratio of the hazard of Death in each treatment group estimated from the stratified Cox model. The ratio is Baricitinib + RDV to Placebo + RDV. 
P-value calculated using the stratified Log-rank test. 
 
Tables with similar format: 
Table 67: 
Time to Death through Day 15 and 29 by Treatment Group and Actual Disease Severity – As Treated Population 
Table 68: 
Time to Death through Day 15 and 29 by Treatment Group within Subgroups – ITT Population 
Table 69: 
Time to Death through Day 15 and 29 by Treatment Group: Medications of Interest Sensitivity Analysis – ITT Population 
Table 70: 
Time to Death through Day 15 and 29 by Treatment Group: Interaction Modeling – ITT Population 
Programming notes for Table 68:  
Log-rank p-values will not be included in this table so the column will be removed.  The Disease Severity column will be removed and to the left of the 
Study Day column, a column titled “Analysis/Subgroup” will be inserted.  Rows will be generated for each subgroup.   


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-2) 
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Programming notes for Table 69: 
Log-rank p-values will not be included in this table so the column will be removed.  The table will include a column to the left of the “n” column titled 
“m”.  The corresponding footnote will read “m = Number of subjects reporting use of the medication of interest.”  The Disease Severity column will be 
removed and a “Medication of Interest” column will be inserted to the left of Study Day.  Separate models will be fit for the following categories of 
medications (see Section 6.4): 
• Any Medication of Interest 
• Hydroxychloroquine/Chloroquine  
• Corticosteroids 
• Anti-Inflammatory Drugs 
The table will include the following footnote: “In this analysis, subjects that reported use of the specified medications of interest (Section 6.4 of the SAP) 
are censored at time of medication receipt.” 
Programming notes for Table 70: 
This table will only include the Treatment Group and HR columns only as well as a column to the left of Treatment Group titled “Interaction”. Two 
models will be run: “Treatment – Randomized Disease Severity” will include a treatment*randomized disease severity interaction term.  “Treatment – 
Baseline Ordinal Score” will include a treatment*baseline ordinal score interaction term. For each interaction model, the p-value for the interaction term 
will be provided in a footnote reading “The p-value for the treatment by [randomized disease severity/baseline ordinal score] interaction term was 
0.xxxx.”. 
 


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Table 71: 
Time to Death through Day 15 and 29 by Treatment Group: Restricted Mean Survival Time Analysis – ITT Population 
Study Day 
Treatment Group 
Randomized Disease Severity 
n 
Restricted Mean Recovery Time 
Difference 
Estimate 
95% CI 
Estimate 
95% CI 
Day 15 
Baricitinib + RDV (N=X) 
Moderate 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Baricitinib + RDV (N=X) 
Severe 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Baricitinib + RDV (N=X) 
Any Severity 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Day 29 
Baricitinib + RDV (N=X) 
Moderate 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Baricitinib + RDV (N=X) 
Severe 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
Baricitinib + RDV (N=X) 
Any Severity 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x.x 
x.x, x.x 
N= Number of subjects in the specified treatment group, disease severity, and analysis population.  
n = Number of subjects who died by the specified study day.  
Difference is the difference in the restricted mean mortality time between Baricitinib + RDV and Placebo + RDV. 
 


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Table 72: 
Subjects Experiencing Grade 3 or 4 AEs and SAEs through Day 29 by Treatment Group and Actual Disease Severity – As 
Treated Population 
Safety Event Outcome 
Baricitinib + RDV 
Placebo + RDV 
P-value 
n 
% 
95% CI 
n 
% 
95% CI 
Any Severity (N = X) 
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 
Moderate (N = X) 
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 
Severe (N = X) 
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 As Treated Population and specified actual disease severity stratum.  
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 73: 
Analysis of Time to Death, SAEs, or Grade 3 or 4 AEs by Treatment Group – As Treated Population 
Actual Disease Severity 
Treatment Group 
n 
Median Time 
HR 
P-value 
 
Estimate 
95% CI 
Estimate 
95% CI 
Any Severity (N=X) 
Baricitinib + RDV (N=X) 
X 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
x.xxx 
Placebo + RDV (N=X) 
X 
x.x 
x.x, x.x 
Moderate (N=X) 
Baricitinib + RDV (N=X) 
X 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo + RDV (N=X) 
X 
x.x 
x.x, x.x 
Severe (N=X) 
Baricitinib + RDV (N=X) 
X 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo + RDV (N=X) 
X 
x.x 
x.x, x.x 
N= Number of subjects in the As Treated Population and specified actual disease severity stratum.  
n = Number of subjects who died or experienced SAEs or Grade 3 or 4 AEs.  
HR is the ratio of the hazard of Death/SAE/AE of Grade 3 or 4 in each treatment group estimated from the stratified Cox model. The ratio is Baricitinib + RDV to Placebo + RDV.P-value calculated 
using the Log-rank test 
 


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Table 74: 
Infections by Treatment Group – As Treated Population, Moderate Disease Severity 
Anatomical 
Location 
Pathogen 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
Severe 
Life-Threatening 
Death 
Severe 
Life-Threatening 
Death 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
Any Location  
Any Pathogen  
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Location 1  
Any Pathogen 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pathogen 1  
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pathogen 2  
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Location 2  
Any Pathogen 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pathogen 1  
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pathogen 2  
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Note:  Percents may not add to 100 because participants may have infections with multiple pathogens. All Grade 3 or 4 infections are also reported as AEs.  
N=Number of participants randomized to Treatment group.  
n=Number of participants with infection.  
 
