Clinical trial NCT04640168
Conditions: COVID-19
Keywords: ACTT Adaptive COVID-19 Efficacy Multicenter novel coronavirus Safety
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2020-12-02; Completion date: 2021-06-18
Enrollment: 1010 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
ACTT-4 will evaluate the combination of baricitinib and remdesivir compared to dexamethasone and remdesivir. 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, oropharyngeal (OP) swabs, plasma (Day 29), and serum for secondary research as well as clinical outcome data. However, if infection control or other restrictions limit the ability of the subject to return to the clinic, 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 objective is to evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir as assessed by the mechanical ventilation free survival 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-4 will evaluate the combination of baricitinib and remdesivir compared to dexamethasone and remdesivir. 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, oropharyngeal (OP) swabs, plasma (Day 29), and serum for secondary research as well as clinical outcome data. However, if infection control or other restrictions limit the ability of the subject to return to the clinic, 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 objective is to evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir as assessed by the mechanical ventilation free survival by Day 29. The key secondary objective is to evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir according to clinical status (8-point ordinal scale) at Day 15.

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; 4 mg of baricitinib administered as 2 tablets taken orally daily while hospitalized for up to a 14-day total course; and dexamethasone placebo administered as an intravenous injection daily while hospitalized for up to a 10-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; baricitinib placebo administered as 2 tablets taken orally daily while hospitalized for up to a 14-day total course; and 6 mg of dexamethasone administered as an intravenous injection daily while hospitalized for up to a 10-day total course.
Interventions: intervention 1: Baricitinib intervention 2: Dexamethasone intervention 3: Placebo intervention 4: Remdesivir
Intervention descriptions: intervention 1: 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. intervention 2: Dexamethasone Sodium Phosphate Injection, USP, is an adrenocortical steroid anti-inflammatory drug. It is a water-soluble inorganic ester of dexamethasone. Each mL contains dexamethasone sodium phosphate equivalent to dexamethasone phosphate 4 mg or dexamethasone 3.33 mg; benzyl alcohol 10 mg added as preservative; sodium citrate dihydrate 11 mg; sodium sulfite 1 mg as an antioxidant. intervention 3: Placebo matching oral baricitinib or intravenous dexamethasone. intervention 4: Drug remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524. In addition to the active ingredient, the lyophilized formulation of remdesivir contains the following inactive ingredients: water for injection, sulfobutylether beta-cyclodextrin sodium (SBECD), and hydrochloric acid and/or sodium hydroxide.

Protocol documents:
ICF_000.pdf: 
Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 1 of 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
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: 
 
20-0006 
 
Principal Investigator: 
(Study Doctor) 
 
Faheem Guirgis, MD 
 
Telephone: 
 
(904) 244-4986 
 
 
Address: 
University of Florida-Jacksonville  
15255 Max Leggett Pkwy 
Jacksonville, FL    32218 
 
University of Florida-Jacksonville 
UF-Health Jacksonville 
655 West Eighth Street 
Jacksonville, FL    32209 
 
 
 
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. In this study, we will be studying U.S. Food and Drug Administration (FDA)-approved 
(licensed) drugs that are usually used to treat other diseases to see if these drugs are safe and work 
in people hospitalized with COVID-19, an illness caused by the new coronavirus, SARS CoV-2. 
The use of these study drugs is “investigational” or “experimental”, because the combination of 
these study drugs have not been approved by the FDA to treat COVID-19. 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 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
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 now a few FDA-licensed medications to treat COVID-19, one is an antiviral drug called 
remdesivir (Veklury®). Data from an earlier related study (ACTT-1) found that hospitalized 
participants with COVID-19 who got remdesivir recovered faster than participants who did not 
get remdesivir. This study will also test two other licensed, anti-inflammatory drugs. One of these 
drugs, Baricitinib, has been issued an Emergency Use Authorization by the FDA for use in 
combination with remdesivir for the treatment of suspected or laboratory confirmed COVID-19 in 
hospitalized adults requiring supplemental oxygen, invasive mechanical ventilation, or 
extracorporeal membrane oxygenation (ECMO). Each study drug will be given with remdesivir 
(Veklury®) to learn which combination study treatment is better and safer for treating adult 
participants hospitalized with COVID-19. 
 
What drugs are being studied? 
Remdesivir (Veklury®) is given to all people who enroll in this study. 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 
your arm.  
 
Half of participants will get a licensed drug called baricitinib, plus remdesivir (Veklury®). 
Baricitinib is used to treat rheumatoid arthritis. Data from an earlier related study (ACTT-2) found 
that hospitalized participants with COVID-19 who got baricitinib plus remdesivir got better faster 
than participants who got remdesivir alone. Baricitinib is given as 1 to 2 tablets that you swallow. 
 
Half of participants will get a licensed drug called dexamethasone, plus remdesivir (Veklury®).  
Dexamethasone is a steroid used to treat diseases that cause inflammation of the lungs, skin, eye, 
joints, and nervous system. Data from a study found that hospitalized participants with COVID-
19 who got dexamethasone had a lower death rate than those who did not get dexamethasone.  It 
is given as an intravenous (IV, into the vein) infusion over 3 to 5 minutes. 
 
All participants will also get either a placebo tablet that looks like baricitinib or a placebo infusion 
that looks like dexamethasone (plus remdesivir). Placebo tablets or placebo infusions are not active 
drugs and are often used in research studies. The placebo tablet is made of inactive ingredients, 
like sugar (lactose monohydrate). The placebo infusion is a salt solution.   
 


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 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
Will you get the study drug or placebo? 
If you join this study, you will be randomly put into one of two study groups. This is decided by 
chance (like tossing a dice) and you will have an equal chance of being in either study group. Out 
of every two participants, one will get baricitinib and placebo infusion plus remdesivir, and one 
will get placebo tablets and dexamethasone plus remdesivir. You and the study staff will not know 
what group you are in or what study drug you are getting until the end of the study. However, your 
study doctor can find out which group you are in if there is an emergency. 
 
What will happen on this study? 
If you agree to be screened for this study, we will first do some tests, including blood draws, to 
make sure it is safe for you to join the study. Only hospitalized adults 18 years old and older who 
are not pregnant and who test positive for COVID-19 can join this study. If you are breastfeeding 
you may only join the study if you agree to discard the breastmilk from the time the first dose of 
study drug is given until 2 weeks after last study drug is given. You may not be able to join this 
study if you have abnormal kidney tests or very low levels of white blood cells, or if you have 
received a biologic therapy (including B-cell or T-cell targeted therapies) for the treatment of 
COVID-19 in the last 2 weeks. You may not also be able to join this study if you are taking high 
dose corticosteroids such as prednisone, take a medicine for gout called probenecid, have recently 
received live vaccines, or if you have influenza, deep vein thrombosis, tuberculosis, or another 
serious infection.  
 
If you qualify for this study and decide to join, you will be placed into one of two study groups. 
One group will get baricitinib and placebo infusion and one group will get placebo tablets and 
dexamethasone. All participants will also get one remdesivir infusion every day for up to 10 days.   
 
We will take blood and swab samples from you on Days 1, 3, 5, 8, 11, 15 and 29 for as long as 
you remain in the hospital. We will use the samples for research and safety tests. If you are 
discharged from the hospital before Day 15, you will come back to the site for study visits on Day 
15 and 29 to have blood and swab samples collected. At these outpatient visits, we will ask if you 
were readmitted to a hospital and also ask about your health and recovery. If you are unable to 
come back for study visits, we will call you. We will also call you on Day 22 and Day 60 to ask 
you about your health, hospital readmissions and recovery. Your total amount of time on this study 
will be about 60 days.  
 
What are the main study risks? 
Remdesivir has recently been licensed for treatment of COVID-19. The most common side effects 
of remdesivir include:  
• Abnormal liver function test results 
• Abnormal blood clotting test results 
• Constipation 
• Nausea 
• Vomiting 
• Decreased appetite  
• Headache  
 
 
 


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 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
The study drug baricitinib is FDA approved for the treatment of rheumatoid arthritis. The side 
effects of baricitinib in this group of patients are well known. Baricitinib blocks the effects of 
proteins in the body called Janus kinases. Blocking these proteins can affect the immune system 
and this can increase the risk of infection and cancer. Side effects of baricitinib include:  
• Increased upper respiratory tract infections 
• Urinary tract infections 
• Inflammation of the nasal passages, throat and or lungs 
• Flu symptoms 
• Stomach pain which may cause diarrhea, nausea and or vomiting  
• Cold sores and shingles (herpes zoster virus or herpes simplex) 
• Increases in blood tests related to the liver 
• Higher number of platelets (part of the blood that helps in clotting) 
• Upset stomach 
• Rash 
• Headache 
 
Allergic Reactions can occur during or after receiving remdesivir. Tell your study doctor if you 
experience any of the following symptoms of an allergic reaction: 
• Changes in heart rate 
• Fever 
• Shortness of breath 
• Swelling of the lips or mouth 
• Rash 
• Sweating 
• Shivering 
 
Dexamethasone is a steroid approved to treat inflammation.  
 
The side effects of dexamethasone are also well known. The most common side effects include: 
• Increased blood glucose (sugar) levels 
• Infections 
• Upset stomach 
• Stomach irritation (peptic ulcer) 
• Vomiting 
• Dizziness 
• Inability to fall asleep (insomnia) 
• Restlessness 
• Depression 
• Anxiety 
• Easy bruising  
 
 
 


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 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
Other Risks Associated with Study Participation 
We will insert a new, clean needle into a vein in your arm to take blood samples. We will also 
insert a needle into your vein which will be attached to IV tubing so that we can give you 
remdesivir and dexamethasone infusions, or IV placebo. You may feel pain when the needle goes 
through your skin. You may have a bruise, soreness or swelling where the needle entered skin, but 
these 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. 
 
People can rarely have allergic reactions to a drug, including hives, rash, trouble breathing, low 
blood pressure, dizziness and fainting, swelling around the mouth, throat or eyes, a fast pulse, or 
sweating. Allergic reactions may be severe or life-threatening. Short-term medical care will be 
provided if there are side effects from study drugs that can be treated. It is important that you 
always tell the study staff if you have any problems.  
 
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.  
 
Are there benefits to being in the study? 
Results from previous studies suggest that the study drugs work in participants hospitalized with 
COVID-19 but we do not know if you will benefit from being in this study. If one of the two 
combination study treatments work and you received that study treatment on this study, you may 
benefit by getting better sooner or having less severe disease. Information learned from the study 
may help other people in the future.  
 
What instructions do you need to follow? 
Female participants of childbearing potential must use effective contraception through Day 29. 
You need to wait until after the study before you become pregnant. 
 
You should not volunteer for another study that gives participants 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 includes people who have or have had COVID-19, you should talk to a member 
of the study team first especially if the other study will collect blood from you.  
 
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. 
 
For Women, Risks Related to Pregnancy 
If you are pregnant or nursing a child during the study, there may be risks to you, the embryo, 
fetus, or nursing child. Because of the potential risks, 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, unless you agree to discard breast milk from the time you start receiving 
the study drug until 2 weeks after you receive the last dose of study drug 
 
 
 


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 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
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. 
 
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 decide that you would like to be in the study, we will perform tests to see if you are eligible 
to participate (study screening). We will ask you to sign and date this consent form. When you 
sign your name or put your mark 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.  
 
You will also be asked if you consent to genetic testing. Participation in genetic testing is up to 
you and is completely voluntary. You can choose not to be part of that part of genetic testing at 
the end of this consent form. 
 
After you sign and date the consent form, we will decide if you are eligible for the study. To do 
this, we will ask you questions about your health, including whether you have kidney disease and 
allergies to medications, and which medications you received from your treating doctor during this 
COVID-19 illness. We will take some of your blood to determine if your kidneys are working well 
and if you have a low white blood cell count. We may get 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.  
 
If you meet all requirements to be in the study, you will be enrolled in the study. About 1,500 
eligible hospitalized adults with COVID-19 will be enrolled in this study. 
 
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 7 of 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
2. 
What does the study involve? 
 
If you are eligible for this study and decide to join, you will be enrolled and randomly placed into 
either study group 1 or study group 2 and receive the following study drugs:  
 
Study Group 1 
Study Group 2 
• Baricitinib 1 or 2 tablets daily for 14 days 
• Placebo IV infusion daily for 10 days 
• Remdesivir IV infusion daily for 5 to 10 days 
• Placebo 1 or 2 tablets daily for 14 days 
• Dexamethasone IV infusion daily for 10 days  
• Remdesivir IV infusion for 5 to 10 days 
 
The number of tablets you receive each day will depend upon your kidney function. The remdesivir 
IV infusion takes about 1 hour and the dexamethasone IV infusion about 3 to 5 minutes. We will 
watch you closely for side effects while study drugs are being given. After you are discharged 
from the hospital, you will not receive any more infusions or tablets.   
 
After study enrollment, the study doctor or your treating doctor will do a physical examination. 
We will collect your height and weight and information about you from your inpatient hospital 
records, such as medicines you are being given and whether you are receiving oxygen or need 
additional help breathing.  This information will help us determine how sick you are and whether 
you are improving during the study.  
 
Sample Collection 
Blood and swab samples will be collected from you on Days 1, 3, 5, 8, 11, 15 and 29, as long as 
you remain a patient in the hospital. The swabs may be taken from 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). 
If you are discharged before Day 15, you will come back to the site for study visits on Days 15 
and 29. During these follow-up visits, you will be asked if you were readmitted to a hospital and 
about your health and recovery, and blood and a swab sample will be collected for research and 
safety tests. Swab samples will be tested for presence of the virus that causes COVID-19.  
 
We will also call you on Day 22 and Day 60 to ask you about your health and recovery and if you 
were readmitted to a hospital or have seen a doctor for any reason. If you are an inpatient in the 
study hospital at Day 22 or Day 60 we will do the visit in-person. No samples will be collected. 
We may also collect health information from your hospital records on Day 29 and 60. 
Secondary Research 
As part of this study, we will collect 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. Secondary research 
will be done in the future to 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.  
 
 
 


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 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
Genetic Component of the Research 
This study will also include optional genetic research testing. If you agree to genetic research 
testing, we will evaluate how your body responds to COVID-19 by identifying RNA. RNA is 
genetic material in your cells that tells us how your body works. The genetic research testing is for 
research purposes only and it will not be able to tell you about relatives, paternity, or country of 
origin. The genetic research testing done in this study will not tell you about diseases that you may 
get in the future. We will not give you the results from the genetic research testing. Genetic 
research samples will be collected on Days 1, 3, 8 and 29 for a total blood volume of approximately 
2 – 3 teaspoons. 
 
The Sponsor will generally not provide this information to others without your consent. Your study 
site also has to follow privacy laws to protect your information. The Genetic Information 
Nondiscrimination Act (GINA) is a federal law that prohibits plans and health insurers from 
requesting genetic information or using genetic information. It also prohibits employment 
discrimination based on your health information. However, GINA does not address discrimination 
by companies that sell life insurance, disability insurance, or long-term care insurance. GINA also 
does not protect you against discrimination based on an already-diagnosed condition or disease 
that has a genetic component. 
 
3. 
What could be the side effects from the study drugs? 
 
In earlier studies in healthy normal volunteers, the most common adverse events for remdesivir 
were abnormal liver function and blood clotting test results, constipation, nausea and vomiting, 
headache, dizziness, and infusion site pain or infection. In previous study with participants 
hospitalized with COVID-19, the most common adverse events included decreased renal 
function, decreased hemoglobin (anemia), decreased lymphocyte count, respiratory failure, fever, 
and increased blood glucose. The occurrence of these adverse events were similar in the 
remdesivir and placebo groups. 
 
The abnormal liver function tests may last longer than a few days but come back to normal 
levels. Remdesivir contains a compound that caused changes in the kidneys of animals but did 
not affect how well the kidneys worked and went back to normal after the drug was stopped. We 
have not seen any long-lasting kidney problems in humans who have taken remdesivir. We will 
be following your kidney function during the study. 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 9 of 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
Baricitinib is a licensed drug that has a known safety profile for patients with rheumatoid arthritis 
who have taken the drug for long periods of time. The following table summarizes the risks and 
discomforts associated with baricitinib according to the package insert: 
 
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) 
• infections such as cold sores and 
shingles 
• upset stomach 
• rash 
• headache 
• changes in blood tests related to muscles 
• 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 
 
Baricitinib was studied in hospitalized participants with COVID-19 and the most common side 
effects were high blood glucose levels, anemia, decreased white blood cells (lymphocytes), and 
acute kidney injury. However, these events also occurred at a similar frequency in participants 
who got baricitnib and remdesivir, and in participants who got remdesivir alone. 
 
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 
with your current illness, 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.   
 
Dexamethasone is a steroid with a known safety profile. For this study, the most likely side effects 
will be:  
• Increased blood glucose levels 
• Infections 
• Upset stomach 
• Stomach irritation (peptic ulcer) 
• Vomiting, dizziness 
• Inability to fall asleep (insomnia) 


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 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
• Restlessness 
• Depression 
• Anxiety 
• Easy bruising 
 
It is less likely that you will have side effects that happen with long term use of dexamethasone 
including:  
• Muscle weakness 
• Muscle inflammation (steroid myopathy) 
• Bone loss (osteoporosis) 
• Impaired wound healing 
• Thin fragile skin 
• Skin bleeding and easy bruising 
• Reddened skin 
• Seizures 
• Elevation of blood pressure 
• Salt and water retention 
• Increased loss of potassium  
 
4. 
What are the other risks or discomforts of the study? 
 
This is a summary of the other risks or discomforts of being in the study: 
• Pain during blood draws or placement of the tube in your arm for the IV infusions.  
• Bruising, swelling and soreness at blood collection and IV infusion needle sites.  
• Infection risk at blood collection and IV infusion needle sites. 
• Temporary minor irritation at the nasal or oral swab site. 
• Coughing, sneezing or gagging when swabs are taken. 
• Allergic reactions (for example, hives, trouble breathing) to study drugs that may be severe 
or life-threatening.  
• Private information accidently seen by someone not involved in the study. 
• Risk to fetus or unborn child if you become pregnant during study. 
• Other unknown risk may occur since  dexamethasone has not been studied in combination 
with remdesivir, and dexamethasone and baricitinib are not licensed to treat COVID-19.  
 
You will be monitored for safety until study day 29 and short-term medical care will be provided 
if there are side effects 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. 
 
5. 
Are there benefits to being in the study? 
 
You may not benefit from being in this study. If the study drugs you received in this study work, 
you may benefit by getting better sooner and/or getting less severe disease. Your participation in 
this study is important to learn more about the study drugs if they are safe and work in hospitalized 
participants 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.  


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 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
 
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 
so this information cannot be traced back to you. The only risk of allowing us to store your samples 
and/or information would be an accidental release of your identity. 
 
Your samples will not be sold. Your samples collected during this study may be used for 
commercial profit (even if identifiers are removed). You will not be paid for any products that 
result from this research.  
 
Some (about 5 teaspoons) of the blood collected at Day 1, 3, 5, 8, 11, 15 and 29 will be used for 
secondary research. We plan to store and use these samples 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 done in the future to help us understand how the study drugs work, study other 
infections or diseases, or develop new laboratory tests. You will not be told about the future 
research. Secondary research DOES NOT include genetic testing. 
 
If you consent for blood collection for genetic research testing, you will have approximately 2 - 3 
teaspoons of blood collected during the study. A summary of the genetic results from all 
participants in this study will be placed in a public, unrestricted open access database that anyone 
can freely use. No individual genetic research testing information or results will be placed in an 
open access database. The risk of anyone identifying you with this information is very unlikely 
and state and federal laws provide some protections against genetic discrimination.   
 
You may change your mind about secondary research and/or genetic research testing 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. 
 
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 when you if you have been discharged 
from the hospital. We may ask you to return to the clinic for a medical exam and possible sampling.  
 
8. 
Will it cost you anything to be in this study? 
 
It will not cost you anything to be in this study. 
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 12 of 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
9. 
Will you be paid if you join this study? 
 
You will be paid up to $100 for your participation in this study, broken down as follows: 
 
• 
$25 for completion of today’s visit,  
• 
$25 for the completion of the day 15 in-person follow-up visit,   
• 
$25 for the phone visit on day 22, and  
• 
$25 for the in-person follow-up visit on day 29.  
 
Payment will be provided in the form of a gift card, which you will receive at the end of each in-
person visit.  
 
If you are paid more than $75 for taking part in this study, your name and social security number 
will be reported to the appropriate University employees for purposes of making and recording the 
payment as required by law. You are responsible for paying income taxes on any payments 
provided by the study. Payments to nonresident aliens must be processed through the University 
of Florida Payroll and Tax Services department. If the payments total $600 or more in a calendar 
year, the University must report the amount you received to the Internal Revenue Service (IRS). 
The IRS is not provided with the study name or its purpose. If you have questions about the 
collection 
and 
use 
of 
your 
Social 
Security 
Number, 
please 
visit: 
http://privacy.ufl.edu/SSNPrivacy.html.  
 
Your payment for participation in this research study is handled through the University of Florida’s 
Human Subject Payment (HSP) Program.  Your information which will include your name, 
address, date of birth, and SSN (depending on amount of money you are paid) is protected.  Access 
to the (HSP) Program site is limited to certain staff with the assigned security role.  You will be 
randomly assigned a specific identification (ID) number to protect your identity. 
 
If you have any problems regarding your payment contact the study coordinator. 
 
10. 
Who is watching over this study? 
 
A Data and Safety Monitoring Board (DSMB) will be looking at the study information very closely 
including safety data. The DSMB is made up of doctors and other people who are not directly 
involved in the study and who are experts on COVID-19 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 NIH, local ethics and health authorities, and the U.S. Food and Drug 
Administration (FDA) will also be watching over this study and have the authority to stop the 
study at any time.   
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 13 of 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
11. 
How will your privacy be protected? 
 
We will keep your study information private. All files with information that could identify you 
will be kept in locked cabinets or secure password protected computers. People responsible for 
making sure that the research is done properly may look at your study records. This might include 
people involved in this study from this hospital, the NIH, the FDA, and the drug companies that 
make the study drugs (remdesivir is made by Gilead Sciences, Inc., and baricitinib is made by Eli 
Lilly and Company). All of these people will also keep your identity private. By signing and dating 
this consent form, you agree that results from this study, but not your identity, may be shared with 
local medical providers, makers of the study drugs or government health organizations to help 
them better understand COVID-19. When results of an NIH research study are reported in medical 
journals or at scientific meetings, the participants who take part in the study are not named or 
identified.  
 
To help us protect your privacy, we have a Certificate of Confidentiality (Certificate) from the 
NIH. Study staff cannot provide to any person not connected with the research your name, or any 
materials that contain identifiable, sensitive information about you, unless permitted or required 
by a legal exception, such as state laws that require reporting of some contagious diseases. The 
most important protection provided by the Certificate is that the study staff cannot be forced to 
provide any of your identifiable, sensitive information, in any Federal, State, or local civil, 
criminal, administrative, legislative, or other proceeding, such as if there is a court subpoena, 
without your permission. The study team will use the Certificate to resist any demands for 
information that would identify you. 
 
Your information protected by the Certificate may still be disclosed or used when the information: 
1. Is disclosed to people connected with the research, for example, information may be used 
for  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 US Food and Drug 
Administration (FDA);  
3. Is necessary for your medical treatment and you have consented to this disclosure;  
4. Is for other research; 
5. Is disclosed with your consent (for example, an insurer or medical care provider gets your 
written consent for us to disclose the research information). 
 
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 and dating below you 
consent to those disclosures. 
 
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 study team may ask to see your health care records from your other 
health care providers. This is done so we can track your improvement during the study. For 
example, need for oxygen, physical examination findings, and readmissions. You may be asked to 
give us a list of other health care providers that you use. 


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 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
 
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. 
 
We are doing genetic testing for research purposes only and will not diagnose or look for inherited 
disease or defects. The genetic test results will not give information on paternity or your 
country/region of origin.  We will not give you the results from the genetic research testing.  
 
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 policy of the NIH is to evaluate investigators at least yearly for any conflicts of interest. 
Research participants may review the system for assessing conflicts of interest by checking the 
web site link: http://ethics.od.nih.gov/forms/Protocol-Review-Guide.pdf. Copies of the 
standards may also be requested by research participants. No NIH investigator involved in this 
study receives payments or other benefits from any company whose drug, product or device is 
being tested. This study has investigators that are NIH employees and some that are not. All 
non-NIH investigators are required to follow the principles of the Protocol Review Guide but 
are not required to report their financial holdings to the NIH. 
 
Gilead Sciences, Inc., the company that makes remdesivir, and Eli Lilly and Company, the 
company that makes baricitinib, are providing these study drugs for this study to NIH without 
charge. No NIH investigator involved in this study receives payments or other benefits from 
any company whose drug, product or device is being tested. However, there are some research 
partners not associated with the NIH working on this study who may receive payments or 
benefits, limited by the rules of their workplace. 
 
 
 


Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0006 
Page 15 of 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
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.  
 
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. 
 
What should you do if you are injured or ill as a result of being in this study? 
 
If you become ill or are injured while you are in the study, get the medical care that you need right 
away. You should inform the healthcare professional treating you that you are participating in this 
study. If you tell the study staff that you think you have been injured then they will help you get 
the care you need.  
 
The study site 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 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, baricitinib, and dexamethasone 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). 
 
 
 


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 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
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. 
 
Study staff have described this research study to me. I have read this consent form. All the 
questions that I have been answered by the study staff to my satisfaction. I voluntarily consent to 
participate in this research study. My consent includes allowing storage of samples and/or use of 
my study information and samples for an indefinite period of time for secondary research. By 
signing and dating this consent form, I have not given up any of my legal rights. I will get a 
signed and dated copy of this consent form for my records. 
 
If you agree to be in this study, please sign and date below. 
 
________________________________________                                  Date: _____/_____/_____ 
Signature of participant 
dd      mm      yy 
 
________________________________________ 
Printed name of participant 
 
________________________________________                                   Date: ____/_____/_____ 
Signature of investigator/designee 
dd       mm      yy 
 
________________________________________ 
Printed name of investigator/designee 
 
FOR ADULTS NOT CAPABLE of GIVING CONSENT  
 
________________________________________                                  Date: _____/_____/_____ 
Signature or fingerprint of Legally Authorized Representative (LAR)  
       dd      mm      yy 
 
_____________________________________ 
Printed name of LAR 
 
_____________________________________                                        Date: _____/_____/_____ 
Relationship of LAR to Participant                                                                       dd      mm      yy 
(Indicate why the LAR is authorized to act as a surrogate health care decision-maker under state or applicable local law) 
 
 
 


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 17   
 
 
Faheem Guirgis, MD 
Advarra IRB Approved Version 22 Jan 2021 
Revised 22 Jan 2021 
 
Complete if participant is illiterate: 
 
 
Witness to Consent Interview 
 
On the date given next to my signature, I witnessed the consent interview for the research study 
named above in this document. I attest that the information in this consent form was explained to 
the participant, and the participant indicated that his/her questions and concerns were adequately 
addressed. 
 
________________________________________                                  Date: _____/_____/_____ 
Signature of witness 
dd       mm      yy 
 
________________________________________ 
Printed name of witness 
 
Genetic Research Testing 
As stated above, we will perform genetic research testing on your blood sample. This genetic 
research testing will give us information about how your body responds to infection with the virus 
that causes COVID-19. With your consent, your genetic testing information and samples may be 
shared. A summary of the genetic results from all participants in this study can be placed in a 
public, unrestricted open access database that anyone can freely use. No individual genetic 
research testing information or results will be placed in an open access database. The risk of anyone 
identifying you with this information is very unlikely.   
 
Since your genetic data and health information and samples may be stored and shared with other 
researchers, there may be a risk that information resulting from research genetic research testing 
could be misused for discriminatory purposes. However, state and federal laws provide some 
protections against genetic discrimination. If you have any questions, please ask your Principal 
Investigator. Researchers who will have access to genetic information about you will take 
measures to maintain the confidentiality of your information. 
 
Please initial your decision for us to use and/or share your information and samples for 
genetic research for this research study: 
 
______ YES, you may use and/or share my information and samples for genetic research. 
 
______ NO, you may not use and/or share my information and samples for genetic research. 
 
 

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-4) 
 
NCT04640168 
 
ACTT-4 Version 2.0 
 
DATE: 09-June-2021 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL  


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
Version 2.0 
09JUN2021 
- 2 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
STUDY TITLE 
Protocol Number Code: 
DMID Protocol: 20-0006 (ACTT-4) 
Development Phase: 
Phase 3 
Products: 
Baricitinib + IV Placebo + Remdesivir 
PO Placebo + Dexamethasone + Remdesivir 
Form/Route: 
IV (Remdesivir, Dexamethasone/Placebo) and Oral Tablet 
(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: 
December 1, 2020 
Clinical Trial Completion Date: 
Trial Ongoing 
Date of the Analysis Plan: 
June 9, 2021 
Version Number: 
2.0 
This study was performed in compliance with Good Clinical Practice. 
Information contained in this publication is the property of Division of Microbiology and Infectious Diseases and is confidential. This 
information may not be disclosed to third parties without written authorization from Division of Microbiology and Infectious Diseases. This 
report may not be reproduced, stored in a retrieval system or transmitted in any form or by any means - electronic, mechanical, recording or 
otherwise - without the prior authorization from Division of Microbiology and Infectious Diseases. This document must be returned to Division 
of Microbiology and Infectious Diseases upon request. 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
Version 2.0 
09JUN2021 
- 3 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
TABLE OF CONTENTS 
STUDY TITLE ................................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................7 
1. 
PREFACE .....................................................................................................................9 
2. 
INTRODUCTION ......................................................................................................10 
2.1. 
Purpose of the Analyses ..............................................................................................11 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................12 
3.1. 
Study Objectives .........................................................................................................12 
3.2. 
Endpoints ....................................................................................................................13 
3.3. 
Study Definitions and Derived Variables ...................................................................16 
3.3.1. 
Baseline Value ............................................................................................................16 
3.3.2. 
Study Day and Time to Event .....................................................................................16 
3.3.3. 
Mechanical Ventilation-Free Survival at Day 29 .......................................................16 
3.3.4. 
Clinical Status Ordinal Score at Specific Timepoints ................................................17 
3.3.5. 
Progression to Clinical Status Category 6, 7, or 8 by Day 29 ....................................17 
3.3.6. 
Time to Death .............................................................................................................18 
3.3.7. 
Recovery and Time to Recovery ................................................................................18 
3.3.8. 
Time to Clinical Status Improvement .........................................................................18 
3.3.9. 
Desirability of Outcome Ranking (DOOR) ................................................................19 
3.3.10. 
Days of Oxygen ..........................................................................................................19 
3.3.11. 
Days of Non-Invasive Ventilation/High-Flow Oxygen ..............................................19 
3.3.12. 
Days of Invasive Mechanical Ventilation/ECMO ......................................................19 
3.3.13. 
Days of Hospitalization ..............................................................................................20 
3.3.14. 
Composite Endpoint of Death, SAEs, Severe AEs .....................................................20 
4. 
INVESTIGATIONAL PLAN .....................................................................................21 
4.1. 
Overall Study Design and Plan ...................................................................................21 
4.2. 
Selection of Study Population ....................................................................................21 
4.2.1. 
Treatments Administered ............................................................................................21 
4.2.2. 
Identity of Investigational Product(s) .........................................................................22 
4.2.3. 
Method of Assigning Subjects to Treatment Groups (Randomization) .....................22 
4.2.4. 
Selection of Doses in the Study ..................................................................................22 
4.2.5. 
Selection and Timing of Dose for Each Subject .........................................................23 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
Version 2.0 
09JUN2021 
Table of Contents (continued) 
- 4 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
4.2.6. 
Blinding ......................................................................................................................23 
4.2.7. 
Prior and Concomitant Therapy ..................................................................................23 
4.2.8. 
Treatment Compliance ................................................................................................23 
4.3. 
Efficacy and Safety Variables ....................................................................................23 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................26 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................27 
6.1. 
General Principles .......................................................................................................27 
6.2. 
Timing of Analyses .....................................................................................................28 
6.2.1. 
Interim Analyses .........................................................................................................28 
6.2.2. 
Final Analyses ............................................................................................................28 
6.3. 
Analysis Populations ..................................................................................................28 
6.3.1. 
Intention-to-Treat (ITT) Population ...........................................................................28 
6.3.2. 
Modified Intention-to-Treat (mITT) and As Treated Populations .............................28 
6.4. 
Covariates and Subgroups ..........................................................................................29 
6.5. 
Missing Data ...............................................................................................................31 
6.6. 
Interim Analyses and Data Monitoring ......................................................................33 
6.6.1. 
Planned Interim and Early Analyses...........................................................................33 
6.6.2. 
Interim Safety Review ................................................................................................33 
6.6.3. 
Interim Efficacy Review .............................................................................................33 
6.7. 
Multicenter Studies .....................................................................................................34 
6.8. 
Multiple Comparisons/Multiplicity ............................................................................34 
7. 
STUDY SUBJECTS ...................................................................................................36 
7.1. 
Disposition of Subjects ...............................................................................................36 
7.2. 
Protocol Deviations ....................................................................................................36 
8. 
EFFICACY EVALUATION ......................................................................................37 
8.1. 
Primary Efficacy Analysis ..........................................................................................37 
8.1.1. 
Primary Analysis of Mechanical Ventilation-Free Survival ......................................37 
8.1.2. 
Hierarchical Sequence of Secondary Endpoints Analyses .........................................38 
8.1.2.1. 
Clinical Status Ordinal Scale at Day 15 .....................................................................38 
8.1.2.2. 
Proportion of Subjects Not Progressing to Clinical Status 6, 7, or 8 by Day 
29 ................................................................................................................................38 
8.1.2.3. 
Mortality by Day 29 ....................................................................................................38 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
Version 2.0 
09JUN2021 
Table of Contents (continued) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
8.1.2.4. 
Time to Recovery .......................................................................................................38 
8.2. 
Additional Secondary Efficacy and Sensitivity Analyses ..........................................39 
8.2.1. 
Sensitivity and Corroborative Analyses of the Primary Endpoint ..............................39 
8.2.2. 
Additional Analyses of Clinical Status Ordinal Scale at Day 15 ...............................40 
8.2.3. 
Additional Analyses of Failure to Progress to Clinical Status 6, 7, or 8 ....................40 
8.2.4. 
Additional Analyses of Mortality ...............................................................................40 
8.2.5. 
Additional Analyses of Time-to-Recovery .................................................................40 
8.2.6. 
Time-to Improvement in Clinical Status ....................................................................41 
8.2.7. 
Clinical Status Ordinal Scale While Hospitalized, Day 22, Day 29 ...........................41 
8.2.8. 
Desirability of Outcomes Response (DOOR) .............................................................42 
8.2.9. 
Days of Oxygenation ..................................................................................................42 
8.2.10. 
Incidence of New Oxygen Use ...................................................................................42 
8.2.11. 
Days of Non-Invasive Ventilation/High-Flow Oxygen ..............................................42 
8.2.12. 
Incidence of New Non-Invasive Ventilation/High-Flow Oxygen ..............................42 
8.2.13. 
Days of Invasive Mechanical Ventilation/ECMO ......................................................42 
8.2.14. 
Incidence of New Invasive Mechanical Ventilation/ECMO ......................................43 
8.2.15. 
Days of Hospitalization ..............................................................................................43 
8.3. 
Exploratory Efficacy Analyses ...................................................................................43 
8.3.1. 
Clinical Status Ordinal Scale at Day 60 .....................................................................43 
9. 
SAFETY EVALUATION ..........................................................................................44 
9.1. 
Demographic and Other Baseline Characteristics ......................................................44 
9.1.1. 
Prior and Concurrent Medical Conditions ..................................................................44 
9.1.2. 
Prior and Concomitant Medications ...........................................................................44 
9.2. 
Measurements of Treatment Compliance ...................................................................44 
9.3. 
Adverse Events ...........................................................................................................45 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ....................45 
9.5. 
Pregnancies .................................................................................................................46 
9.6. 
Clinical Laboratory Evaluations .................................................................................46 
9.7. 
Vital Signs and Physical Evaluations .........................................................................47 
9.8. 
Concomitant Medications ...........................................................................................47 
9.9. 
Other Safety Measures ................................................................................................47 
10. 
PHARMACOKINETICS ...........................................................................................48 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
Version 2.0 
09JUN2021 
Table of Contents (continued) 
- 6 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
11. 
IMMUNOGENICITY ................................................................................................49 
12. 
OTHER ANALYSES .................................................................................................50 
13. 
REPORTING CONVENTIONS ................................................................................51 
14. 
TECHNICAL DETAILS ............................................................................................52 
15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ............................................................................................53 
15.1. 
Test Statistic for Primary Endpoint of Time to Mechanical Ventilation or 
ECMO .........................................................................................................................53 
15.2. 
AE Reporting of Clinical Laboratory Results for eGFR, Creatinine, INR and 
Glucose .......................................................................................................................53 
15.2.1. 
eGFR and Creatinine Grading ....................................................................................53 
15.2.2. 
Glucose Grading .........................................................................................................53 
15.2.3. 
INR Grading ...............................................................................................................53 
15.3. 
Changes to the SAP from Version 1.0 to Version 2.0 ................................................54 
16. 
REFERENCES ...........................................................................................................55 
17. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..............................................56 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................57 
APPENDIX 2. FIGURE MOCK-UPS ......................................................................................136 
APPENDIX 3. LISTINGS MOCK-UPS ...................................................................................156 
 