Tables with similar format: 
Table 75: 
Opportunistic Infections by Treatment Group – As Treated Population, Moderate Disease Severity 
Table 76: 
Infections by Treatment Group – As Treated Population, Severe Disease Severity 
Table 77: 
Opportunistic Infections by Treatment Group – As Treated Population, Severe Disease Severity 
Table 78: 
Infections by Treatment Group – As Treated Population, All Subjects 
Table 79: 
Opportunistic Infections by Treatment Group – As Treated Population, All Subjects 
 
Programming Notes for Table 75, Table 77, Table 79: Opportunistic infections will be identified by the sponsor and will be documented in a 
spreadsheet/SAS dataset to be imported into ADaM dataset programming. 
 


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Table 80: 
Abnormal Laboratory Results of Grade 3 or 4 by Parameter, Maximum Severity, Time Point, and Treatment Group – As 
Treated Population 
Laboratory 
Parameter 
Time Point 
Treatment Group 
N 
Severe/ Grade 3 
 
Life Threatening/ Grade 4 
 
Severe/Grade 3 or 
Life Threatening/Grade 4 
n 
% 
n 
% 
n 
% 
Any Parameter 
Baseline 
Baricitinib + RDV  
x 
x 
x 
x 
x 
x 
x 
 
Placebo + RDV  
x 
x 
X 
x 
x 
x 
x 
Day 3 
Baricitinib + RDV 
x 
x 
X 
x 
x 
x 
x 
 
Placebo + RDV  
x 
x 
X 
x 
x 
x 
x 
Day 5 
Baricitinib + RDV 
x 
x 
X 
x 
x 
x 
x 
 
Placebo + RDV  
x 
x 
X 
x 
x 
x 
x 
Day 8 
Baricitinib + RDV 
x 
x 
X 
x 
x 
x 
x 
 
Placebo + RDV  
x 
x 
X 
x 
x 
x 
x 
Day 11 
Baricitinib + RDV 
x 
x 
X 
x 
x 
x 
x 
 
Placebo + RDV  
x 
x 
X 
x 
x 
x 
x 
Day 15 
Baricitinib + RDV 
x 
x 
X 
x 
x 
x 
x 
 
Placebo + RDV  
x 
x 
X 
x 
x 
x 
x 
Day 29 
Baricitinib + RDV 
x 
x 
X 
x 
x 
x 
x 
 
Placebo + RDV  
x 
x 
X 
x 
x 
x 
x 
Maximum Severity Post 
Baseline 
Baricitinib + RDV  
x 
x 
X 
x 
x 
x 
x 
 
Placebo + RDV  
x 
x 
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 and assessments beyond Day 29. 
N = Number of subjects in the As Treated Population 
 
Programming Note: D-dimer and CRP results are not included in this table.  Include all lab parameters that are being graded in this table. 
 


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Tables with similar format: 
Table 81: 
Abnormal Laboratory Results of Grade 3 or 4 by Parameter, Maximum Severity, Time Point, and Treatment Group – Moderate 
Disease Severity, As Treated Population 
Table 82: 
Abnormal Laboratory Results of Grade 3 or 4 by Parameter, Maximum Severity, Time Point, and Treatment Group – Severe 
Disease Severity, As Treated Population 
Programming Notes for Table 81 and Table 82: Actual Disease Severity will be used.  Include all lab parameters that are being graded in this table. 
 
Table 83: 
Treatment-Emergent Laboratory Abnormalities - As Treated Population 
Laboratory Parameter 
Grade 
Baricitinib + RDV 
(N=X) 
Placebo + RDV 
(N=X) 
N 
n 
% 
N 
n 
% 
Any Parameter 
1 
x 
x 
x 
x 
x 
x 
2 
x 
x 
X 
x 
x 
x 
3 
x 
x 
X 
x 
x 
x 
4 
x 
x 
X 
x 
x 
x 
Any Grade 
x 
x 
X 
x 
x 
x 
Continue for all graded parameters 
N = number of subjects in the As Treated Population with any post-baseline data available for the specified Lab Parameter. 
n = number of subjects in the As Treated Population with treatment emergent abnormalities for the specified Lab Parameter. 
A treatment emergent laboratory abnormality is defined as a post-baseline abnormal value with a severity grade greater than at baseline. 
 


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Table 84: 
Summary Statistics of Laboratory Results by Parameter, Study Visit Day, and Treatment Group – As 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 
Baricitinib + RDV 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
--- 
--- 
--- 
--- 
--- 
 
Placebo + RDV 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
--- 
--- 
--- 
--- 
--- 
Day 3 
Baricitinib + RDV 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Placebo + RDV 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
Day 5 
Baricitinib + RDV 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Placebo + RDV 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
Day 8 
Baricitinib + RDV 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Placebo + RDV 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
Day 11 
Baricitinib + RDV 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Placebo + RDV 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
Day 15 
Baricitinib + RDV 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Placebo + RDV 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
Day 29 
Baricitinib + RDV 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Placebo + RDV 
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 As Treated Population with laboratory data available for the parameter at the specified study visit. 
 
Programming Notes:  Include all lab parameters in this table. 
 
Tables with similar format: 
Table 85: 
Summary Statistics of Laboratory Results by Parameter, Study Visit Day, and Treatment Group – Moderate Disease Severity, As 
Treated Population 
Table 86: 
Summary Statistics of Laboratory Results by Parameter, Study Visit Day, and Treatment Group – Severe Disease Severity, As 
Treated Population 
Programming Notes for Tables 85 and 86: Actual Disease Severity will be used.  Include all lab parameters in this table. 