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LIST OF ABBREVIATIONS 
ACTT 
A Multicenter, Adaptive Randomized Blinded Controlled Trial of the Safety 
and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 
in Hospitalized Adults (Adaptative COVID-19 Treatment Trial) 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
CI 
Confidence Interval 
CoV / COV 
Coronavirus 
CRF / eCRF 
Case Report Form / Electronic Case Report Form 
CRP 
C-reactive protein 
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 
ICH 
International Conference on Harmonisation 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
Milligram 
mITT 
Modified Intention-to-Treat 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NIH 
National Institutes of Health 
OP 
Oropharyngeal 
PBO 
Placebo 
PCR 
Polymerase Chain Reaction 
PI 
Principal Investigator 
PO 
"Per os", by mouth 
PT 
Preferred Term / Prothrombin Time 


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RCD 
Reverse Cumulative Distribution  
RDV 
Remdesivir 
RMST 
Restricted Mean Survival Time 
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 
SQ 
Subcutaneous 
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 4th stage “ACTT-4”: Baricitinib + Placebo + Remdesivir vs. Placebo + 
Dexamethasone + 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 (Appendix 1, Appendix 2, Appendix 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 
Data from ACTT-1 showed that hospitalized adults with COVID-19 who were randomized to receive 
remdesivir alone resulting in the U.S. Food and Drug Administration (FDA) issuing an Emergency Use 
Authorization (EUA) to permit the use of remdesivir for treatment of suspected or laboratory-confirmed 
COVID-19 in adults and children hospitalized with severe disease. Remdesivir has also received, full or 
conditional approval in several other countries. On August 28, 2020, the FDA expanded the scope of the EUA 
to include hospitalized patients with suspected or laboratory-confirmed mild or moderate COVID-19 based on 
final data from ACTT-1 and two other clinical studies. 
While remdesivir is considered the standard antiviral for COVID-19, significant morbidity and mortality still 
occur despite its use. Early in the outbreak, it was observed that COVID-19 patients who developed severe 
respiratory disease including acute respiratory distress syndrome (ARDS) had increased levels of cytokines 
consistent with that seen in patients infected with other pathogenic coronaviruses (e.g., SARS). It is postulated 
that this dysregulated inflammatory immune response contributes to the excessive mortality and targeting this 
response would further improve outcomes. While multiple strategies have been proposed to counter the 
hyper-inflammation, to date only two anti-inflammatory strategies have demonstrated efficacy in large 
randomized trials – dexamethasone and baricitinib.  
In ACTT-2, subjects receiving the combination treatment of baricitinib and remdesivir had a shorter median 
time-to-recovery of 7 days (95% confidence interval (CI), 6 to 8 days) when compared with patients who 
received remdesivir and placebo (8 days; 95% CI, 7 to 9 days) with control [rate ratio for recovery [RRR] 
1.16, 95% CI 1.01 to 1.32; P=0.03)]. Patients who received combination treatment were 30% more likely to 
have clinical improvement by day 15 than those in the control arm (odds ratio [OR] 1.3; 95%CI 1.0 to 1.6). 
The patients who benefited the most from combination treatment were those requiring high-flow oxygen or 
non-invasive ventilation at enrollment with a median of 10 days to recovery compared with 18 days in control 
group (RRR 1.5, 95% CI 1.1 to 2.1) and the best clinical improvement by day 15 (OR 2.2; 95% CI 1.4 to 3.6). 
Baricitinib also showed benefit to those on low flow oxygen with a median of 5 days to recovery compared 
with 6 days in control group (RRR 1.17, 95% CI 0.98 to 1.39) and the clinical improvement by day 15 (OR 
1.2; 95% CI 0.9 to 1.6). Patients who received combination treatment with baricitinib and remdesivir and 
those in the control arm had a similar incidence of adverse and serious adverse events including infections and 
venous thromboembolic events (VTE). 
The Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial is a controlled, open- label 
randomized trial, involving all major hospitals in the UK. The trial compared a range of possible treatments in 
patients who were hospitalized with COVID-19. Included, was a treatment arm assigned to receive oral or 
intravenous dexamethasone (at a dose of 6 mg once daily for up to 10 days) or to received usual care alone. 
Overall, 22.9% in the dexamethasone group and 25.7% in the usual care group died within 28 days after 
randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). In the 
dexamethasone group, the incidence of death was lower than that in the usual care group among patients 
receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and 
among those receiving supplemental oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate 
ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no supplemental oxygen 
respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55). Remdesivir 
was not used routinely in the RECOVERY trial. 
The ACTT-2 and RECOVERY trials are very different and direct comparison is difficult (see Protocol 
Appendix D Section 2.2.1) However, the relative risk ratios also suggest these two anti-inflammatory 
strategies may be optimal in different inpatient populations, with baricitinib having the larger effect in the 


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high flow or low flow oxygen group and dexamethasone having the largest effect in those on mechanical 
ventilation. 
For this reason, direct comparison of these two anti-inflammatory interventions is important. ACTT-4 will 
evaluate patients hospitalized with COVID-19 and requiring oxygen and determine if baricitinib or 
dexamethasone (both in addition to remdesivir) is superior or if they are comparable. 
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 
dexamethasone + 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. Safety interim analyses will 
occur on an ongoing basis to review safety data in the event that the experimental agents inflicts harm. A 
single interim efficacy analysis will be conducted if enrollment of 1/3 of all subjects is not completed within 
1.5 months of study activation. More rapid enrollment will obviate the interim analysis since only a small 
fraction of remaining enrollment would be impacted by resulting decisions. The goal of the efficacy interim 
analyses is to review endpoint data in order to recommend whether the current study arm should proceed or to 
stop early for benefit or futility. 
This SAP describes the planned analysis to be conducted by the Investigational New Drug (IND) sponsor 
NIAID. The analyses in this SAP are intended to be executed to support a Clinical Study Report (CSR) 
following the last patient’s Study Visit Day 60, including all primary and secondary endpoints. Protocol-
defined exploratory analyses and additional analyses, if any, performed by the product manufacturer may be 
pre-specified and described 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 of baricitinib + remdesivir versus dexamethasone + remdesivir as assessed by 
the mechanical ventilation free survival by Day 29. 
Secondary Objectives 
The key secondary objective is to evaluate the clinical efficacy of baricitinib + placebo + remdesivir versus 
placebo + dexamethasone + remdesivir according to the clinical status 8-point ordinal scale at Day 15. 
The other secondary objectives are to evaluate clinical efficacy of baricitinib + placebo + remdesivir as 
compared placebo + dexamethasone + remdesivir as assessed by: 
• Among subjects with actual baseline Clinical Status ordinal score in Ordinal Score 5, the proportion 
that do not progress to Clinical Status score 6, 7, or 8 at any time prior to Day 29. 
• Mortality 
o Death by Day 15 
o Death by Day 29  
• Time to recovery by Day 29. 
• Time to an improvement of one category and two categories from Day 1 using the ordinal scale. 
• Subject clinical status using 8-point ordinal scale at Days 3, 5, 8, 11, 15, 22, and 29.  
• Desirability of Outcome Ranking (DOOR) at Day 15 and Day 29. 
• Oxygenation: 
o Oxygenation use up to Day 29. 
o Incidence and duration of new oxygen use through Day 29. 
• Non-invasive ventilation/high flow oxygen: 
o Non-invasive ventilation/high flow oxygen use up to Day 29. 
o Incidence and duration of new non-invasive ventilation or high flow oxygen use through Day 29. 
• Invasive Mechanical Ventilation / extracorporeal membrane oxygenation (ECMO): 
o Ventilator/ECMO use up to Day 29. 
o Incidence and duration of new mechanical ventilation or ECMO use through Day 29.  
• Duration of hospitalization (in days) through Day 29.  
• Laboratory Efficacy assessed by d-dimer, and C-reactive protein (CRP) over time 


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Safety Objectives 
Evaluate the safety of baricitinib + remdesivir and dexamethasone + remdesivir through 29 days of follow-up 
as assessed overall 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), prothrombin time (PT 
reported as and INR) over time (analysis of lab values in addition to AEs noted above). 
Exploratory Objective  
The exploratory objectives are: 
1. Evaluate alternate Desirability of Outcome Ranking (DOOR) scales to combine safety and efficacy. 
2. To evaluate the virologic efficacy of baricitinib + remdesivir as compared to dexamethasone + remdesivir 
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.  
• Quantitative SARS-CoV-2 virus in blood at Day 3, 5, 8, and 11. 
3. To evaluate the influence of baricitinib and dexamethasone on SARS-CoV-2 antibody response. 
4. To define immunophenotype of subjects by analyzing markers of inflammation, transcriptomics. 
5. To describe clinical status of subjects 2 months after treatment, overall and by treatment arm. 
3.2. 
Endpoints 
The 8-point ordinal scale is utilized as the principal clinical assessment tool during the study and is the basis 
for the primary and multiple secondary endpoints. The 8-point ordinal scale is defined as (worst to best):   
Category 8: Death; 
Category 7: Hospitalized, on invasive mechanical ventilation or ECMO; 
Category 6: Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
Category 5: Hospitalized, requiring supplemental oxygen; 
Category 4: Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-
19 related or otherwise); 
Category 3: Hospitalized, not requiring supplemental oxygen - no longer requiring ongoing medical care. 
This would include those kept in hospital for quarantine/infection control, awaiting bed in rehabilitation 
facility or homecare, etc.; 
Category 2: Not hospitalized, but has new or increased limitation on activities and/or new or increased 
requirement for home oxygen over baseline, pre-COVID-19 status; 


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Category 1: Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, no new or 
increased limitations on activities and no new or increased oxygen use compared with baseline. 
Primary Endpoint 
Mechanical ventilation free survival by Day 29 will be assessed as the proportion of subjects not meeting 
criteria for either of the following categories on the 8-point ordinal scale at any time before or at Day 29.: 
Category 8: Death 
Category 7: Hospitalized, on invasive mechanical ventilation or ECMO 
Secondary Endpoints 
The key secondary endpoint is the proportion of subjects meeting criteria for each of the 8-point ordinal scale 
categories on Day 15. 
Other Secondary Endpoints are: 
• Proportion of subjects not meeting criteria for one of the following ordinal scale categories at any time 
by Day 29 
Category 8: Death 
Category 7: Hospitalized, on invasive mechanical ventilation or ECMO 
Category 6: Hospitalized, on non-invasive ventilation or high flow oxygen devices 
• Days from randomization and cause of death (if applicable). 
• The time to recovery defined as the days from randomization to the first day on which the subject 
satisfies the criteria for any of the following three categories on the 8-point ordinal scale at any time 
before or at Day 29:  
Category 3: Hospitalized, not requiring supplemental oxygen - no longer requiring ongoing medical 
care. This would include those kept in hospital for quarantine/infection control, awaiting 
bed in rehabilitation facility or homecare, etc.; 
Category 2: Not hospitalized, but has new or increased limitation on activities and/or new or increased 
requirement for home oxygen over baseline, pre-COVID-19 status; 
Category 1: Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, no new or 
increased limitations on activities and no new or increased oxygen use compared with 
baseline. 
• The time improvement of one category in score defined as the days from randomization to the first day 
on which the subject satisfies the criteria for a category at least one-step better (e.g., 5 to 4) than their 
baseline category. 
• The time improvement of two categories in score defined as the days from randomization to the first 
day on which the subject satisfies the criteria for a category at least two-steps better (e.g., 5 to 3) than 
their baseline category. 
• The proportion of subjects meeting the criteria for each of the 8-point ordinal scale categories while 
hospitalized (Days 3, 5, 8, 11) and on Days 15, 22 and 29. 


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• Proportion of subjects in each level of the Desirability of Outcome Ranking (DOOR) categories at 
Day 15 and Day 29. DOOR levels are based on the 8-point ordinal score and the occurrence or 
absence of SAEs prior to or on the date of the assessment, defined as (best to worst): 
1 - Recovered (Category 1, 2 or 3 Ordinal Score) 
2 - Improved (≥ 1 category improvement in Ordinal Score compared with baseline) & no SAE 
3 - Improved (≥ 1 category improvement in Ordinal Score compared with baseline) & SAE (related 
or unrelated) 
4 - No change in Ordinal Score from baseline & no SAE 
5 - No change in Ordinal Score from baseline & SAE (related or unrelated) 
6 - Worsening (≥ 1 category worse in Ordinal Score compared with baseline)  
7 - Death  
• Days of supplemental oxygen (if applicable) up to Day 29. 
• Days of non-invasive ventilation/high-flow oxygen (if applicable) up to Day 29. 
• Days of invasive mechanical ventilation/ECMO (if applicable) up to Day 29. 
• Days of hospitalization up to Day 29. 
• D-dimer and CRP on Day 1, while hospitalized (Days 3, 5, 8, 11), and on Days 15 and 29 (if attends 
in-person visit or still hospitalized). 
Safety Endpoints 
Safety endpoints are: 
• SAEs 
• Grade 3 and 4 treatment emergent adverse events 
• Incidence and number of discontinuation or temporary suspension of study product 
• WBC with differentials, hemoglobin, platelets, creatinine, glucose, total bilirubin, ALT, AST, 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 Endpoints  
• Alternate DOOR scales 
None of the remaining exploratory endpoints will be described in this SAP, but they include the following: 
• Virology endpoints: 
− 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). 
• Serology endpoint: SARS-CoV-2 antibody titers on Day 1, 8, and 29. 


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• Immunophenotype endpoints: 
− Proteomic analysis of cytokines, markers of inflammation, and other circulating proteins on Day 1; 
Days 3, 5, 8, and 11 (while hospitalized) and Day 29. 
− Additionally, in a subset of subjects who consent to genetic testing, transcriptomic analysis of 
RNA in whole blood and individual immune cells on Days 1, 3, 8, and 29. 
• Chronic Clinical Sequelae: Ordinal score, incidence of supplemental oxygen use and physical 
disability (more than baseline pre-COVID-19 status), readmission to hospital; proportion of subjects 
with new diagnoses including deep venous thrombosis (DVT), infections, post-traumatic stress 
disorder (PTSD), anxiety and/or depression. 
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 on-trial 
dose of any study product (baricitinib, dexamethasone, remdesivir, or placebo). If the exact time of the 
assessment or the first dose is not available, but collected on the same date, the assessment will be assumed to 
have occurred prior to receipt of study product.  
A small subset of subjects may receive dexamethasone as standard of care on the same day as but prior to 
randomization then forgo the dexamethasone / placebo component of the Day 1 study product administration. 
For these subjects, the baseline value of efficacy assessments will be the last value prior to randomization, as 
in the preceding paragraph. But, for these subjects, the value of baseline safety assessments will be defined as 
the last value obtained prior to the dexamethasone dose. If the exact time of the assessment of the pre-
randomization dexamethasone or on-trial doses of study product are not available, but collected on the same 
date, the assessments will be assumed to have occurred prior to receipt of study product and prior to 
randomization. 
3.3.2. 
Study Day and Time to Event 
Use of "Day 29" or "Day 15" are references to actual study days and represent 28 and 14 days post-
randomization, respectively. References to visits such as "Study Visit Day 29" and "Study Visit Day 15" 
pertain to protocol-defined visits which may occur on any day within the defined visit window and not 
necessarily on Day 29 and Day 15. 
Time-to-event endpoints are based on actual study days, e.g., Day 29 or Day 15. Endpoints that are not 
specifically defined as a time-to-event are based on Study Visits, irrespective of the study day upon which the 
visit was conducted. As a result, time-to-event endpoints at Day 15 and Day 29 may not match corresponding 
Clinical Status Ordinal Scores at Study Visit Day 15 and Study Visit Day 29. For example, all subjects with 
Clinical Status in Category 7 or 8 recorded for Study Visit Day 29 performed on or after Day 31 may not 
count as events by Day 29 unless there is additional corroborating data (e.g., Death or Supplemental Oxygen 
Case Report Forms). 
3.3.3. 
Mechanical Ventilation-Free Survival at Day 29 
Subjects who do not report an ordinal score in Category 8 (Death) or Category 7 (hospitalized on invasive 
mechanical ventilation or ECMO) at any point following randomization up to and including Day 29 will be 


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considered to have survived free from mechanical ventilation. The proportion of subjects who survive through 
Day 29 free from mechanical ventilation will be estimated using a Kaplan-Meier method, allowing definition 
of time-to-event and time-to-censoring for all subjects. 
The time-to mechanical ventilation or death is defined as the elapsed time in days from randomization to the 
earliest day at which the subject requires mechanical ventilation or dies. The day the subject requires 
mechanical ventilation is defined as the first day reporting an ordinal score in Category 7. Note (as in 
Section 3.3.4), this should be the date the subject is assessed, and not the date the score is reported. The time-
to-event for subjects discharged to hospice or other end-of-life care prior to Day 29, but for whom a death 
date is unknown and with Day 60 data unavailable, will be the number of days from randomization to 
discharge. 
Subjects with Day 29 ordinal score in Categories 6, 5, 4, 3, 2 or 1 will be considered censored on Day 29, if 
Category 7 was never experienced during the 28 days on study.  Subjects completing the Day 29 Study Visit 
within window, but after Day 29, for which the Day 29 assessment can be completed or confirmed in 
Categories 6, 5, 4, 3, 2, or 1 will be considered censored on Day 29. Subjects who withdraw from the study or 
are lost-to-follow-up while hospitalized, prior to reporting a Clinical Status score in Category 7 or 8 will be 
censored at the date of their last Clinical Status assessment. Subjects who are discharged from hospital (but 
not to hospice or other end-of-life care) and are not hospitalized at the last contact, who do not have a Day 29 
Ordinal Score will be considered censored at Day 29 (i.e., 28 days after randomization). If a subject has a gap 
in Ordinal Score data available while hospitalized (e.g., the subject is transferred to another hospital or 
hospice, re-admitted to another facility), the subject may be reviewed by the blinded Endpoint Review 
Committee to assess whether any data suggests the subject may have progressed to mechanical ventilation in 
the interim time period. Additionally, if a treated subject terminates early from the study while hospitalized 
(e.g., due to worsening condition) and without observed progression to mechanical ventilation, the subject’s 
data will be reviewed by the blinded Endpoint Review Committee. Subjects not completing Day 29 or 
discharged to hospice or other end-of-life care prior to Day 29 with a death date unknown but completing Day 
60 will be reviewed by the blinded Endpoint Review Committee to assess whether the Day 60 data impacts 
handling of the subject for the Day 29 timepoint. Other special cases may also be included for review by the 
blinded Endpoint Review Committee, as needed. 
3.3.4. 
Clinical Status Ordinal Score at Specific Timepoints 
The Primary Endpoint, Key Secondary Endpoint, and several other Secondary Endpoints rely on evaluation of 
the Clinical Status ordinal score at specific days. For these endpoints, the Study Visit Day is the timepoint of 
interest, not the actual study day (e.g., Study Visit Day 29 as opposed to study day 29). The Clinical Status 
Score collected at the Study Visit corresponding to the specific endpoint will be used for the outcome. 
Specifically, results from Study Visit Day 29 will be used for the Primary Endpoint and results from Study 
Visit Day 15 will be used for the Key Secondary Endpoint, with these and other Study Visit Days (3, 5, 8, 11, 
22) used for other Secondary Endpoints. For analyses involving Clinical Status at specific timepoints, 
imputation of missing scores may be performed following the rules described in Section 6.5. 
3.3.5. 
Progression to Clinical Status Category 6, 7, or 8 by Day 29 
This Secondary Endpoint will be assessed similarly to Mechanical Ventilation-free survival (Section 3.3.2), 
but the event of interest is any report of a Clinical Status ordinal score in Category 8 (Death), Category 7 
(invasive mechanical ventilation or ECMO), or Category 6 (non-invasive ventilation or high-flow oxygen 
device). This endpoint will only be assessed in those with actual baseline Clinical Status in Category 5 
(hospitalized, requiring supplement oxygen). 


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3.3.6. 
Time to Death 
For analysis of time to death, the time to death will be defined as the elapsed time (in days) from 
randomization to death. For the safety analysis, this will be elapsed time (in days) from the first dose of study 
treatment (baricitinib, dexamethasone, remdesivir, or placebo). 
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). Subjects who complete 
follow-up will be censored at the earliest of their Study Visit Day 29 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. 
3.3.7. 
Recovery and Time to Recovery 
A Secondary Endpoint measure requires the time to recovery assessed through Study Visit Day 29. Recovery 
will be defined as having a value of 1, 2, or 3 on the 8-point ordinal Clinical Status score. The time to 
recovery will be defined as the elapsed time (in days) from randomization to the earliest day at which a 
subject reaches recovery. Note that since clinical status assessments are recorded as defined in Section 4.3, the 
day that is being assessed (not necessarily the day the response is collected) will be used to determine the 
timing of events. For example, a subject with a score of 5 recorded on study days 1-3 and a score of 3 
recorded on study day 4 will have a time to recovery equal to 3 days. It is also possible that a subject has a 
clinical status ordinal score > 3 reported for a particular day but was subsequently discharged on the same 
day. If a subject is discharged to a location other than hospice or another hospital the subject will be 
considered recovered at the time of discharge but may be reviewed by the Endpoint Review Committee, if 
other data suggests the subject may not be recovered (e.g., the subject is re-admitted). If a subject is 
discharged to hospice or another hospital, re-admitted, or is a special case where recovery handling may be 
unclear , the subject’s data will be reviewed by the Endpoint Review Committee to make the determination of 
whether the subject should be considered recovered and, if so, at what time point in the 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, comfort and care), and any information regarding readmittance. Additional information may be 
solicited to assess recovery.  
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 Study Visit Day 29. All deaths that occur on or before Study Visit Day 29 
(and prior to any observed recovery) will be considered censored at Day 29. 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.  
3.3.8. 
Time to Clinical Status Improvement 
Several Secondary Endpoints involve evaluation of the time to improvement of at least one or two points on 
the clinical status 8-point ordinal scale. The time to improvement will be defined as the elapsed time (in days) 


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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 endpoint, 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 Clinical Status score. Subjects who complete follow-up but do not experience 
improvement will be censored at the day of their Study Visit Day 29. All deaths that occur on or before Study 
Visit Day 29 (and prior to any observed improvement) will be considered censored at Day 29. 
3.3.9. 
Desirability of Outcome Ranking (DOOR) 
The DOOR is based on categorization of the 8-point ordinal Clinical Status score, changes in the score, or 
combination with the occurrence (or absence) of SAEs. The DOOR category will be determined by the 
Clinical Status score at Baseline and at the Study Visit Day (15 and 29), and any SAEs that have occurred up 
to and including the respective Study Visit Day. Since this endpoint involving Clinical Status at specific 
timepoints, imputation of missing scores may be performed following the rules described in Section 6.5. 
3.3.10. 
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. 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 for any time period the subject is not hospitalized at the study hospital. Individual 
subject of post-discharge oxygen use will be generated (Listing 28). 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. 
3.3.11. 
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 ordinal score is equal to 6. The Post-Discharge Supplemental Oxygen CRF questions regarding days of 
non-invasive ventilation or high-flow oxygen will be used for any time period the subject is not hospitalized 
at the study hospital. 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. 
3.3.12. 
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. The Post-Discharge Supplemental Oxygen CRF questions regarding days of ECMO or 
invasive ventilation will be used for any time period the subject is not hospitalized at the study hospital. 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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3.3.13. 
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 reasons. It will also be calculated as the total 
number of days hospitalized, including any readmissions regardless of cause. See Section 6.5 for the plan for 
handling subjects who do not have data through Day 29 or die prior to Day 29. 
3.3.14. 
Composite Endpoint of Death, SAEs, Severe AEs 
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 treatment emergent AE 
The time to this composite endpoint will be defined as the elapsed time (in days) from the day of the first dose 
of study treatment (baricitinib, dexamethasone, remdesivir, or placebo) 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 Study Visit Day 29.  


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
ACTT-4 will evaluate the combination of baricitinib and remdesivir compared to dexamethasone and 
remdesivir. Subjects will be assessed daily while hospitalized. After the subjects are discharged from the 
hospital, they will have a study visit at Days 15, 22, and 29 (as applicable). For discharged subjects, it is 
preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests and OP swab, plasma 
(Day 29) and serum 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.  
Additionally, subjects will be contacted by phone at 2 months (Day 60) to assess long term efficacy and safety 
outcomes as an exploratory outcome. A chart review/extraction of data through Day 60 may be done if the 
subject is not available for the phone contact.  
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 D of the study protocol for the full list of inclusion and exclusion 
criteria. 
4.2.1. 
Treatments Administered  
Dosing of the medications does not need to occur at the same time. All subjects 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 prior 
to study enrollment, then start at 100 mg/day on Day 1. Any doses of remdesivir given prior to enrollment 
will be counted, so the total duration of remdesivir (i.e. pre-enrollment + on this trial) is 10 days (i.e., a 
maximum of 10 total infusions). Any doses of remdesivir were administered prior to study enrollment should 
be documented in Advantage eClinical as a concomitant medication given prior to Day 1. The duration of 
dosing may be adjusted by the site similar to what is described in the package insert and based on a subject’s 
clinical course and ultimate disease severity.  
For the baricitinib component, subjects receive either active product or placebo as follows: 
• Baricitinib will be administered as a 4 mg orally (po) (two 2mg tablets) or dissolved 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 dissolved for NG tube, daily for the duration of the 
hospitalization up to a 14-day total course.  
o Any pre-study dexamethasone (max 1 dose per inclusion criteria) is not counted towards the 
10-day course. 
For dexamethasone component, subjects receive either active product or placebo as follows: 
• Dexamethasone administered as a 6 mg slow IV push over 3 to 5 minutes daily for the duration of the 
hospitalization up to a 10-day total course. 


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• A placebo will be given as an equal volume normal saline, as a slow IV push daily for the duration of 
the hospitalization up to a 10-day total course. 
• If site local standards use other means of administration (such as IV infusion), these may be used for 
both active and placebo after approval of the sponsor.  
• Any pre-study dexamethasone (max 1 dose per inclusion criteria) is not counted towards the 10 day 
course. 
Duration of therapy: 
• IV remdesivir – up to 10 days while hospitalized (i.e., maximum of 10 total infusions pre-enrollment 
and during study). 
• Oral baricitinib (or oral placebo) – 14 days while hospitalized (i.e., maximum of 14 total doses). 
• IV dexamethasone (or IV placebo) – 10 days while hospitalized (i.e., maximum of 10 total doses). 
• All study medications stop on discharge from hospital.  
o Of note, if a subject is retained in the hospital for non-COVID-19 related issues and no longer 
requires supplemental oxygen and ongoing medical care (i.e., ordinal scale category 3), the PI may 
decide to discontinue all medications.  
• If readmitted after discharge, see Appendix D Section 7.4 of the study protocol. 
4.2.2. 
Identity of Investigational Product(s) 
See Section 6.1.1 of Appendix D of the study protocol. 
4.2.3. 
Method of Assigning Subjects to Treatment Groups (Randomization) 
Randomization will be stratified by: 
• Site 
• Clinical Status at enrollment (by ordinal scale) 
o Category 6: Hospitalized, on non-invasive ventilation or high flow oxygen devices, OR 
o Category 5: Hospitalized, requiring supplemental oxygen 
4.2.4. 
Selection of Doses in the Study 
The dose of remdesivir used in this study is the same dose used in previous ACTT studies, and is the US FDA 
approved dosage. The duration of dosing may be adjusted by the site according to clinical severity. The 
maximum number of doses to be given during hospitalization is ten doses. This includes the loading dose and 
all maintenance doses given during the study and pre-study if applicable. This study will use the same dose 
and duration of baricitinib that was evaluated in ACTT-2. The 4 mg daily dose of baricitinib was originally 
selected for use in this population of adults hospitalized with COVID-19 based on clinical data showing an 
inhibitory effect on cytokine signaling. This study will use the same dose and duration of dexamethasone that 
was evaluated in the RECOVERY trial, the largest and most influential study of dexamethasone in 
COVID-19.  


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4.2.5. 
Selection and Timing of Dose for Each Subject 
See Sections 6.1.2 through 6.1.5 of Appendix D 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. The dexamethasone/placebo IV component is blinded. Dexamethasone and 
intravenous placebo are identical in appearance. 
Unblinding of the study will occur after all subjects enrolled have reached the end of study, these visits are 
monitored, and data is cleaned or if the DSMB recommends unblinding. Data through Day 29 will be locked 
prior to the completion and lock of Day 60 data. DMID and the SDCC will be unblinded after the Day 29 
database lock. Clinical sites will not be unblinded to subject-level treatment assignments until after the Day 
60 database lock.  
If a subject’s clinical status worsens to require mechanical ventilation (ordinal 7), the treating clinician may 
request unblinding in order to use the prior treatment assignment to inform future treatment. See protocol 
Appendix D Section 6.3.2.2. 
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. If unblinded for SAE, the investigator may decide to have the blinded study product 
and/or remdesivir infusions discontinued based on the adverse event that led to unblinding and the benefit-risk 
analysis. See protocol Appendix D Section 6.3.2.3. 
4.2.7. 
Prior and Concomitant Therapy  
See Section 6.5.1 of Appendix D of the study protocol for permitted concomitant therapy and procedures. See 
Section 6.5.2 of Appendix D of the study protocol for prohibited concomitant therapies. 
4.2.8. 
Treatment Compliance 
See Section 6.1.4 of Appendix D 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 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: 
Category 8: Death; 
Category 7: Hospitalized, on invasive mechanical ventilation or ECMO; 


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Category 6: Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
Category 5: Hospitalized, requiring supplemental oxygen; 
Category 4: Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 
Category 3: Hospitalized, not requiring supplemental oxygen - no longer requiring ongoing medical 
care. This would include those kept in hospital for quarantine/infection control, awaiting 
bed in rehabilitation facility or homecare, etc.; 
Category 2: Not hospitalized, but has new or increased limitation on activities and/or new or increased 
requirement for home oxygen over baseline, pre-COVID-19 status; 
Category 1: Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, no new or 
increased limitations on activities and no new or increased oxygen use compared with 
baseline. 
A modified version of the ordinal scale will be used in sensitivity analyses of the Key Secondary and Other 
Secondary Endpoints of time-to-recovery and time-to-improvement. 
The “Modified Recovery” ordinal scale combines Category 1 and 3 of the original Clinical Status scale and is 
defined as follows:  
Category 8: Death; 
Category 7: Hospitalized, on invasive mechanical ventilation or ECMO; 
Category 6: Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
Category 5: Hospitalized, requiring supplemental oxygen; 
Category 4: Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 
Category 3: Not hospitalized, but new or increased limitation on activities and/or requiring new or 
increased home oxygen; 
Category 2: Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical 
care; or Not hospitalized, no limitations on activities. 
Desirability of outcomes response (DOOR) is an ordinal scale combining current clinical status with SAEs. 
SAE may be related or unrelated to study product. Any SAE occurring after study product administration 
through Day 15 (or through Day 29) will be counted: 
1- Recovered (Ordinal Score Category 1,2,3) 
2- Improved by at least 1 Ordinal Score from baseline & no SAE 
3- Improved by at least 1 Ordinal Score Category from baseline & SAE 
4- No change in Ordinal Score Category from baseline & no SAE 
5- No change in Ordinal Score Category from baseline & SAE 
6- Worsened by at least 1 Ordinal Score Category from baseline 
7- Death (Ordinal Score Category 8) 


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Oxygenation, Non-invasive ventilation/high flow oxygen, Invasive Mechanical Ventilation/extracorporeal 
membrane oxygenation (ECMO), hospitalization and mortality will be assessed using results of the Clinical 
Status 8-point ordinal scale, medical history, 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 treatment-emergent AEs. 
• Discontinuation or temporary suspension of study product administration (for any reason). 
• Changes in white cell count, hemoglobin, platelets, creatinine, total bilirubin, ALT, AST, and INR, d-
dimer, C-reactive protein over time. Note D-dimer and CRP are not graded. 
• Time to the Composite Endpoint of the first of death, SAE, or Severe AE from the day of first dose of 
study treatment to the earliest date of any of these events.  
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. CRP values from sites using a high-sensitivity assay will be excluded from all 
CRP summaries and any analyses that use CRP values. 
Virologic efficacy is an exploratory endpoint and will be assessed by the following: 
• Qualitative and quantitative PCR for SARS-CoV-2 in OP swab on Days 1, 3, 5, 8, 11 (while 
hospitalized); and Day 15 and 29 (if able to return to clinic or still hospitalized). 
• Qualitative and quantitative PCR for SARS-CoV-2 in blood on Days 1, 3, 5, 8, 11 (while 
hospitalized). 
The schedule of study procedures is provided in Section 1.2 of Appendix D of the study protocol. 