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APPENDIX 2. FIGURE MOCK-UPS 
General Programming Notes for figures: 
• Treatment group labeling will be the following: 
o Baricitinib + RDV 
o Placebo + RDV 
• If the treatment group labels need to be abbreviated to improve fit, the following 
abbreviations will be used: 
o B + R 
o P + R 
• Use the same color for a treatment on the different graphs: 
o Baricitinib + RDV = Blue 
o Placebo + RDV = 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 .......................................................................................106 
Figure 2: 
Kaplan-Meier Curves of Time to Recovery by Treatment Group – ITT 
Population .................................................................................................................107 
Figure 3: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group – As Treated 
Population .................................................................................................................108 
Figure 4: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group and 
Randomized Disease Severity – ITT Population ......................................................108 
Figure 5: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group and 
Randomized Disease Severity – As Treated Population ..........................................108 
Figure 6: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group – Baseline 
Ordinal Score 7, ITT Population ..............................................................................108 
Figure 7: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group – Baseline 
Ordinal Score 6, ITT Population ..............................................................................108 
Figure 8: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group – Baseline 
Ordinal Score 5, ITT Population ..............................................................................108 
Figure 9: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group – Baseline 
Ordinal Score 4, ITT Population ..............................................................................108 
Figure 10: Forest Plot of Hazard Ratios of Time to Recovery by Subgroup - ITT 
Population .................................................................................................................109 
Figure 11: Forest Plot of Hazard Ratios of Time to Recovery by Subgroup - As Treated 
Population .................................................................................................................109 
Figure 12: Forest Plot of Hazard Ratios of Time to Recovery by Comorbidity - ITT 
Population .................................................................................................................109 
Figure 13: Forest Plot of Hazard Ratios of Time to Recovery: Leave One Site Out 
Sensitivity Analysis - ITT Population ......................................................................109 
Figure 14: Study Visit Day 15 Clinical Status Score by Baseline Score and Treatment 
Group – ITT Population ............................................................................................110 
Figure 15: Kaplan-Meier Curves of Time to Improvement by at least One Category of 
Clinical Status Score by Treatment Group – ITT Population ...................................111 
Figure 16: Kaplan-Meier Curves of Time to Improvement by at least Two Categories of 
Clinical Status Score by Treatment Group – ITT Population ...................................112 
Figure 17: Kaplan-Meier Curves of Time to Improvement by at least One Category of 
Clinical Status Score by Treatment Group – Baseline Ordinal Score 7, ITT 
Population .................................................................................................................112 
Figure 18: Kaplan-Meier Curves of Time to Improvement by at least One Category of 
Clinical Status Score by Treatment Group – Baseline Ordinal Score 6, ITT 
Population .................................................................................................................112 


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Figure 19: Kaplan-Meier Curves of Time to Improvement by at least One Category of 
Clinical Status Score by Treatment Group – Baseline Ordinal Score 5, ITT 
Population .................................................................................................................112 
Figure 20: Kaplan-Meier Curves of Time to Improvement by at least One Category of 
Clinical Status Score by Treatment Group – Baseline Ordinal Score 4, ITT 
Population .................................................................................................................112 
Figure 21: Kaplan-Meier Curves of Time to Improvement by at least Two Categories of 
Clinical Status Score by Treatment Group – Baseline Ordinal Score 7, ITT 
Population .................................................................................................................112 
Figure 22: Kaplan-Meier Curves of Time to Improvement by at least Two Categories of 
Clinical Status Score by Treatment Group – Baseline Ordinal Score 6, ITT 
Population .................................................................................................................112 
Figure 23: Kaplan-Meier Curves of Time to Improvement by at least Two Categories of 
Clinical Status Score by Treatment Group – Baseline Ordinal Score 5, ITT 
Population .................................................................................................................112 
Figure 24: Kaplan-Meier Curves of Time to Improvement by at least Two Categories of 
Clinical Status Score by Treatment Group – Baseline Ordinal Score 4, ITT 
Population .................................................................................................................112 
Figure 25: Distribution of Clinical Status Scores by Day by Treatment Group – ITT 
Population .................................................................................................................113 
Figure 26: Bar Plots of Clinical Status Scores by Study Day and Treatment Group – 
ITT Population ..........................................................................................................114 
Figure 27: Kaplan-Meier Curves of Time to Discharge or NEWS ≤ 2 by Treatment 
Group – ITT Population ............................................................................................115 
Figure 28: Kaplan-Meier Curves of Time to Discharge or NEWS ≤ 2 by Treatment 
Group – Baseline Ordinal Score 7, ITT Population .................................................115 
Figure 29: Kaplan-Meier Curves of Time to Discharge or NEWS ≤ 2 by Treatment 
Group – Baseline Ordinal Score 6, ITT Population .................................................115 
Figure 30: Kaplan-Meier Curves of Time to Discharge or NEWS ≤ 2 by Treatment 
Group – Baseline Ordinal Score 5, ITT Population .................................................115 
Figure 31: Kaplan-Meier Curves of Time to Discharge or NEWS ≤ 2 by Treatment 
Group – Baseline Ordinal Score 4, ITT Population .................................................115 
Figure 32: Mean NEWS by Day and Treatment Group – ITT Population ................................116 
Figure 33: Bee Swarm Plot of Oxygen Days by Treatment Group – ITT Population ...............117 
Figure 34: Bee Swarm Plot of Non-invasive Ventilation/High-Flow Oxygen Days by 
Treatment Group – ITT Population ..........................................................................117 
Figure 35: Bee Swarm Plot of Invasive Mechanical Ventilation/ECMO Days by 
Treatment Group – ITT Population ..........................................................................117 