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5. 
SAMPLE SIZE CONSIDERATIONS 
Sample Size for Primary Analysis 
The primary hypothesis will be a test of the difference in proportions surviving without requiring invasive 
mechanical ventilation between the two treatment arms by Day 29. Estimating the expected treatment effect 
of baricitinib relative to dexamethasone is difficult given the differences between the ACTT-2 and 
RECOVERY studies as discussed above. In Table 1 the first row of treatment effects is based on estimates 
from the ACTT-2 and RECOVERY results amongst the cohort that most closely resembles the ACTT-4 target 
population (those in ordinal 5 and 6). In the second row, the relative findings were changed to assume a 
gradual improvement in standard of care. This corresponds to a sample size of 1382 subjects. Sample size 
calculations were based on an exact unconditional score test of proportions using StatXact v11.1.0. Assuming 
8% lost to follow-up, the sample size is planned to be approximately 1500 subjects.  
The remaining lines demonstrate the power of the proposed sample size. There is good power of this trial for 
multiple scenarios unless the proportions surviving without invasive mechanical ventilation is much higher 
than anticipated (thought to be unlikely) or the difference in the proportions is smaller than anticipated 
(possible, but difficult to anticipate given the data available).  
The protocol defined primary analyses were to be based on Kaplan-Meier estimates of the proportion of 
patients surviving without mechanical ventilation by Day 29 using a large sample normal approximation with 
Greenwood’s variance formula. Accordingly, power for the final analysis is assumed to be equal or slightly 
higher than the power for the exact score as seen below. 
Table 1: 
Sample Size Estimates and Study Power 
 
Total 
Sample 
Size 
Proportion 
Dex Arm 
Surviving Through 
Day 29 Without 
Mechanical 
Ventilation  
Proportion 
Bari Arm 
Surviving Through 
Day 29 Without 
Mechanical 
Ventilation 
Power 
(unconditional 
exact score) 
Power 
(KM + 
Greenwood) 
- Baricitinib from ACTT-2 (OS 5 and 6)  
- Dexamethasone relative efficacy (only 
those on oxygen) from RECOVERY 
applied to ACTT-2 placebo arm 
1342 
0.814 
0.87 
80.9% 
80.6% 
Estimate of the above proportion applied 
to current outcomes given gradual 
improvement in care 
1382 
0.85 
0.9 
80% 
80.5% 
 
Other scenarios showing study power for 
the sample size of 1382 
1382 
0.9 
0.95 
94.5% 
94.9% 
1382 
0.9 
0.925 
37.0% 
37.5% 
1382 
0.85 
0.925 
99.4% 
99.4% 
1382 
0.8 
0.875 
96.6% 
96.6% 
1382 
0.8 
0.85 
68.2% 
68.9% 
Note: two-sided type I error rate 5%; Exact unconditional score test of proportions. 


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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. Proportions will be estimated using the Kaplan-
Meier Day 29 survival estimate with Wald-type confidence intervals assuming large-sample normality with 
standard errors estimated using Greenwood’s formula for variance. For hazard ratio and odds ratio estimates, 
Wald confidence intervals will also be used. For other efficacy outcomes (e.g. proportions), 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 baricitinib + placebo + remdesivir 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 comparison of Day 29 mechanical ventilation free survival, the following SAS pseudocode will 
be used to obtain Kaplan-Meier survival estimates, standard errors and confidence intervals, for each 
treatment within strata. Survival estimates and standard errors will be used to calculate the test statistic and 
compared to a standard normal distribution as in Section 8.1.1. 
proc lifetest data=dataset plots=(s) method = km outsurv = survests; 
   time TimeVariable * CensorVariable(1); 
   strata TreatmentVariable StrataVariable; 
run; 
 
Note that the interim efficacy analyses will be performed using R. For all interim and final analyses, the 
software used will calculate the test 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=Dxa_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 proportional odds model with treatment arm and 
actual baseline ordinal score as covariates and to generate the treatment odds ratio, p-value, and predicted 
probabilities of the ordinal scale levels by treatment arm and actual baseline ordinal score: 
proc logistic data=dataset  
plots(only)=effect(x=ResponseVariable sliceby= actualbaselinestrata 
*TreatmentVariable individual connect); 
   class actualbaselinestrata(param=ref ref=category5)  
   TreatmentVariable(param=ref ref=RemdesivirLabel); 
   model ResponseVariable = TreatmentVariable StrataVariable; 
   oddsratio TreatmentVariable; 
   ods output OddsRatiosWald = ORest; 
run; 
6.2. 
Timing of Analyses 
6.2.1. 
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 6.6.3 below. The summaries to be generated for the interim analysis are provided in the separate 
DSMB shell report. 
The separate Futility Analysis Plan describes the methods for the Futility Analysis conducted in April 2021.  
6.2.2. 
Final Analyses 
The final analyses of all outcomes and planned summaries/listings will be performed on the final full locked 
database through Day 29 and provided in the final report. If substantial Day 60 data is available, results from 
Day 60 may also be included in the final report and this SAP amended appropriately. In addition, the final 
report may be amended to include the totality of the Day 60 data when locked. 
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 modified intention-to-treat (mITT) population and As 
Treated population.  
6.3.1. 
Intention-to-Treat (ITT) Population 
The intention-to-treat (ITT) population includes all subjects who were randomized. ITT subjects will be 
classified by their randomized treatment assignment and randomized disease severity stratum (i.e., the stratum 
to which the subject randomized at enrollment, which is not necessarily equivalent to their baseline ordinal 
score if the subject was mis-stratified). 
6.3.2. 
Modified Intention-to-Treat (mITT) and As Treated Populations 
The modified intention-to-treat (mITT) population includes all subjects who were randomized. mITT subjects 
will be classified by their randomized treatment assignment and actual baseline ordinal score ordinal stratum 
(i.e., the stratum corresponding to their baseline ordinal score, not necessarily the stratum within which the 
subject was randomized at enrollment). 


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The As Treated population includes all randomized subjects who received the study product, even if only one 
dose was administered. 
For As Treated analyses of efficacy outcomes, subjects will be classified by their actual treatment assignment 
and their actual baseline ordinal score, unless otherwise specified in the table or figure shell. Note that if no 
subjects are administered the incorrect treatment and all subjects receive at least one dose of 
baricitinib/placebo, dexamethasone/placebo, the As Treated efficacy analysis will not be performed as they 
will be identical to the mITT analyses. 
For As Treated analyses of safety outcomes, concomitant medications, and medical history, subjects will be 
classified by their actual treatment assignment and actual baseline ordinal score stratum. 
6.4. 
Covariates and Subgroups 
As additional secondary analysis, the primary efficacy outcome will be summarized within each of the 
baseline actual ordinal score subgroups (5 and 6). Analysis of all secondary outcomes will be performed in 
subgroups based on the baseline actual ordinal score.  
Further subgroup analyses for the primary and key secondary efficacy outcomes will evaluate the treatment 
effect within the following subgroups:  
• Prior Corticosteroid use 
− Yes / No 
− Dexamethasone on the day of randomization / not 
− Number of on-study dexamethasone/placebo infusion (9 vs 10). Some subjects who received 
dexamethasone on the day of randomization may skip their first post-randomization, on-study 
dexamethasone / placebo infusion and therefore receive only 9, rather than the expected 10, on-
study infusions. 
• Geographic region 
o US sites; Non-US sites 
o North American sites; Asian sites; European sites  
• Duration of symptoms prior to randomization 
o Quartiles 
o <= 10 days; > 10 days 
o <= Median; > Median 
• Race (White; Black/African American; Asian; Other) 
• Comorbidities  
o None; Any 
o None, One, Two or more 
o Obese; Non-Obese 
• Age (<40; 40-64; 65 and older) 
• Sex (Female; Male) 


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• Randomized strata 
o 5 or 6 (separately) on ordinal scale used for randomization 
Note: separate analyses for randomized/actual severity will only be performed if at least one subject is 
erroneously randomized into the incorrect baseline ordinal score stratum. 
Additionally, analyses of all remaining secondary efficacy outcomes and the time to death by Day 15/29 
outcomes will evaluate the treatment effect within the following subgroups (among subjects enrolled with 
baseline ordinal score of 5 or 6 only): 
• Duration of symptoms prior to randomization (<= Median; > Median) 
• Severity of disease  
o Randomization stratification: 5 or 6 (separately) on ordinal scale.  
o Actual ordinal score at baseline: 5 or 6 (separately) on ordinal scale. 
Note: separate analyses for randomized/actual severity will only be performed if at least one subject is 
erroneously randomized into the incorrect baseline ordinal score stratum. 
There will also be a sensitivity analysis of the primary, 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”: 
• Vaccine for SARS-CoV-2 (Pfizer, Moderna, or other) including 1 or 2 doses received 
• Antivirals 
o Protease inhibitors 
o Polymerase inhibitors 
• Other Potential Treatments for COVID-19 
− Aplidin® (plitidepsin) 
− Colchicine (Colcrys) 
− Monoclonal antibodies targeting the spike protein of SARS-CoV-2 including casirivimab, 
imdevimab and bamlanivimab 
− Ivermectin (stromectol, Soolantra, Sklice) 
• Corticosteroids 
• Renin-angiotensin system (RAS) Inhibitors and HMG-CoA reductase inhibitors (statins) 
• 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. 


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In addition, the sensitivity analyses will consider the following categories (individually): 
• Any Medication of Interest 
• Vaccines to SARs-CoV-2 
• Antivirals 
• COVID-19 treatments 
• Monoclonal antibody treatments for COVID-19 
• Corticosteroids 
• RAS Inhibitors and HMG-CoA reductase inhibitors (statins) 
• Other Anti-Inflammatory Drugs 
Three initiation and duration groups will be constructed for each of the above categories: 
1. Prior and During: Subjects taking medication of interest before randomization and during study (on or 
after Day 1). 
2. Prior Only: Subjects taking medications of interest prior to randomization but stopping prior to 
randomization. 
3. During Only: Subjects initiating mediations of interest during the study (on or after Day 1). 
For the analysis of mechanical ventilation free survival, subjects will be censored at the time of 
medication/therapy initiation. 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. For the analysis of the proportion of subjects that do not 
progress to Clinical Status Ordinal Score of 6, 7, or 8 by Day 29, subjects will be censored at the time of 
medication / therapy initiation. For the recovery analyses, subjects will be censored at the time of 
medication/therapy initiation. 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.  
The effect of on-study treatment on select efficacy outcomes will also be explored among subjects who 
reported use of HMG-CoA reductase inhibitors (statins), angiotensin receptor blockers (ARBs), or angiotensin 
converting enzyme inhibitors (ACEIs) via subgroup analyses.  
Lastly, 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 randomization, 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. Other 
rules for censoring are listed for the specific endpoint in Section 3.3. 


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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 ordinal score, their clinical ordinal 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 (but not to hospice or other end-of-life care) 
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. 
• 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 


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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. 
• Lab Efficacy (d-dimer and CRP) 
o If results are not available for any visit day(s) but are available for visits before or after that visit, 
the average of the two nearest visits will be imputed for all missing visits between them. If a 
subject dies or is otherwise lost to follow-up, their last available observation will be carried 
forward. If baseline is missing, another pre-treatment dose will be used, or the earliest post-
treatment dose will be used.  
6.6. 
Interim Analyses and Data Monitoring 
6.6.1. 
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. 
6.6.2. 
Interim Safety Review 
Safety analyses will evaluate Grade 3 and 4 AE and SAEs by treatment arm. Safety monitoring will be 
ongoing with the DSMB reviewing safety data approximately every one to two weeks during the study. The 
unblinded statistical team will prepare these reports for review by the DSMB. 
6.6.3. 
Interim Efficacy Review 
The time of the interim efficacy analysis for ACTT-4 will be assessed by enrollment 1.5 months after the first 
enrollment: 
• If the study reaches or exceeds 1/3 of total enrollment within 1.5 months (assumes slightly slower 
enrollment at the beginning), no interim efficacy analysis will be performed.  
• If the study does not reach 1/3 of total enrollment within 1.5 months, an interim analysis will occur 
after the first third of enrolled subjects have reached Day 29. 
If an interim efficacy analysis is performed, 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 with 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 
𝛼∗(𝑡) = 2[1 −Φ{2.241/𝑡
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. The planned boundaries at 
33% and 100% of information on the z-scale are +/- 3.7307 (nominal p  = 0.00019153) and 1.9605 (nominal p 
= 0.049937). 


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All available data at the time of lock will be included in the Interim Efficacy data. Subjects who are on-study 
but have not yet completed the Day 29 study visit will also be included but will be censored at their last 
assessment unless they have progressed to mechanical ventilation or died.  
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% when 
assuming the trial’s design 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.  
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 8.2.1. 
6.8. 
Multiple Comparisons/Multiplicity 
A fixed sequence testing scheme will control the overall family-wise Type I error rate at a two-sided α level 
of 0.05. If the primary hypothesis is rejected at two-sided α <0.05, hypothesis testing will proceed to four key 
secondary endpoints. Hypothesis testing will follow the fixed ordering below (Figure 1): 


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Figure 1: 
Elements of the fixed-sequence hierarchical testing procedure 
 
1) Mechanical Ventilation-Free Survival 
by Day 29 (i.e., Proportion not 
progressing to ordinal scale 7 or 8) 
 
2) Day 15 Clinical Status Ordinal Score;  
 
3) Proportion not progressing to ordinal 
scale 6, 7 or 8 (amongst actual 
baseline Clinical Status ordinal scale 5 
only);  
 
4) Overall mortality (Day 29); and 
 
5) Time to recovery (Day 29). 
Hypothesis testing will continue at the next endpoint with α = 0.05 only if the previous hypothesis is rejected 
at α=0.05. This method of carrying forward the α -level from the previous test is described in the FDA 
guidance on Multiple Endpoints in Clinical Trials [https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/multiple-endpoints-clinical-trials-guidance-industry]. See Section 8.1.2 for details on the 
sequence of hierarchical analyses. 
There is no planned multiplicity adjustment for the evaluation of safety (Section 9) or additional sensitivity or 
additional secondary efficacy (Section 8.2) or exploratory (Section 8.3) analyses. 


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7. 
STUDY SUBJECTS 
7.1. 
Disposition of Subjects 
A summary of the reasons that subjects were screened but not randomized will be tabulated (Table 2). 
The composition of analysis populations, including reasons for subject exclusion will be summarized by 
treatment group and actual baseline ordinal score (Table 3). A subject listing of subjects excluded from the As 
Treated Population will be generated (Listing 1). 
The disposition of subjects will be tabulated by treatment group and actual baseline ordinal score (Table 4). 
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 Visit Day 15, completed Study Visit Day 22, 
and completed Study Visit Day 29. For the calculation of percentages, subjects who die will not be included 
in the denominators for visits/assessments beyond their death. Subject status at study termination will be 
summarized by treatment group and baseline ordinal score (Table 5). 
Treatment exposure will be summarized by treatment group (Table 6, Table 7, and Table 8). Summaries of 
prior remdesivir treatment, prior remdesivir, and prior dexamethasone treatment by treatment group and 
actual baseline ordinal score will also be provided (Table 9, Table 10, and Table 11).  
A flowchart showing the disposition of study subjects, adapted from the Consort Statement [1] will be 
generated (Figure 2). This figure will present the number of subjects screened, randomized, lost to follow-up, 
and analyzed, by treatment group and actual baseline ordinal score (ordinal scale 5, 6,). The number of 
subjects that terminated early by hospitalization status at the time of the last ordinal score collection will be 
summarized graphically (Figure 3). 
A listing of subjects who discontinued dosing or terminated study follow-up and the reason will be generated 
(Listing 2). A listing of subjects who received incorrect treatment and a listing of subjects who were 
randomized to the incorrect stratum will also be generated (Listing 5 and Listing 6). 
The disposition of subjects at Day 60 will be tabulated by treatment group and actual baseline ordinal score 
(Table 12). 
7.2. 
Protocol Deviations 
Subject-specific protocol deviations will be summarized by the reason for the deviation, the deviation 
category, treatment group, and actual baseline ordinal score (Table 13). A summary of major deviations will 
also be generated (Table 14). 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 Analysis of Mechanical Ventilation-Free Survival 
The primary efficacy analysis will be performed in the mITT population and is a test of superiority of the 
proportion of participants with invasive mechanical ventilation free survival, between the two treatment 
groups at Day 29 (Table 15). The test statistic will be a large sample test of the difference in Kaplan-Meier 
estimates of the 28-day probability of mechanical ventilation free survival with a two-sided type I error rate of 
0.05. The test of difference will assume asymptotic normality and use Greenwood’s variance formula. The 
primary analysis will utilize a test statistic adjusting by actual baseline Clinical Status ordinal score strata [2] 
(Klein 2007) and be based on the weighted complementary log-log transformation of the Kaplan-Meier 
estimator. The two primary baseline Clinical Status strata will be patients with baseline ordinal score 5 or 
baseline ordinal score 6. 
The primary analysis will utilize a test statistic adjusting by actual baseline ordinal score ordinal score strata 
(Klein 2007) and be based on the complementary log-log transformation of the Kaplan-Meier estimator. 
The test statistic to be used is, as in Klein 2007: 
𝑋STRAT
2
=
(∑
𝑤̂𝑠(log (−log (𝑆̂1𝑠(𝑡))) −log (−log (𝑆̂2𝑠(𝑡)))
3
𝑠=1
))
2
∑
𝑤̂𝑠2(𝑉̂
3
𝑠=1
(log (−log (𝑆̂1𝑠(𝑡)))) + 𝑉̂ (log (−log (𝑆̂2𝑠(𝑡)))))
 
Where 𝑉̂(∙) is the estimated variance of the transformed survival function which is equal to 
𝜎̂𝑘𝑠(𝑡)2 (log (𝑆̂𝑖𝑠(𝑡)))
2
⁄
 for the treatment group k and strata s and where 𝜎̂𝑘𝑠(𝑡)2 is estimated using 
Greenwood’s formula: 
𝜎̂𝑘𝑠(𝑡)2 = ∑
𝑑𝑘𝑠𝑖
𝑌𝑘𝑠𝑖(𝑌𝑘𝑠𝑖−𝑑𝑘𝑠𝑖)
𝑡𝑘𝑠𝑖≤𝑡
 
And k = 1, 2 is the treatment group, s = 1, 2 is the actual baseline Clinical Status strata, 𝑆̂𝑘𝑠(𝑡) is the estimated 
survival at time t  = 28 and 𝑤̂𝑠 is inverse variance of the difference divided by the sum of inverse variances of 
the difference. 
This test-statistic follows a Chi-square distribution with 1-degree of freedom or, alternatively, the square-root 
follows a standard-normal distribution. 
As noted in Section 6.6.3, 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, square-root of the test statistic and p-value from a standard normal distribution function 
will be calculated using the pseudocode and formulae provided in Section 6.1 and compared to the final 
boundary and nominal p-value as determined using the ‘ldlbound’ package listed in Section 6.6.3.  
If the trial is stopped at the interim analysis, then to derive the p-value and confidence intervals for the early 
and final analysis sets, stage-wise ordering of the sample space will be used [3]. The resulting p-value, 
proportions, and confidence interval will be presented in the final report.  