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Figure 36: Bee Swarm Plot of Hospitalization Days by Treatment Group – ITT 
Population .................................................................................................................117 
Figure 37: Frequency of Non-Serious Related Adverse Events by MedDRA System 
Organ Class, Severity, and Treatment Group - As Treated Population ....................118 
Figure 38: Frequency of Non-Serious Related Adverse Events by MedDRA System 
Organ Class, Severity, and Treatment Group – Moderate Disease Severity, 
As Treated Population ..............................................................................................118 
Figure 39: Frequency of Non-Serious Related Adverse Events by MedDRA System 
Organ Class, Severity, and Treatment Group – Severe Disease Severity, As 
Treated Population ....................................................................................................118 
Figure 40: Incidence of Non-Serious Related Adverse Events by MedDRA System 
Organ Class, Severity, and Treatment Group - As Treated Population ....................119 
Figure 41: Incidence of Non-Serious Related Adverse Events by MedDRA System 
Organ Class, Severity, and Treatment Group – Moderate Disease Severity, 
As Treated Population ..............................................................................................119 
Figure 42: Incidence of Non-Serious Related Adverse Events by MedDRA System 
Organ Class, Severity, and Treatment Group – Severe Disease Severity, As 
Treated Population ....................................................................................................119 
Figure 43: Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group 
– ITT Population .......................................................................................................120 
Figure 44: Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group 
and Randomized Disease Severity – ITT Population ...............................................121 
Figure 45: Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group 
– As Treated Population ...........................................................................................121 
Figure 46: Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group 
and Actual Disease Severity – As Treated Population .............................................121 
Figure 47: Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group 
– Baseline Ordinal Score 7, ITT Population .............................................................121 
Figure 48: Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group 
– Baseline Ordinal Score 6, ITT Population .............................................................121 
Figure 49: Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group 
– Baseline Ordinal Score 5, ITT Population .............................................................121 
Figure 50: Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group 
– Baseline Ordinal Score 4, ITT Population .............................................................121 
Figure 51: Kaplan-Meier Curve of Time to Death, SAE, Discontinuation of Study 
Infusions or Grade 3 or 4 AE through Day 29 by Treatment Group – As 
Treated Population ....................................................................................................122 


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Figure 52: Kaplan-Meier Curve of Time to Death, SAE, Discontinuation of Study 
Infusions or Grade 3 or 4 AE through Day 29 by Treatment Group and 
Actual Disease Severity – As Treated Population ....................................................122 
Figure 53: [Parameter X] Results by Scheduled Visits: Change from Baseline by 
Treatment Group – As Treated Population ...............................................................123 
 
 


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Figure 1: 
CONSORT Flow Diagram 
 
 
 
Programming Note: Disease Stratum will be included in the final CONSORT diagram as separate diagrams.  
Content of individual boxes may be altered from the shell.


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Figure 2: 
Kaplan-Meier Curves of Time to Recovery by Treatment Group – ITT Population 
 
Programming Note:  For Subjects at risk counts, only display Days 1, 3, 5, 8, 11, 15, 22, 29.  Report p-value 
to 3 decimal places as noted in Section 13. 
 
Figures with similar format: 


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Figure 3: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group – As Treated Population 
Figure 4: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group and Randomized Disease 
Severity – ITT Population 
Figure 5: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group and Randomized Disease 
Severity – As Treated Population 
Figure 6: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group – Baseline Ordinal Score 
7, ITT Population 
Figure 7: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group – Baseline Ordinal Score 
6, ITT Population 
Figure 8: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group – Baseline Ordinal Score 
5, ITT Population 
Figure 9: 
Kaplan-Meier Curve of Time to Recovery by Treatment Group – Baseline Ordinal Score 
4, ITT Population 
 


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Figure 10: 
Forest Plot of Hazard Ratios of Time to Recovery by Subgroup - ITT Population 
 
 
Figures with similar format: 
Figure 11: 
Forest Plot of Hazard Ratios of Time to Recovery by Subgroup - As Treated Population 
Figure 12: 
Forest Plot of Hazard Ratios of Time to Recovery by Comorbidity - ITT Population  
Figure 13: 
Forest Plot of Hazard Ratios of Time to Recovery: Leave One Site Out Sensitivity 
Analysis - ITT Population 
 
Programming Notes for Figure 12: Use the comorbidities listed in Table 52. 
 


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Figure 14: 
Study Visit Day 15 Clinical Status Score by Baseline Score and Treatment Group – ITT 
Population 
 
 


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Figure 15: 
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: 


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Figure 16: 
Kaplan-Meier Curves of Time to Improvement by at least Two Categories of Clinical 
Status Score by Treatment Group – ITT Population 
Figure 17: 
Kaplan-Meier Curves of Time to Improvement by at least One Category of Clinical 
Status Score by Treatment Group – Baseline Ordinal Score 7, ITT Population 
Figure 18: 
Kaplan-Meier Curves of Time to Improvement by at least One Category of Clinical 
Status Score by Treatment Group – Baseline Ordinal Score 6, ITT Population 
Figure 19: 
Kaplan-Meier Curves of Time to Improvement by at least One Category of Clinical 
Status Score by Treatment Group – Baseline Ordinal Score 5, ITT Population 
Figure 20: 
Kaplan-Meier Curves of Time to Improvement by at least One Category of Clinical 
Status Score by Treatment Group – Baseline Ordinal Score 4, ITT Population 
Figure 21: 
Kaplan-Meier Curves of Time to Improvement by at least Two Categories of Clinical 
Status Score by Treatment Group – Baseline Ordinal Score 7, ITT Population 
Figure 22: 
Kaplan-Meier Curves of Time to Improvement by at least Two Categories of Clinical 
Status Score by Treatment Group – Baseline Ordinal Score 6, ITT Population 
Figure 23: 
Kaplan-Meier Curves of Time to Improvement by at least Two Categories of Clinical 
Status Score by Treatment Group – Baseline Ordinal Score 5, ITT Population 
Figure 24: 
Kaplan-Meier Curves of Time to Improvement by at least Two Categories of Clinical 
Status Score by Treatment Group – Baseline Ordinal Score 4, ITT Population 
 


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Figure 25: 
Distribution of Clinical Status Scores by Day by Treatment Group – ITT Population 
 
 
Programming Note: Heat map coloring will be used for the clinical score scale. The y-axis will be percentages 
instead of frequency counts. The same categories presented in the tabular summary will be use in this figure. 
The “no clinical score” categories will displayed at the top of the stacked bars using colors distinct from the 
heat map colors. Use the format/coloring used for ACTT-1. 
 


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Figure 26:  Bar Plots of Clinical Status Scores by Study Day and Treatment Group – ITT Population 
 
 
Programming Note: The same categories presented in the tabular summary will be use in this figure. The “no 
clinical score” categories will be displayed at the x = 9, 10, 11 (and 12 if the Completed Study without 
reporting score category is needed).  
 
  
 
    
 
   
   
   
   
   
   
   


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Figure 27: 
Kaplan-Meier Curves of Time to Discharge or NEWS ≤ 2 by Treatment Group – ITT 
Population 
 
 
Figures with similar format: 
Figure 28: 
Kaplan-Meier Curves of Time to Discharge or NEWS ≤ 2 by Treatment Group – Baseline 
Ordinal Score 7, ITT Population 
Figure 29: 
Kaplan-Meier Curves of Time to Discharge or NEWS ≤ 2 by Treatment Group – Baseline 
Ordinal Score 6, ITT Population 
Figure 30: 
Kaplan-Meier Curves of Time to Discharge or NEWS ≤ 2 by Treatment Group – Baseline 
Ordinal Score 5, ITT Population 
Figure 31: 
Kaplan-Meier Curves of Time to Discharge or NEWS ≤ 2 by Treatment Group – Baseline 
Ordinal Score 4, ITT Population 
 


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Figure 32: Mean NEWS by Day and Treatment Group – ITT Population 
 
 
Programming Note: Add the footnote: Subjects who die or are discharged are not reflected in Study Days 
after their date of death/discharge. 
 
 
 


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Figure 33: 
Bee Swarm Plot of Oxygen Days by Treatment Group – ITT Population 
 
Programming Note: Use the format used for ACTT-1 which incorporated summary statistics. 
Figures with similar format: 
Figure 34: 
Bee Swarm Plot of Non-invasive Ventilation/High-Flow Oxygen Days by Treatment 
Group – ITT Population  
Figure 35: 
Bee Swarm Plot of Invasive Mechanical Ventilation/ECMO Days by Treatment Group – 
ITT Population  
Figure 36: 
Bee Swarm Plot of Hospitalization Days by Treatment Group – ITT Population  
 
0


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Figure 37: 
Frequency of Non-Serious Related Adverse Events by MedDRA System Organ Class, 
Severity, and Treatment Group - As Treated Population 
 
 
Programming Note: Two separate sub-figures will be generated for each disease severity. Actual disease 
severity will be used for each figure. 
 
Figures with similar format: 
Figure 38: 
Frequency of Non-Serious Related Adverse Events by MedDRA System Organ Class, 
Severity, and Treatment Group – Moderate Disease Severity, As Treated Population 
Figure 39: 
Frequency of Non-Serious Related Adverse Events by MedDRA System Organ Class, 
Severity, and Treatment Group – Severe Disease Severity, As Treated Population 
 
 


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Figure 40: 
Incidence of Non-Serious Related Adverse Events by MedDRA System Organ Class, 
Severity, and Treatment Group - As Treated Population 
 
 
Programming Note: Two separate sub-figures will be generated for each disease severity. Actual disease 
severity will be used for each figure. 
 
Figures with similar format: 
Figure 41: 
Incidence of Non-Serious Related Adverse Events by MedDRA System Organ Class, 
Severity, and Treatment Group – Moderate Disease Severity, As Treated Population 
Figure 42: 
Incidence of Non-Serious Related Adverse Events by MedDRA System Organ Class, 
Severity, and Treatment Group – Severe Disease Severity, As Treated Population 
 


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Figure 43: 
Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group – ITT 
Population 
 
 


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Figures with similar format: 
Figure 44: 
Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group and 
Randomized Disease Severity – ITT Population 
Figure 45: 
Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group – As 
Treated Population 
Figure 46: 
Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group and Actual 
Disease Severity – As Treated Population 
Figure 47: 
Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group – Baseline 
Ordinal Score 7, ITT Population 
Figure 48: 
Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group – Baseline 
Ordinal Score 6, ITT Population 
Figure 49: 
Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group – Baseline 
Ordinal Score 5, ITT Population 
Figure 50: 
Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group – Baseline 
Ordinal Score 4, ITT Population 
 
Programming Notes for Figure 44 and Figure 46: The figures will have two panels, one for each disease 
severity. 
 


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Figure 51: 
Kaplan-Meier Curve of Time to Death, SAE, Discontinuation of Study Infusions or 
Grade 3 or 4 AE through Day 29 by Treatment Group – As Treated Population 
 
 
Figure with similar format: 
Figure 52: 
Kaplan-Meier Curve of Time to Death, SAE, Discontinuation of Study Infusions or 
Grade 3 or 4 AE through Day 29 by Treatment Group and Actual Disease Severity – As 
Treated Population 
 
Programming Note: Figure will have two panels, one for each disease severity. 
 


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Figure 53: 
[Parameter X] Results by Scheduled Visits: Change from Baseline by Treatment Group – 
As Treated Population 
 
 
Programming Note: The shell provided is a generic figure. The Groups within a panel will be treatment 
groups and the panels will be actual disease severity. The points will be the median change from baseline and 
the bars will represent the Q1 and Q3 quartiles of the change from baseline at each time point. Panels for each 
laboratory parameter will be generated. 
 