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A graphical hierarchical design will be used to control the study-wide alpha as described in Section 6.8. This 
will not change the construction of p-values or their interpretation for the primary analysis, but will influence 
secondary analyses listed in Section 8.1.2. 
Kaplan-Meier curves (Figure 4) and p-values with estimates of mechanical ventilation-free survival at 28 days 
will be calculated and accompanied by confidence intervals adjusted to be consistent with the nominal alpha 
level at the interim or final analysis and constructed using the complementary log-log transformation. 
8.1.2. 
Hierarchical Sequence of Secondary Endpoints Analyses 
Analyses described in this section will be subject to the fixed-sequence hierarchical testing procedure 
described in Section 6.8. Any reference to p-values in this section is conditional on preceding hypothesis tests 
in the hierarchy. 
If a superior test fails to reject the null hypothesis, the analyses will still be performed to provide estimated 
effects with confidence intervals for relevant statistics and associated confidence-interval by-arm, but p-
values will not be generated. Confidence intervals for all analyses of secondary endpoints, will be 95% 
confidence intervals. 
8.1.2.1. 
Clinical Status Ordinal Scale at Day 15 
In the mITT population, the distribution of the 8-point Clinical Status ordinal score at Study Visit Day 15 (not 
necessarily actual study day 15), will be analyzed using a proportional odds model with treatment arm and 
actual baseline ordinal score (baseline ordinal score 5 or baseline ordinal score 6) as covariates. The treatment 
odds ratio estimated from the model will be presented along with the p-value, (Table 21). This analysis will be 
repeated for the As Treated population (Table 22). The Study Visit Day 15 clinical status score will be 
depicted graphically using shifted bar plots; the outcomes will be presented by actual baseline ordinal score 
and treatment group (Figure 13).  
8.1.2.2. 
Proportion of Subjects Not Progressing to Clinical Status 6, 7, or 8 by Day 29 
In the mITT population and among only those with an actual baseline ordinal score of 5, the proportion of 
subjects not progressing to ordinal score 6, 7, or 8 by Day 29 (see Section 3.3.4) will be analyzed using the 
same modeling approach as the primary outcome and described in Section 8.1.1. Kaplan-Meier curves 
(Figure 31) and p-values with estimates of proportions at the Day 29 study visit will be calculated and 
accompanied by confidence intervals (Table 23). 
8.1.2.3. 
Mortality by Day 29 
Mortality through Day 29 will be analyzed as a time to event endpoint (see Section 3.3.5). 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. Differences in time-to-event endpoints by treatment will be 
summarized with Kaplan-Meier curves (Figure 27).  
8.1.2.4. 
Time to Recovery 
In the mITT population, the time to recovery, as defined in Section 3.3, will be analyzed using a stratified log 
rank test to compare treatment to control through Day 29. Stratification is based on actual baseline Status 
ordinal score (ordinal score 5, ordinal score 6). 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 


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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. 
The treatment hazard ratio estimate and confidence interval and p-value from the stratified log rank test will 
be presented (Table 28). The median time to event and 95% confidence intervals will be summarized by 
treatment group and actual baseline Clinical Status ordinal score. Kaplan-Meier curves will also be generated 
by treatment arm (Figure 15, Figure 16, Figure 17). 
8.2. 
Additional Secondary Efficacy and Sensitivity Analyses 
This section describes the planned sensitivity analyses for the Primary Efficacy analysis and for the secondary 
efficacy outcome measures that will be executed outside of the hierarchical testing procedure governing the 
study-wide type 1 error described in the preceding section. Results described here are considered supportive 
and corroborative to the primary analysis from Section 8.1. 
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 mITT population. As Treated analyses may be 
explored to investigate consistency of results compared to the mITT analyses. 
8.2.1. 
Sensitivity and Corroborative Analyses of the Primary Endpoint 
The primary analysis will be repeated in the As Treated analysis population and in the ITT analysis 
population. The tabular and graphical summaries described in the previous section will be replicated for this 
As Treated analysis (Figure 5) and by baseline ordinal score (Figure 6 and Figure 7). 
Sensitivity analyses will be performed using Cox proportional hazards models to estimate the hazard ratio or 
progression to mechanical-ventilation or death (Table 16). A Cox model will be fit with binary indicators for 
treatment group and actual baseline Clinical Status ordinal score (5 or 6) as well as a treatment * actual 
baseline Clinical Status score interaction terms. The models will be fit to the mITT analysis population. The 
treatment group hazard ratios and CIs will be reported for both sets of models and the interaction term p-value 
will be reported for the interaction models. The tabular summary will also include results from an analysis of 
time to death or mechanical ventilation controlling for age and duration of symptoms as continuous covariates 
and baseline d-dimer and CRP values as continuous covariates.  
The primary analysis will also be repeated using the other subgroups defined in Section 6.4 in place of actual 
baseline Clinical Status. Each subgroup will be considered separately, and the tabular and graphical 
summaries described in the previous section will be replicated for each subgroup. A forest plot (Figure 8, 
Figure 9, Figure 10, Figure 11) will be generated to display the overall treatment hazard ratio estimate and CI 
from each of the within-subgroup analyses (Table 17).  
As noted in Section 6.4, analyses that take into account concomitant medication will be performed (Table 18 
and Table 19).  
In addition, a forest plot will be generated for the “leave one out” sensitivity analyses described in Section 6.7 
(Figure 12); estimated proportions and CIs will be provided for each subgroup that leaves a single site out.  


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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 did not require mechanical ventilation or ECMO (and are alive), 
- did not recover and required mechanical ventilation or ECMO (and are alive), and 
- dead by Day 29. 
The summary will also include the numbers and percentages, grouping deaths and ventilation required 
together (Table 20). 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. 
8.2.2. 
Additional Analyses of Clinical Status Ordinal Scale at Day 15 
Analysis of the key secondary outcome measure, the distribution of the Clinical Status 8-point ordinal score at 
Study Visit Day 15 will be repeated in the subgroups defined in Section 6.4 (Table 21). 
In addition to the subgroup analyses, the main analysis will be repeated including a treatment * baseline 
ordinal score interaction term, where the interaction term p-value will be reported for the interaction model 
(Table 21). 
8.2.3. 
Additional Analyses of Failure to Progress to Clinical Status 6, 7, or 8 
Additional analyses as described for the mechanical ventilation free survival (Section 8.2.1) will be performed 
(Table 24, Table 25, Table 26, and Table 27).  
8.2.4. 
Additional Analyses of Mortality 
Analyses of mortality will be performed in the mITT and the As Treated analysis populations and at Day 15 
(Table 67 and Table 68). As a supplemental analysis, a Cox model will be fit with binary indicators for 
treatment group and actual baseline ordinal score as well as a treatment * actual baseline ordinal score 
interaction term. The model will be fit in the mITT and As Treated analysis populations (Table 74). The 
treatment group hazard ratios and CIs and the interaction term p-value will be reported. Finally, the results of 
the subgroup and sensitivity time-to event analyses described in Section 6.4 will be presented in a table. 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 actual baseline 
ordinal score stratum as well as the difference in restricted mean recovery time between treatment groups 
within each of the baseline ordinal score strata (Table 75). 
8.2.5. 
Additional Analyses of Time-to-Recovery 
The analysis of Time-to-Recovery will be repeated in the mITT population but including only subjects with 
actual baseline Clinical Status scores in ordinal score 5 or 6 (excluding those with any other baseline score) 
and in the As-Treated population. The analysis will also be repeated using the Modified Recovery ordinal 
scale described in Section 4.3 (Table 29). 
Sensitivity analyses will be performed using Cox proportional hazards models to estimate the hazard ratio 
(Table 29). First, a mITT 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 


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model will be fit with binary indicators for treatment group and baseline ordinal score (5 or 6) as well as a 
treatment * baseline ordinal score (as a continuous variable) interaction terms. The models will be fit to the 
mITT analysis population. The treatment group hazard ratios and CIs will be reported for both sets of models 
and the interaction term p-value will be reported for the interaction models. The tabular summary will also 
include results from an analysis of time to recovery controlling for age and duration of symptoms as 
continuous covariates and baseline d-dimer and CRP values as continuous covariates.  
The time-to-recovery analysis will also be repeated using the other subgroups defined in Section 6.4 in place 
of actual baseline ordinal score. Each subgroup will be considered separately, and the tabular and graphical 
summaries described in the previous section will be replicated for each subgroup. Forest plots (Figure 18 and 
Figure 19) will be generated to display the overall treatment hazard ratio estimate and CI from each of the 
within-subgroup analyses (Table 30).  
As noted in Section 6.4, analyses that take into account concomitant medication will be performed (Table 32). 
An additional sensitivity analysis will evaluate the effect of recoveries that were not sustained as indicated in 
Section 3.3.2 (Table 31). 
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 actual baseline ordinal score stratum as 
well as the difference in restricted mean recovery time between treatment groups within each of the baseline 
ordinal score strata (Table 34). 
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 35). The summaries will also be provided by the Modified Recovery ordinal scale 
(Table 33) and the duration of symptoms categorizations specified in Section 6.4. 
Other censoring techniques and additional analyses of the primary outcome may be performed. 
8.2.6. 
Time-to Improvement in Clinical Status 
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 36). Differences in time-to-event endpoints by 
treatment arm will be summarized with Kaplan-Meier curves (Figure 14). 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.  
The above analyses will be repeated with the modification to the ordinal scale described in Section 4.3 
(Table 37). The only subgroup analysis that will be performed for time to improvement will be an analysis 
that classifies subjects by the duration of symptoms at baseline subgroups (above/below the median) 
(Table 38). 
8.2.7. 
Clinical Status Ordinal Scale While Hospitalized, Day 22, Day 29 
The number and proportion of subjects along with 95% confidence intervals by category of clinical status will 
be presented by treatment arm at Study Visit (not necessarily actual) Days 1, 3, 5, 8, 11, 15 and 29 (Table 39). 


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Change from baseline will also be summarized at Days 3, 5, 8, 11, 15, 22, and 29 (Table 39) and by subgroup 
(Table 40). Individual subject listings of clinical status scores will be presented (Listing 5). 
8.2.8. 
Desirability of Outcomes Response (DOOR) 
Proportions of subjects in each category of DOOR response (1 through 7) and 95% confidence intervals will 
be presented by treatment arm at Study Visit 15 and 29 (Table 41) in the mITT population. DOOR score will 
be summarized at Day 3, 5, 8, 11, 15, 22, and 29 mITT population (Table 42). The treatment arms will be 
compared at Day 15 and Day 29 using a Mann-Whitney U-statistic. Additionally, the mean DOOR score by 
Day and treatment group will be displayed in Figure 20. Individual subject listings of DOOR scores will be 
presented (Listing 6). 
8.2.9. 
Days of Oxygenation 
Duration of oxygenation use will be summarized in a table using means, standard deviations, medians and 
quartiles by treatment arm (Table 43). Analyses will be performed in the mITT and As Treated populations, 
and by duration of symptoms at baseline (Table 44). 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 21). 
8.2.10. 
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-randomization score of at least 
5; the number of subjects reporting new use and the incidence rate (and CI) will be reported (Table 43). 
8.2.11. 
Days of Non-Invasive Ventilation/High-Flow Oxygen 
Duration of non-invasive ventilation/high flow oxygen use will be summarized in a table using means, 
standard deviations, medians, and quartiles by treatment arm (Table 45). Analyses will be performed in the 
mITT and As Treated populations and by duration of symptoms at baseline (Table 46). 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 (Figure 22). 
8.2.12. 
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 5 or 6 at randomization. New use will be identified 
by a post-randomization score of 6. The number of subjects reporting new use and the incidence rate (and CI) 
will be reported (Table 45).  
8.2.13. 
Days of Invasive Mechanical Ventilation/ECMO 
Duration of Invasive Mechanical Ventilation/ECMO use will be summarized in a table using means, standard 
deviations, medians, and quartiles by treatment arm (Table 47). Analyses will be performed in the mITT and 
As Treated populations and by duration of symptoms at baseline (Table 48). Bee swarm plots of Invasive 
Mechanical Ventilation/ECMO 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 
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8.2.14. 
Incidence of New Invasive Mechanical Ventilation/ECMO 
The incidence and duration of new Invasive Mechanical Ventilation/ECMO use will be analyzed by treatment 
arm. New use will be identified by a post-randomization score of 7. The number of subjects reporting new use 
and the incidence rate (and CI) will be reported (Table 47). 
8.2.15. 
Days of Hospitalization 
Duration of hospitalization will be summarized in a table using means, standard deviations, medians, and 
quartiles by treatment arm. Incidence of readmittance will also be summarized (Table 49). A listing of 
subjects who were readmitted will be generated (Listing 29). Analyses will be performed in the mITT and As 
Treated population and by duration of symptoms at baseline (Table 50). 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 (Figure 24).  
8.3. 
Exploratory Efficacy Analyses 
Only Day 60 exploratory outcome measures are covered in this SAP. 
8.3.1. 
Clinical Status Ordinal Scale at Day 60 
The number and proportion of subjects along with 95% confidence intervals by category of clinical status will 
be presented by treatment arm and actual ordinal score for Day 60 (Table 52). Change from Day 29 to Day 60 
will be summarized categorically (e.g., maintained recovery, worsened) at Day 60 (Table 53).  
 


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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 randomization, and actual baseline ordinal 
score (Table 54 and Table 55). 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, autoimmune hepatitis, cancer, cardiac 
arrythmia, 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, depression or psychotic disorder, diabetes I and II, epilepsy/seizure, 
hypertension, immune deficiency, obesity, systemic lupus erythematosus, and thyroid disease. History and 
risk factors for DVT/PE, major surgery in the past month, prolonged immobility, delivery in the past 6 weeks, 
pre-COVID oxygen use, blood type, and COVID-19 vaccination are also collected. 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 56). 
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, actual baseline ordinal score, 
and treatment group (Table 57). Summaries of overall use of medications/therapies of interest 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 58 and Table 59 ). 
Individual subject listings will be presented for all concomitant medications (Listing 9), corticosteroid use 
(Listing 10), and medications of interest (Listing 11). 
9.2. 
Measurements of Treatment Compliance 
Section 7 provides the descriptions of summaries of key treatment compliance milestones/variables. 
Individual subject listings will be presented for all subjects who discontinued dosing (Listing 2). Individual 
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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 As Treated population. All adverse events reported and treatment emergent will 
be reported in tables and listings; treatment emergent events are adverse events or events increasing in 
severity anytime following the initiation of administration with any study product (baricitinib, 
dexamethasone, remdesivir, or any placebo). 
An overall summary by treatment arm and actual baseline ordinal score 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 for all subjects (Table 60 and 
Table 61). 
Adverse events occurring in 5% of subjects (by MedDRA preferred term) in any treatment group will be 
presented (Table 63). 
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, actual baseline ordinal score 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, baseline ordinal score and treatment group: 
• Renal adverse events by preferred term (Table 64); 
• Hepatic adverse events by preferred term (Table 65) 
• Related adverse events by MedDRA system organ class and preferred term (Table 66); 
• Subject listing of non-serious adverse events (Listing 13) and listing of related adverse events 
(Listing 14); 
• Bar chart of non-serious related adverse events by actual baseline ordinal score and MedDRA system 
organ class (Figure 25, Figure 26); 
A table of new diagnoses between the Day 29 visit and the Day 60 visit will be summarized by condition, 
treatment arm, actual baseline ordinal score and overall (Table 67). Conditions reported at the Day 60 visit 
will be listed (Listing 30). 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events 
Serious adverse events will be summarized by MedDRA system organ class and preferred term (Table 62). 
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 to Treatment, Alternate Etiology if not 
Related, Action Taken with Study Treatment, Subject Discontinuation, Outcome, MedDRA SOC, and 
MedDRA PT (Listing 15 and Listing 17). 
The number of subjects who die by Day 15 and Day 29 will be presented by treatment arm. The 14-, 28-and 
exploratory 60- day mortality rate, which will use Kaplan-Meier estimator, will be presented (Table 69). 
Differences in time-to-event endpoints by treatment will be summarized with Kaplan-Meier curves 
(Figure 28, Figure 29, Figure 30). 


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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 70). Differences in time-to-event endpoints by 
treatment will be summarized with Kaplan-Meier curves (Figure 27). Analyses of mortality will be performed 
in the mITT and the As Treated analysis populations (Table 71). As a supplemental analysis, a Cox model 
will be fit with binary indicators for treatment group and actual baseline ordinal score as well as a treatment * 
actual baseline ordinal score interaction term (Table 74). The model will be fit in the mITT and As Treated 
analysis populations. The treatment group hazard ratios and CIs and the interaction term p-value will be 
reported. Finally, the results of the subgroup and sensitivity time-to event analyses described in Section 6.4 
will be presented in a table (Table 72 and Table 73). 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 actual baseline ordinal score stratum as well as the difference in 
restricted mean recovery time between treatment groups within each of the actual baseline ordinal score strata 
(Table 75). 
Rates of Grade 3 and 4 AE occurrence will be summarized by treatment arm (Table 76). 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 77). 
Differences in time-to-event endpoints by treatment will be summarized with Kaplan-Meier curves 
(Figure 33). 
A summary of the infection culture results will be summarized by treatment group and AE severity 
(Table 78). The anatomical location(s) of the infection and causative pathogen(s) determined by culture will 
be summarized (Table 79, Table 81, Table 83). A listing of culture results will be generated (Listing 16). 
Infections considered to be opportunistic, as identified by the sponsor, will also be included in the summaries 
(Table 80, Table 82, Table 84). Both summaries will be repeated by Dexamethasone use prior to enrollment 
(Table 85 and Table 86). 
A summary of venous thromboembolisms, comprised of deep vein thrombosis and pulmonary embolisms by 
Treatment Group, will be included (Table 87). 
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 18, Listing 19, Listing 20, Listing 21, and 
Listing 22). 
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). For sites that do not 


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report an upper (lower) limit for the value of a laboratory parameter, the median of the reported upper (lower) 
limits across the other sites will be used. Medians and calculated LLN/ULN used if any, will be documented 
in the ADaM documentation. Vitamin D is collected on Day 1 and is not graded, but results will be 
summarized. 
The distribution of Grade 3 and 4 chemistry and hematology laboratory results by maximum severity, time 
point, actual baseline ordinal score and treatment group will be presented (Table 88). Treatment-emergent 
laboratory abnormalities will be summarized by parameter and grade (Table 89). 
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 actual baseline ordinal score and treatment arm (Table 51 and Table 90). Changes in 
chemistry and hematology laboratory values will be presented in line graphs over time with median, Q1 and 
Q3 plotted by actual baseline ordinal score and treatment arm (Figure 34).  
Listings will provide a complete listing of individual chemistry and hematology laboratory results with 
applicable reference ranges (Listing 23). 
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 at Day 1) and will be listed in Listing 24.  
Targeted Physical examinations are performed at Day 1 and may be 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 25). 
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 and corticosteroid use will be presented in subject listings (Listing 9 and 
Listing 10). 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, actual baseline 
ordinal score and treatment group for the As Treated population (Table 55).  
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, confidence intervals, 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”.  
For all other estimators, the NEJM statistical reporting guidelines will be followed: results will be presented 
with no more precision than is of scientific value and is meaningful. For example, measures of association, 
such as odds ratios, will be reported to two or three significant digits. Results derived from models will be 
limited to the appropriate number of significant digits. 


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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 
15.1. 
Test Statistic for Primary Endpoint of Time to Mechanical Ventilation or 
ECMO 
The test statistic in Section 8.1.1 was modified to account for unequal weighting in each stratum. The 
weighting is based on the inverse variance of the difference of the complementary log-log transformation of 
the Kaplan-Meier estimator at Day 29. The version of the formula reported in Klein 2007 gave equal weight 
to each stratum. As rationale for the modification, consider the extreme scenario where the difference in 
Kaplan-Meier Estimators is 10% in one stratum and -10% in the other stratum.  However, the first stratum has 
n=10,000 and the second stratum has n=100. Using the original formula, both strata would be equally 
weighted and show no difference. By adding a weighting to the formula, the strata with the higher information 
will be given more weight in computing the final test statistic.  
15.2. 
AE Reporting of Clinical Laboratory Results for eGFR, Creatinine, INR and 
Glucose  
The DAIDS Toxicity Table will be applied to clinical laboratory results and the corresponding grade 3 or 4 
AEs reported based on these laboratory results, with the below clarifications for AE reporting. 
15.2.1. 
eGFR and Creatinine Grading 
The DAIDS Toxicity Table has two grading options for eGFR and Creatinine, “Change from baseline” or 
“absolute value”. The absolute values will be used for AE reporting. 
15.2.2. 
Glucose Grading  
No change to the grading per the DAIDS Toxicity Table. However, a baseline condition of diabetes mellitus 
will be factored into reporting of grade 3 or grade 4 adverse events, as follows: 
• If a subject has no history of any type of diabetes mellitus and baseline glucose levels are normal, 
grade 1 or grade 2, then any grade 3 or 4 glucose spike will be reported as an AE. 
• If a subject has a history of any type of diabetes mellitus, then: 
o All grade 4 glucose elevations will be reported as AEs. 
o If baseline glucose levels are normal, grade 1, grade 2 and there are two or more consecutive 
elevations of glucose to grade 3, this will be reported as an AE. 
o If baseline glucose levels are normal, grade 1 or grade 2, a single elevation of glucose to grade 3 
will not be reported as an AE or reported as related to Dexamethasone.  
15.2.3. 
INR Grading  
The DAIDS Toxicity Table includes grading for subjects not on anticoagulant therapy. As many of the 
subjects will be on anticoagulant therapy, these subjects’ INR values will not be graded. Additionally, 
reporting of AEs will be based on the following guidelines: 
• If a subject is on anticoagulant therapy, INR in the 2.0-<3.0 times the upper limit of normal is 
expected and an AE does not need to be reported. However, an INR 3.0 or more times the upper limit 
of normal is reported in the context of a clinical syndrome. 


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• If a subject is not on anticoagulant therapy or on Low Molecular Weight Heparin (LMWH) like 
Enoxaparin (Lovenox) and has any INR values at least 2.0 times the upper limit of normal (grade 3+) 
then an AE for INR should be reported. Note that abnormal INR values should be reported as part of a 
clinical syndrome (e.g., coagulopathy secondary to sepsis; GI bleed; multi-organ failure, etc.) and not 
reported as a separate AE. 
15.3. 
Changes to the SAP from Version 1.0 to Version 2.0 
The below summarizes the changes made to the SAP from version 1.0 to version 2.0. 
• As described in Section 15.1, the primary analysis was updated to use a weighted test statistic. 
• As described in Section 15.2, text was added to describe reporting of AEs for eGFR, Creatinine, 
Glucose and INR. 
• It was decided that the Day 60 analyses would be included in the final study report, rather than an 
addendum. The SAP was amended to include data through Day 60. 
• At the time of the SAP update, all subjects were enrolled and there was only one known stratification 
error where a subject was neither ordinal score 5 nor 6 at baseline. Since only one subject fell into the 
“other” category in SAP version 1.0, tables were updated to include the one stratification error in the 
overall summaries but exclude the subject from subgroup analyses and modeling with adjustments for 
baseline strata. The SAP was left flexible enough to handle any additional stratifications errors 
identified prior to database lock. 
• Modeling including baseline strata was updated to only be run based on handling the baseline ordinal 
score as continuous since there are only two levels included (i.e., baseline ordinal score 5 or 6). 
• SAP version 1.0 table title “Infections by Treatment Group” was updated to be “Culture Results by 
Treatment Group and AE Severity”. Additional tables of infections by MedDRA preferred term were 
added. 
• Section 3.3.3, the following sentence was removed: “Subjects who are randomized but do not initiate 
treatment will be censored at time 0.” Additionally, the following sentence was added: "Subjects not 
completing Day 29 or discharged to hospice or other end-of-life care prior to Day 29 with a death date 
unknown but completing Day 60 will be reviewed by the blinded Endpoint Review Committee to 
assess whether the Day 60 data impacts handling of the subject for the Day 29 timepoint." 
• Throughout the document: 
o Typos and errors introduced via copying/pasting language from other sections were corrected. 
o Clinical Status was updated to be “Ordinal Score” in the tables for consistency with language used 
in prior ACTT clinical study reports. 
o Titles for tables and figures were updated to include “by Day 29”, where applicable, to distinguish 
from Day 60 outcomes. 


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16. 
REFERENCES 
1. Drummond R. CONSORT Revised: Improving the Reporting of Randomized Clinical Trials. JAMA. 
2001; 285(15):2006-2007. 
2. Klein JP, Logan B, Harhoff M, Andersen PK. Analyzing survival curves at a fixed point in time. Stat 
Med. 2007;26(24):4505-19. 
3. 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 Appendix 1, Appendix 2, and Appendix 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: 
Sample Size Estimates and Study Power ....................................................................26 
Table 2: 
Ineligibility Summary of Screen Failures ...................................................................63 
Table 3: 
Analysis Population Eligibilities by Treatment Group and Actual Baseline 
Ordinal Score ..............................................................................................................64 
Table 4: 
Subject Disposition by Treatment Group and Actual Baseline Ordinal Score 
– mITT Population ......................................................................................................65 
Table 5: 
Subject Status at Study Termination by Treatment Group and Actual 
Baseline Ordinal Score – mITT Population................................................................67 
Table 6: 
Baricitinib / PO Placebo Exposure by Treatment Group and Actual Baseline 
Ordinal Score – mITT Population ..............................................................................68 
Table 7: 
Dexamethasone / IV Placebo Exposure by Treatment Group and Actual 
Baseline Ordinal Score – mITT Population................................................................70 
Table 8: 
Remdesivir Exposure by Treatment Group and Actual Baseline Ordinal 
Score – mITT Population ............................................................................................71 
Table 9: 
Subjects Reporting Prior Remdesivir Treatment by Actual Baseline Ordinal 
Score and Treatment Group – mITT Population ........................................................72 
Table 10: Subjects Reporting Prior Baricitinib Treatment by Actual Baseline Ordinal 
Score and Treatment Group – mITT Population ........................................................73 
Table 11: Subjects Reporting Prior Dexamethasone Treatment by Actual Baseline 
Ordinal Score and Treatment Group – mITT Population ...........................................74 
Table 12: Day 60 Subject Disposition by Treatment Group and Actual Baseline 
Ordinal Score – mITT Population ..............................................................................75 
Table 13: Distribution of Subject Specific Protocol Deviations by Category, Type, 
Treatment Group, and Actual Baseline Ordinal Score -mITT Population .................76 
Table 14: Distribution of Major Subject Specific Protocol Deviations by Category, 
Type, Treatment Group, and Actual Baseline Ordinal Score – mITT 
Population ...................................................................................................................78 
Table 15: Mechanical Ventilation-free Survival by Day 29 by Treatment Group and 
Actual Baseline Ordinal Score ....................................................................................79 
Table 16: Mechanical Ventilation Free Survival by Day 29 by Treatment Group and 
Actual Baseline Ordinal Score: Sensitivity and Exploratory Analyses – 
mITT Population, Actual Baseline Ordinal Score 5 or 6 ............................................80 
Table 17: Mechanical Ventilation Free Survival by Day 29 by Treatment Group within 
Subgroups – mITT Population, Actual Baseline Ordinal Score 5 or 6 ......................81 


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Table 18: Mechanical Ventilation Free Survival by Day 29 by Treatment Group: Prior 
Corticosteroid Use – mITT Population, Actual Baseline Ordinal Score 5 or 6 .........81 
Table 19: Mechanical Ventilation Free Survival by Day 29 by Treatment Group: 
Medications of Interest Sensitivity Analysis – mITT Population, Actual 
Baseline Ordinal Score 5 or 6 .....................................................................................81 
Table 20: Summary of Recoveries, Ventilator/ECMO Requirement, and Deaths by 
Day 29 – mITT Population .........................................................................................83 
Table 21: Odds Ratio for Better (Lower) Clinical Status Score at Study Visit Day 15 
by Treatment Using a Proportional Odds Model, Baricitinib + PBO + RDV 
Relative to PBO + Dexamethasone + RDV – mITT Population, Actual 
Baseline Ordinal Score 5 or 6 .....................................................................................84 
Table 22: Odds Ratio for Better (Lower) Clinical Status Score at Study Visit Day 15 
by Treatment Using a Proportional Odds Model, Baricitinib + PBO + RDV 
Relative to PBO + Dexamethasone + RDV – As Treated Population, Actual 
Baseline Ordinal Score 5 or 6 .....................................................................................85 
Table 23: Proportion of Subjects Not Progressing to Clinical Status Ordinal Score 6, 7, 
or 8 by Day 29 by Treatment Group, Actual Baseline Ordinal Score 5 .....................86 
Table 24: Proportion of Subjects Not Progressing to Clinical Status Ordinal Score 6, 7, 
or 8 by Day 29 by Treatment Group and Actual Baseline Ordinal Score: 
Sensitivity and Exploratory Analyses – mITT Population, Actual Baseline 
Ordinal Score 5 ...........................................................................................................87 
Table 25: Proportion of Subjects Not Progressing to Clinical Status Ordinal Score 6, 7, 
or 8 by Day 29 by Treatment Group within Subgroups  – mITT Population, 
Actual Baseline Ordinal Score 5 .................................................................................87 
Table 26: Proportion of Subjects Not Progressing to Clinical Status Ordinal Score 6, 7, 
or 8 by Day 29 by Treatment Group: Prior Corticosteroid Use – mITT 
Population, Actual Baseline Ordinal Score 5 .............................................................87 
Table 27: Proportion of Subjects Not Progressing to Clinical Status Ordinal Score 6, 7, 
or 8 by Day 29 by Treatment Group: Medications of Interest Sensitivity 
Analysis – mITT Population, Actual Baseline Ordinal Score 5 .................................87 
Table 28: Time to Recovery by Day 29 by Treatment Group and Actual Baseline 
Ordinal Score ..............................................................................................................89 
Table 29: Time to Recovery by Day 29 by Treatment Group and Baseline Ordinal 
Score: Sensitivity and Exploratory Analyses – mITT Population, Actual 
Baseline Ordinal Score 5 or 6 .....................................................................................90 
Table 30: Time to Recovery by Day 29 by Treatment Group within Subgroups – mITT 
Population, Actual Baseline Ordinal Score of 5 or 6 ..................................................91 
Table 31: Time to Recovery by Day 29 by Treatment Group and Actual Baseline 
Ordinal Score: Readmittance Sensitivity Analysis – mITT Population, 
Actual Baseline Ordinal Score of 5 or 6 .....................................................................91 


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Table 32: Time to Recovery by Day 29 by Treatment Group and Actual Baseline 
Ordinal Score: Medications of Interest Sensitivity Analysis – mITT 
Population, Actual Baseline Ordinal Score of 5 or 6 ..................................................91 
Table 33: Time to Recovery by Day 29 by Treatment Group using Modified Recovery 
Scale Sensitivity Analysis – mITT Population, Actual Baseline Ordinal 
Score of 5 or 6 .............................................................................................................91 
Table 34: Time to Recovery by Day 29 by Treatment Group and Actual Baseline 
Ordinal Score: Restricted Mean Survival Time Analysis, Actual Baseline 
Ordinal Score 5 or 6 ....................................................................................................93 
Table 35: Summary of Recoveries and Deaths by Day 29 – mITT Population .........................95 
Table 36: Time to One or Two Category Improvement on the 8-Point Ordinal Scale by 
Treatment Group, Actual Baseline Ordinal Score 5 or 6 ............................................96 
Table 37: Time to Improvement on the 8-Point Ordinal Scale by Treatment Group: 
Modified Ordinal Scale, Actual Baseline Ordinal Score 5 or 6 .................................96 
Table 38: Time to Improvement on the 8-Point Ordinal Scale by Treatment Group and 
Duration of Symptoms at Baseline – mITT Population, Actual Baseline 
Ordinal Score 5 or 6 ....................................................................................................96 
Table 39: Clinical Status Scores by Treatment Group and Study Visit, Imputed – mITT 
Population, Actual Baseline Ordinal Score 5 or 6 ......................................................97 
Table 40: Summary of Clinical Status Score by Treatment Group and Study Visit – 
mITT Population, Actual Baseline Ordinal Score 5 or 6 ............................................98 
Table 41: DOOR Category by Treatment Group and Study Visit, Imputed – mITT 
Population, Actual Baseline Ordinal Score 5 or 6 ......................................................99 
Table 42: Summary of DOOR by Treatment Group and Study Visit, Imputed  – mITT 
Population, Actual Baseline Ordinal Score 5 or 6 ....................................................100 
Table 43: Oxygen Use Through Day 29 by Treatment Group – Actual Baseline 
Ordinal Score of 5 or 6 .............................................................................................101 
Table 44: Oxygen Use Through Day 29 by Treatment Group and Duration of 
Symptoms at Baseline – Actual Baseline Ordinal Score of 5 or 6 ...........................102 
Table 45: Non-invasive Ventilation/High-Flow Oxygen Use Through Day 29 by 
Treatment Group – Actual Baseline Ordinal Score of 5 or 6 ...................................102 
Table 46: Non-invasive Ventilation/High-Flow Oxygen Use Through Day 29 by 
Treatment Group and Duration of Symptoms at Baseline – Actual Baseline 
Ordinal Score of 5 or 6 .............................................................................................102 
Table 47: Ventilation/ECMO Use Through Day 29 by Treatment Group – Actual 
Baseline Ordinal Score of 5 or 6...............................................................................102 
Table 48: Ventilation/ECMO Use Through Day 29 by Treatment Group and Duration 
of Symptoms at Baseline – Actual Baseline Ordinal Score of 5 or 6 .......................102 