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APPENDIX 3. LISTINGS MOCK-UPS 
TABLE OF LISTINGS 
Listing 1: Exclusions from the As Treated Population .............................................................125 
Listing 2: Subjects who Early Terminated or Discontinued Treatment ....................................126 
Listing 3: Subject-Specific Protocol Deviations .......................................................................127 
Listing 4: Non-Subject-Specific Protocol Deviations ...............................................................128 
Listing 5: Individual Efficacy Response Data: Clinical Status Score Data ..............................129 
Listing 6: Individual Efficacy Response Data: NEWS .............................................................130 
Listing 7: Demographic Data ....................................................................................................131 
Listing 8: Pre-Existing and Concurrent Medical Conditions ....................................................132 
Listing 9: Concomitant Medications .........................................................................................133 
Listing 10: Medications of Interest .............................................................................................134 
Listing 11: Compliance Data ......................................................................................................135 
Listing 12: Listing of Non-Serious Adverse Events ...................................................................136 
Listing 13: Listing of Related Adverse Events ...........................................................................137 
Listing 14: Listing of Non-Fatal Serious Adverse Events ..........................................................138 
Listing 15: Listing of Infections ..................................................................................................139 
Listing 16: Listing of Deaths .......................................................................................................140 
Listing 17: Pregnancy Reports – Maternal Information .............................................................141 
Listing 18: Pregnancy Reports – Gravida and Para ....................................................................142 
Listing 19: Pregnancy Reports – Live Birth Outcomes ..............................................................143 
Listing 20: Pregnancy Reports – Still Birth Outcomes ...............................................................144 
Listing 21: Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion 
Outcomes ..................................................................................................................145 
Listing 22: Clinical Laboratory Results ......................................................................................146 
Listing 23: Physical Exam Findings ...........................................................................................147 
Listing 24: Subjects who Received the Incorrect Treatment ......................................................148 
Listing 25: Subjects Randomized to the Incorrect Disease Severity Stratum .............................148 
 


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Listing 1: 
Exclusions from the As Treated Population 
Randomized Treatment Group 
Actual Disease Severity 
Subject ID 
Baricitinib + RDV/ 
Placebo + RDV 
Moderate / Severe 
XXXXX 
 
Programming Notes: Include randomized subjects only.  Sort Order = Treatment Group, Disease Severity, 
USUBJID.  
 


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Listing 2: 
Subjects who Early Terminated or Discontinued Treatment 
Actual Treatment Group 
Actual Disease 
Severity 
Subject ID 
Category 
Treatment Discontinued 
Reason for Early Termination or Treatment 
Discontinuation 
Study Day 
Baricitinib + RDV/ 
Placebo + RDV 
Moderate / 
Severe 
XXXXX 
Early Termination/Treatment 
Discontinuation 
NA/Infusions/Tablets/Infusions + 
Tablets 
Xxxxxx 
xxxx 
 
Programming Notes: Sort Order = Treatment Group, Actual Severity, USUBJID, category where Treatment discontinuation is sorted prior to Early 
termination. If there are multiple treatment discontinuations (i.e. distinct dates for each product type) the order will be sorted by Study day. If both 
treatments were discontinued at the same time “Infusions + Tablets” will be displayed in the Treatment Discontinued column. If subjects were 
randomized and not dosed are categorized as “Not Treated” and sorted after Placebo + RDV if applicable. 
 


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Listing 3: 
Subject-Specific Protocol Deviations 
Actual Treatment 
Group 
Actual 
Disease 
Severity 
Subject ID DV Number Deviation 
Major/Minor 
Designation 
Deviation 
Category 
Study 
Day 
Reason for 
Deviation 
Deviation 
Resulted 
in AE? 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Comments 
Baricitinib + RDV/ 
Placebo + RDV 
Moderate / 
Severe 
Xxxxx 
xx 
xxx 
Major/Minor 
xxx 
x 
xxxx 
Yes/No 
Yes/No 
Yes/No 
xxxx 
 
Programming Notes:  Sort Order = Treatment Group, Actual severity, USUBJID, Deviation Number. Concatenate all the specify fields as appropriate. If 
the columns do not fit within the eCTD specified margins, then Actual Treatment Group, Actual Disease Severity, Subject ID will be placed in a header 
row as in the AE listings. 
 


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Listing 4: 
Non-Subject-Specific Protocol Deviations 
Site 
Start Date  
End Date 
Deviation 
Major/Minor 
Designation 
Reason for 
Deviation 
Deviation Resulted in 
Subject Termination? 
Deviation Affected 
Product Stability? 
Deviation 
Category 
Comments 
xxxx 
xxxx 
xxxx 
xxxx 
Major/Minor 
xxxx 
Yes/No 
Yes/No 
xxxx 
Xxxxx 
 
Programming Notes: Sort Order = Site (use site name and not the 5 alphanumeric site code), start date, deviation. Concatenate all the specify fields as 
appropriate  
 


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Listing 5: 
Individual Efficacy Response Data: Clinical Status Score Data 
Actual Treatment Group  
Actual Disease Severity 
Subject ID 
Study Visit Day of Assessment 
Actual Study Day of Assessment 
Clinical Status Score  
Clinical Status 
Baricitinib + RDV/ 
Placebo + RDV 
Moderate / Severe 
xxxxx 
xx 
xx 
xx 
xxxxx 
 
Programming Notes: Sort Order = Treatment Group, Actual severity, USUBJID, Study Day. Clinical status should match the wording of the scale 
definitions in Section 4.3.  


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Listing 6: 
Individual Efficacy Response Data: NEWS 
Study Visit 
Day 
Actual Study 
Day 
Respiratory Rate  
O2 Saturation  
Any Supplemental O2 
Temperature  
Systolic BP  
Heart Rate 
Level of 
Consciousness 
Total 
Score 
bpm 
Score 
% 
Score 
Yes/No 
Score 
°C 
Score 
mmHg 
Score 
bpm 
Score 
A/V/P/U 
Score 
Actual Treatment Group: , Actual Disease Severity: , Subject ID:  
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
If the subject was on ECMO, heart rate and respiratory rate is denoted with a “-“ and score of 3.  If the subject is ventilated, the respiratory rate is denoted with a “-“ and a score of 3. 
 
Programming Notes: Sort Order = Treatment Group, Actual Severity, USUBJID, Study Visit Day.  
 


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Listing 7: 
Demographic Data 
Actual Treatment 
Group 
Actual Disease 
Severity 
Subject ID 
Geographic 
Region 
Sex 
Age at 
Enrollment 
(years) 
Ethnicity 
Race 
Duration of Symptoms 
prior to Enrollment 
(Days) 
Weight (Kg) 
Height 
(Cm) 
BMI 
Baricitinib + RDV/ 
Placebo + RDV 
Moderate / 
Severe 
xxxxx 
xxx 
xxx 
Xx 
xxx 
xxx 
xxx 
xx 
Xx 
Xxx 
 
Programming Notes: Sort Order = Treatment Group, Actual severity, USUBJID.  
 


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Listing 8: 
Pre-Existing and Concurrent Medical Conditions 
Actual 
Treatment 
Group 
Actual 
Disease 
Severity 
Subject 
ID 
History of DVT 
or PE 
Major Surgery, Significant 
Trauma, Long 
Hospitalization within one 
month of screening 
Prolonged Immobility 
within one month of 
screening 
Medical History 
Number 
Medical History 
Term 
MedDRA 
System Organ 
Class 
MedDRA 
Preferred 
Term 
Baricitinib + 
RDV/ 
Placebo + RDV 
Moderate/ 
Severe 
Xxx001 
Yes/No/Unknown 
Yes/No/Unknown 
Yes/No/Unknown 
01 
xxxxx 
Xxxx 
xxxx 
02 
xxxxx 
Xxxx 
xxxx 
 
Programming Notes: Sort Order = Treatment Group, Actual Severity, USUBJID, MH Number. Each subject will have one row per medical condition 
reported on the Medical History CRF. If the subject reported “no” they do not have that pre-existing condition, the condition is not present in the line 
listing. If there is not enough space to fit all columns within the eCTD specified margins, then Actual Treatment Group, Actual Disease Severity, and 
Subject ID can be displayed in a header row as in the AE listings. 
 


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Listing 9: 
Concomitant Medications 
Actual Treatment 
Group 
Actual 
Disease 
Severity 
Subject 
ID 
Medication 
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) 
Baricitinib + RDV/ 
Placebo + RDV 
Moderate/ 
Severe 
xxx 
xx 
xxxx 
x 
x 
xxxx 
Yes/No 
Yes/No 
xxxx / xxxx 
 
Programming Notes:  Sort Order = Treatment Group, Actual severity, 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 


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Listing 10: 
Medications of Interest 
Actual Treatment 
Group 
Actual Disease 
Severity 
Subject 
ID 
Medication 
Number 
Medication 
Medication 
Start Day 
Medication 
End Day 
Indication 
Medication of Interest 
Category 
Medication of Interest 
Subcategory 
Baricitinib + RDV/ 
Placebo + RDV 
Moderate/ 
Severe 
xxx 
xx 
xxxx 
x 
x 
xxxx 
xxxx 
xxxx 
 
Programming Notes:  Sort Order = Treatment Group, Actual severity, 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 
If the medication does not have an applicable subcategory, then display ‘N/A’ 


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Listing 11: 
Compliance Data  
Dose 
Number 
Infusions 
Tablets 
Reason for 
Missed Dose 
Comments 
Infusion 
Administered? 
Infusion Slowed or 
Stopped? 
Reason(s) for 
Slowed/Stopped Infusion 
Volume Administered if 
Stopped/Slowed (mL) 
Number of Tablets 
Administered 
Tablet Administered 
Successfully? 
Actual Treatment Group: , Actual Disease Severity: , Subject ID: , Study Day of Discharge: , Study Day of Death: 
1 
Yes/No 
No/Yes (Slowed)/Yes 
(Stopped) 
Xxxxx / NA 
Xxx 
2/1 
Yes/No 
Xxx/NA 
 
2 
Yes/No 
No/Yes (Slowed)/Yes 
(Stopped) 
Xxxxx / NA 
Xxx 
2/1 
Yes/No 
Xxx/NA 
… 
 
… 
… 
… 
… 
… 
… 
… 
 
Programming Notes:  Sort Order = Treatment Group, Actual severity, USUBJID. If columns do not fit within the eCTD specified margins, then Study 
Day of Discharge and Study Day of Death can be added to the header row after Subject ID. 
 


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Listing 12: 
Listing of Non-Serious Adverse Events 
Adverse 
Event 
Study Day 
Duration 
Severity 
Relationship 
to Study 
Treatment 
If Not 
Related, 
Alternative 
Etiology 
Unanticipated 
Problem 
Action 
Taken with 
Study 
Treatment 
Subject 
Discontinued Due 
to AE 
Outcome 
MedDRA 
System 
Organ 
Class 
MedDRA 
Preferred 
Term 
Actual Treatment Group: Actual Disease Severity: , Subject ID: , AE Number:  
xxx 
xx 
x 
xxx 
Related/Not 
Related 
xxxx 
Yes/No 
xxx 
Yes/No 
xxxx 
xxxx 
xxxx 
Comments: xxxx 
 
Programming Note: Sort order will be Treatment Group, Actual severity, USUBJID, AE Number.  


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Listing 13: 
Listing of Related Adverse Events 
Adverse 
Event 
Study Day 
Duration 
Severity 
Unanticipated 
Problem 
Action Taken with 
Study Treatment 
Subject Discontinued 
Due to AE 
Outcome 
MedDRA 
System Organ Class 
MedDRA 
Preferred Term 
Actual Treatment Group: Actual Disease Severity: , Subject ID: , AE Number:  
xxx 
xx 
x 
xxx 
Yes/No 
xxx 
Yes/No 
xxxx 
xxxx 
xxxx 
Comments: xxx 
 
Programming Note: Sort order will be Treatment Group, Actual severity, USUBJID, AE Number. 


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Listing 14: 
Listing of Non-Fatal Serious Adverse Events 
Adverse 
Event 
Study 
Day 
Duration 
No. of Days 
Post First Dose 
the Event 
Became Serious 
Reason 
Reported 
as an 
SAE 
Severity 
Relationship 
to Study 
Treatment 
If Not 
Related, 
Alternative 
Etiology 
Unanticipated 
Problem 
Action 
Taken 
with 
Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ Class 
MedDRA 
Preferred 
Term 
Actual Treatment Group:  , Actual Disease Severity: , Subject ID: , AE Number:  
xxxx 
x 
x 
x 
xxxxx 
xxx 
Related/Not 
Related 
xxxx 
Yes/No 
xxxx 
Yes/No 
xxxxx 
xxxxx 
xxxxx 
Comments: xxxx 
 
Programming Note: Sort order will be Treatment Group, Actual severity, USUBJID, AE Number.   
 


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Listing 15: 
Listing of Infections 
Study Day 
Anatomical Location 
Pathogen 1 
Pathogen 2 
Pathogen 3 
Pathogen 4 
Associated with AE Number 
Secondary AE Number 
Actual Treatment Group:  , Actual Disease Severity: , Subject ID: 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Programming Note: Sort order will be Treatment Group, Actual severity, USUBJID, AE Number. 
 


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Listing 16: 
Listing of Deaths 
Adverse 
Event 
Study 
Day 
Duration 
No. of Days Post 
First Dose the 
Event Became 
Serious 
Reason 
Reported 
as an SAE 
Severity 
Relationship 
to Study 
Treatment 
If Not 
Related, 
Alternative 
Etiology 
Unanticipated 
Problem 
Action 
Taken with 
Study 
Treatment 
Subject 
Discontinued 
Due to AE 
MedDRA 
System 
Organ 
Class 
MedDRA 
Preferred 
Term 
Actual Treatment Group: ,  Actual Disease Severity: , Subject ID: , AE Number:  
xxxx 
x 
x 
x 
Xxxxx 
xxx 
Related/Not 
Related 
xxxx 
Yes/No 
xxxx 
Yes/No 
xxxxx 
xxxxx 
Comments: xxxx 
 
Programming Note: Sort by actual treatment group, actual severity, USUBJID. 
 


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Listing 17: 
Pregnancy Reports – Maternal Information 
Actual 
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 18: 
Pregnancy Reports – Gravida and Para 
 
Live Births 
 
Actual 
Treatment 
Group 
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? 
Baricitinib 
+ RDV/ 
Placebo + 
RDV 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gravida includes the current pregnancy, para events do not. 
a Preterm Birth 
b Term Birth 
 


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Listing 19: 
Pregnancy Reports – Live Birth Outcomes 
Actual 
Treatment 
Group 
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? 
Baricitinib 
+ RDV/ 
Placebo + 
RDV 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Congenital Anomalies are included in the Adverse Event listing. 
 


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Listing 20: 
Pregnancy Reports – Still Birth Outcomes 
Actual 
Treatment 
Group 
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? 
Baricitinib 
+ RDV/ 
Placebo + 
RDV 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 21: 
Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion Outcomes 
Actual 
Treatment 
Group 
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 
Baricitinib + 
RDV/ 
Placebo + RDV 
 
 
 
 
 
 
 
 


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Listing 22: 
Clinical Laboratory Results 
Actual Treatment 
Group 
Actual 
Disease 
Severity 
Subject ID 
Planned 
Time Point  
Actual 
Study 
Day  
Sex  
Age 
(years) 
Laboratory 
Parameter (Units) 
Result 
(Toxicity Grade) 
Change from 
Baseline 
Reference 
Range Low 
Reference Range 
High 
Baricitinib + RDV/ 
Placebo + RDV 
Moderate/ 
Severe 
xxx 
xx 
xx 
Xx 
x 
xxx (xxx) 
xxx (xxxx) 
xxx 
xxxx 
xxxx 
 
Programming Note: Sort order will be treatment group, Actual severity, USUBJID, planned time point, and lab parameter. If subjects were randomized 
and not dosed “Not Treated” will be used for the actual treatment category and will be sorted after Placebo+ RDV. All parameters will be included in the 
listing. 
 


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Listing 23: 
Physical Exam Findings 
Actual Treatment 
Group 
Actual Disease Severity 
Subject ID 
Planned 
Study Day 
Actual 
Study Day 
Body System 
Abnormal Finding 
Reported as an AE? 
(AE Description; Number) 
Baricitinib + RDV/ 
Placebo + RDV 
Moderate/Severe 
xxx 
xx 
xx 
xxxx 
xxxxxx 
Yes/No/NA 
 
Programming 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. If the finding was not reported as an AE as 
recorded on the CRF or the site did not report whether the finding was reported as an AE, the cell will display 'No'. 
Sort order will be treatment group, actual severity, USUBJID, planned time point, and body system.   


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Listing 24: 
Subjects who Received the Incorrect Treatment 
Subject ID 
Randomized Treatment 
Group 
Number of Infusions 
Received 
Number of Doses Received 
Number of Incorrect Doses 
Received 
xxx 
Baricitinib + RDV/ 
Placebo + RDV 
x 
x 
x 
 
Listing 25: 
Subjects Randomized to the Incorrect Disease Severity Stratum 
Subject ID 
Actual Treatment Group 
Randomized Disease Severity 
Actual Disease Severity 
xxx 
Baricitinib + RDV/ 
Placebo + RDV 
Moderate/Severe 
Moderate/Severe 
 
Programming Note: Sort but USUBJID. If subjects were randomized and not dosed “Not Treated” will be 
used for the actual treatment category.