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Table 49: Hospitalization Through Day 29 by Treatment Group – Actual Baseline 
Ordinal Score of 5 or 6 .............................................................................................103 
Table 50: Hospitalization Through Day 29 by Treatment Group and Duration of 
Symptoms at Baseline – Actual Baseline Ordinal Score of 5 or 6 ...........................103 
Table 51: Summary Statistics of Laboratory Efficacy Results by Study Visit Day, and 
Treatment Group – mITT Population, Actual Baseline Ordinal Score of 5 or 
6 ................................................................................................................................104 
Table 52: Day 60 Ordinal Scores by Treatment Group and Actual Baseline Ordinal 
Score – mITT Population ..........................................................................................106 
Table 53: Day 60 Change in Ordinal Score from Day 29 by Treatment Group and 
Actual Baseline Ordinal Score – mITT Population ..................................................107 
Table 54: Categorical Demographic and Baseline Characteristics by Actual Baseline 
Ordinal Score and Treatment Group – mITT Population .........................................108 
Table 55: Continuous Demographic and Baseline Characteristics by Actual Baseline 
Ordinal Score and Treatment Group – mITT Population .........................................110 
Table 56: Summary of Subjects with Pre-Existing Medical Conditions Treatment 
Group - As Treated Population .................................................................................112 
Table 57: Number and Percentage of Subjects with Prior and Concurrent Medications 
by WHO Drug Classification, Actual Baseline Ordinal Score, and Treatment 
Group – As Treated Population ................................................................................113 
Table 58: Number and Percentage of Subjects Reporting On-Study Use of Medications 
of Interest by Actual Baseline Ordinal Score, and Treatment Group – As 
Treated Population ....................................................................................................114 
Table 59: On-Study Use of Medications of Interest by Study Day, Actual Baseline 
Ordinal Score, and Treatment Group – As Treated Population ................................115 
Table 60: Overall Summary of Adverse Events – As Treated Population ...............................116 
Table 61: Subject-Level Rates of Adverse Events and Differences between Treatment 
Groups – As Treated Population...............................................................................117 
Table 62: Serious Adverse Events by MedDRA System Organ Class and Preferred 
Term, and Treatment Group - As Treated Population ..............................................118 
Table 63: Non-Serious 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 .................................................................................119 
Table 64: Renal Adverse Events by Preferred Term and Treatment Group – As Treated 
Population .................................................................................................................120 
Table 65: Hepatic Adverse Events by Preferred Term and Treatment Group – As 
Treated Population ....................................................................................................120 
Table 66: Related Adverse Events by MedDRA System Organ Class and Preferred 
Term, and Treatment Group - As Treated Population ..............................................121 


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Table 67: Day 60 New Diagnoses Since Day 29 by Treatment Group and Actual 
Baseline Ordinal Score – As Treated Population .....................................................122 
Table 68: Deaths by Day 15, Day 29, or Day 60 by Treatment Group and Actual 
Baseline Ordinal Score – mITT Population..............................................................123 
Table 69: Deaths by Day 15 or Day 29 by Treatment Group and Actual Baseline 
Ordinal Score – As Treated Population ....................................................................123 
Table 70: Time to Death through Day 15 and 29 by Treatment Group and Actual 
Baseline Ordinal Score – mITT Population..............................................................124 
Table 71: Time to Death through Day 15 and 29 by Treatment Group and Actual 
Baseline Ordinal Score – As Treated Population .....................................................125 
Table 72: Time to Death through Day 15 and 29 by Treatment Group within 
Subgroups – mITT Population, Actual Baseline Ordinal Score 5 or 6 ....................125 
Table 73: Time to Death through Day 15 and 29 by Treatment Group: Medications of 
Interest Sensitivity Analysis – mITT Population, Actual Baseline Ordinal 
Score 5 or 6 ...............................................................................................................125 
Table 74: Time to Death through Day 15 and 29 by Treatment Group: Interaction 
Modeling – mITT Population, Actual Baseline Ordinal Score 5 or 6 ......................125 
Table 75: Time to Death through Day 15 and 29 by Treatment Group: Restricted Mean 
Survival Time Analysis – mITT Population, Actual Baseline Ordinal Score 5 
or 6 ............................................................................................................................127 
Table 76: Subjects Experiencing Grade 3 or 4 AEs and SAEs through Day 29 by 
Treatment Group and Actual Baseline Ordinal Score – As Treated 
Population .................................................................................................................128 
Table 77: Analysis of Time to Death, SAEs, or Grade 3 or 4 AEs by Treatment Group 
– As Treated Population ...........................................................................................129 
Table 78: Culture Results by Treatment Group and Infection AE Severity – As Treated 
Population .................................................................................................................130 
Table 79: New Infections by Treatment Group – As Treated Population, Actual 
Baseline Ordinal Score 5 ..........................................................................................131 
Table 80: Opportunistic New Infections by Treatment Group – As Treated Population, 
Actual Baseline Ordinal Score 5 ...............................................................................131 
Table 81: New Infections by Treatment Group – As Treated Population, Actual 
Baseline Ordinal Score 6 ..........................................................................................131 
Table 82: Opportunistic New Infections by Treatment Group – As Treated Population, 
Actual Baseline Ordinal Score 6 ...............................................................................131 
Table 83: New Infections by Treatment Group – As Treated Population, Actual 
Baseline Ordinal Score 5 or 6 ...................................................................................131 
Table 84: Opportunistic New Infections by Treatment Group – As Treated Population, 
Actual Baseline Ordinal Score 5 or 6 .......................................................................131 


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Table 85: New Infections by Treatment Group by Dexamethasone Prior to Enrollment 
– As Treated Population, Actual Baseline Ordinal Score 5 or 6 ..............................131 
Table 86: Opportunistic New Infections by Treatment Group by Dexamethasone Prior 
to Enrollment – As Treated Population, Actual Baseline Ordinal Score 5 or 6 .......131 
Table 87: VTEs by Treatment Group – As Treated Population, Actual Baseline 
Ordinal Score 5 or 6 ..................................................................................................132 
Table 88: Abnormal Laboratory Results of Grade 3 or 4 by Parameter, Maximum 
Severity, Time Point, and Treatment Group – As Treated Population, Actual 
Baseline Ordinal Score of 5 or 6...............................................................................133 
Table 89: Treatment-Emergent Laboratory Abnormalities - As Treated Population, 
Actual Baseline Ordinal Score of 5 or 6 ...................................................................134 
Table 90: Summary Statistics of Laboratory Results by Parameter, Study Visit Day, 
and Treatment Group – As Treated Population, Actual Baseline Ordinal 
Score 5 or 6 ...............................................................................................................135 
 
 


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Table 2: 
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 randomized 
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 randomized will be counted in the denominator. 
 


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Table 3: 
Analysis Population Eligibilities by Treatment Group and Actual Baseline Ordinal Score 
 
 
Baricitinib + PBO + RDV 
PBO + Dexamethasone + RDV 
Analysis Population 
Inclusion / Reason for 
Exclusion 
Baseline 
Ordinal 
Score 5 
Baseline 
Ordinal 
Score 6  
All 
Subjectsd 
Baseline 
Ordinal 
Score 5 
Baseline 
Ordinal 
Score 6  
All 
Subjectsd 
n 
n 
n 
n 
n 
n 
Intent-to-Treat Population 
(Randomized Strata)a 
Included in Population 
x 
x 
x 
x 
x 
x 
Modified Intent-to-Treat 
Population (Actual Baseline 
Clinical Status) b 
Included in Population 
x 
x 
x 
x 
x 
x 
As Treated Populationc 
Included in Population 
x 
x 
x 
x 
x 
x 
Excluded from Population 
x 
x 
x 
x 
x 
x 
Did Not Receive Dose of 
Baricitinib/Placebo 
x 
x 
x 
x 
x 
x 
Did Not Receive Dose of 
Dexamethasone/Placebo 
 
 
 
 
 
 
a Counts are the numbers of subjects randomized to the specified treatment group with the randomized baseline ordinal score. 
b Counts are the numbers of subjects randomized to the specified treatment group with the actual baseline ordinal score. 
c Counts are the numbers of subjects who received the specified treatment with the actual baseline ordinal score. 
d [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 
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].” 
 


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Table 4: 
Subject Disposition by Treatment Group and Actual Baseline Ordinal Score – mITT Population 
Subject Disposition  
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
All Subjects 
(N = X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjects 
(N=X)a 
Baseline 
Ordinal 
Score 5 
(N=X)  
Baseline 
Ordinal 
Score 6 
(N=X)  
All Subjects 
(N=X) a  
Baseline 
Ordinal 
Score 5 
(N=X)  
Baseline 
Ordinal 
Score 6 
(N=X)  
All Subjects 
(N=X) a 
n/N 
% 
n/N 
% 
n/N 
% 
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 
x/x 
100 
x/x 
100 
x/x 
100 
Terminated Early from Study 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
Discharged from Hospital 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
Died During Follow-up 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
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 
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 
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 
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 
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 
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 
x/x 
xx 
x/x 
xx 
x/x 
xx 
Repeat for Days 3, 5, 8, 11 
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 
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 
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 
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 
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 
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 
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 
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 
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 
x/x 
xx 
x/x 
xx 
x/x 
xx 


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Subject Disposition  
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
All Subjects 
(N = X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjects 
(N=X)a 
Baseline 
Ordinal 
Score 5 
(N=X)  
Baseline 
Ordinal 
Score 6 
(N=X)  
All Subjects 
(N=X) a  
Baseline 
Ordinal 
Score 5 
(N=X)  
Baseline 
Ordinal 
Score 6 
(N=X)  
All Subjects 
(N=X) a 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
Safety Laboratory Blood Draw 
x/x 
xx 
x/x 
xx 
x/x 
xx 
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 
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 
x/x 
xx 
x/x 
xx 
x/x 
xx 
N = Number of subjects randomized 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. 
a [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 


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Table 5: 
Subject Status at Study Termination by Treatment Group and Actual Baseline Ordinal Score – mITT Population 
Baseline Ordinal Score 
Category 
Status at Termination 
Baricitinib + PBO + RDV 
PBO + Dexamethasone + RDV 
N 
n 
% 
N 
n 
% 
All Subjectsa 
Any Status 
Any Status 
x 
x 
x 
x 
x 
x 
Recovery 
Recovered 
x 
x 
x 
x 
x 
x 
Not Recovered 
x 
x 
x 
x 
x 
x 
Hospitalization 
Hospitalized 
x 
x 
x 
x 
x 
x 
Not Hospitalized 
x 
x 
x 
x 
x 
x 
Relative to Day 15 
Prior to Day 15 
x 
x 
x 
x 
x 
x 
On or After Day 15 
x 
x 
x 
x 
x 
x 
Continue for Baseline Ordinal Score 5, 6 
… 
… 
… 
… 
… 
… 
… 
… 
N = Number of subjects in the mITT Population with the baseline ordinal score. 
Status at termination based on the time of the last ordinal score collection. 
a [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 


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Table 6: 
Baricitinib / PO Placebo Exposure by Treatment Group and Actual Baseline Ordinal 
Score – mITT Population 
 
Baricitinib + PBO + RDV 
(N = X) 
PBO + Dexamethasone + RDV 
(N = X) 
 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjects 
(N=X)a 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjects 
(N=X)a 
Number of Doses Received 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
Mean (SD) 
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 
Q1, Q3 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
 
 
 
 
 
 
 
Number of Subjects by Doses Received 
 
 
 
 
 
 
1 Dose 
x 
x 
x 
x 
x 
x 
2 Doses 
x 
x 
x 
x 
x 
x 
3 Doses 
x 
x 
x 
x 
x 
x 
4 Doses 
x 
x 
x 
x 
x 
x 
5 Doses 
x 
x 
x 
x 
x 
x 
6 Doses 
x 
x 
x 
x 
x 
x 
7 Doses 
x 
x 
x 
x 
x 
x 
8 Doses 
x 
x 
x 
x 
x 
x 
9 Doses 
x 
x 
x 
x 
x 
x 
10 Doses 
x 
x 
x 
x 
x 
x 
11 Doses 
x 
x 
x 
x 
x 
x 
12 Doses 
x 
x 
x 
x 
x 
x 
13 Doses 
x 
x 
x 
x 
x 
x 
14 Doses 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
Number of Subjects Treatment Temporarily 
Held 
x 
x 
x 
x 
x 
x 
Number of Subjects by Reason for Hold 
x 
x 
x 
x 
x 
x 
[Reason 1] 
x 
x 
x 
x 
x 
x 
[Reason 2] 
x 
x 
x 
x 
x 
x 
Etc… 
x 
x 
x 
x 
x 
x 
Number of Subjects Discontinuing Treatment 
x 
x 
x 
x 
x 
x 
Number of Subjects by Reason for 
Discontinuation 
x 
x 
x 
x 
x 
x 
[Reason 1] 
x 
x 
x 
x 
x 
x 
[Reason 2] 
x 
x 
x 
x 
x 
x 
Etc… 
x 
x 
x 
x 
x 
x 
a [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 


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Table 7: 
Dexamethasone / IV Placebo Exposure by Treatment Group and Actual Baseline Ordinal 
Score – mITT Population 
 
Baricitinib + PBO + RDV 
(N = X) 
PBO + Dexamethasone + RDV 
(N = X) 
 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjects 
(N=X)a 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjects 
(N=X)a 
Number of Doses Received 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
Mean (SD) 
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 
Q1, Q3 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
 
 
 
 
 
 
 
Number of Subjects who Received Dexamethasone 
Prior to Enrollment 
x 
x 
x 
x 
x 
x 
Number of Subjects by Doses Received 
 
 
 
 
 
 
1 Dose 
x 
x 
x 
x 
x 
x 
2 Doses 
x 
x 
x 
x 
x 
x 
3 Doses 
x 
x 
x 
x 
x 
x 
4 Doses 
x 
x 
x 
x 
x 
x 
5 Doses 
x 
x 
x 
x 
x 
x 
6 Doses 
x 
x 
x 
x 
x 
x 
7 Doses 
x 
x 
x 
x 
x 
x 
8 Doses 
x 
x 
x 
x 
x 
x 
9 Doses 
x 
x 
x 
x 
x 
x 
10 Doses 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
Number of Subjects Discontinuing Treatment 
x 
x 
x 
x 
x 
x 
Number of Subjects by Reason for Discontinuation 
x 
x 
x 
x 
x 
x 
[Reason 1] 
x 
x 
x 
x 
x 
x 
[Reason 2] 
x 
x 
x 
x 
x 
x 
Etc… 
x 
x 
x 
x 
x 
x 
a [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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Table 8: 
Remdesivir Exposure by Treatment Group and Actual Baseline Ordinal Score – mITT 
Population 
 
Baricitinib + PBO + RDV 
(N = X) 
PBO + Dexamethasone + RDV 
(N = X) 
 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjects 
(N=X)a 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjects 
(N=X)a 
Number of Doses Received 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
Mean (SD) 
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 
Q1, Q3 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
 
 
 
 
 
 
 
Number of Subjects who Received RDV Prior to Enrollment 
x 
x 
x 
x 
x 
x 
Number of Subjects by Doses Received 
 
 
 
 
 
 
1 Dose 
x 
x 
x 
x 
x 
x 
2 Doses 
x 
x 
x 
x 
x 
x 
3 Doses 
x 
x 
x 
x 
x 
x 
4 Doses 
x 
x 
x 
x 
x 
x 
5 Doses 
x 
x 
x 
x 
x 
x 
6 Doses 
x 
x 
x 
x 
x 
x 
7 Doses 
x 
x 
x 
x 
x 
x 
8 Doses 
x 
x 
x 
x 
x 
x 
9 Doses 
x 
x 
x 
x 
x 
x 
10 Doses 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
Number of Subjects Treatment Temporarily Held 
x 
x 
x 
x 
x 
x 
Number of Subjects by Reason for Hold 
x 
x 
x 
x 
x 
x 
[Reason 1] 
x 
x 
x 
x 
x 
x 
[Reason 2] 
x 
x 
x 
x 
x 
x 
Etc… 
x 
x 
x 
x 
x 
x 
Number of Subjects Discontinuing Treatment 
x 
x 
x 
x 
x 
x 
Number of Subjects by Reason for Discontinuation 
x 
x 
x 
x 
x 
x 
[Reason 1] 
x 
x 
x 
x 
x 
x 
[Reason 2] 
x 
x 
x 
x 
x 
x 
Etc… 
x 
x 
x 
x 
x 
x 
a [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 9: 
Subjects Reporting Prior Remdesivir Treatment by Actual Baseline Ordinal Score and 
Treatment Group – mITT Population 
Prior RDV Treatment Summary 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjects 
(N=X)a 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjects 
(N=X)a 
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 Number of Doses Available 
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 
a [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 10: 
Subjects Reporting Prior Baricitinib Treatment by Actual Baseline Ordinal Score and 
Treatment Group – mITT Population 
Prior RDV Treatment Summary 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjects 
(N=X)a 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjects 
(N=X)a 
Received baricitinib Treatment Prior to Enrollment – n (%) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Number of Doses of Baricitinib Received Prior to Enrollment 
 
 
 
 
 
 
Number of Subjects with Number of Doses Available 
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 
a [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 11: 
Subjects Reporting Prior Dexamethasone Treatment by Actual Baseline Ordinal Score 
and Treatment Group – mITT Population 
Prior RDV Treatment Summary 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjects 
(N=X)a 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjects 
(N=X)a 
Received Dexamethasone Treatment Prior to Enrollment – n 
(%) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Number of Doses of Dexamethasone Received Prior to 
Enrollment 
 
 
 
 
 
 
Number of Subjects with Number of Doses Available 
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 
a [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 12: 
Day 60 Subject Disposition by Treatment Group and Actual Baseline Ordinal Score – mITT Population 
Subject Disposition  
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
All Subjects 
(N=X) 
Ordinal 
Score 5 
(N=X) 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N = X) 
Ordinal 
Score 5 
(N=X) 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N = X) 
Ordinal 
Score 5 
(N=X) 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N = X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Visit Occurred 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Type of Visitb 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Inpatient/In-person Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chart Review 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Deceased After the Day 29 Visit Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Was the Subject Seen by a Doctor, Outside a Hospital Re-Admission after 
Day 29/Last Study Contact? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Was the Subject Re-Admitted after Day 29/Last Study Contact? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If Seen by a Doctor or Re-Admitted after Day 29/Last Study Contact, Was 
the Reason Due to a Worsening or Exacerbated Pre-Existing Condition? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = Number of subjects in the mITT Population. 
n = Number of subjects meeting the criteria. 
a [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
bPercentage based on the number of subjects with a visit.  Visits may be conducted by more than one method (e.g., inpatient and chart review).  
 


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Table 13: 
Distribution of Subject Specific Protocol Deviations by Category, Type, Treatment Group, and Actual Baseline Ordinal Score -
mITT Population 
Category 
Deviation Type 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
All Subjects 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All Subjects 
(N=X)a 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All Subjects 
(N=X)a 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All Subjects 
(N=X)a 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# 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/ 
randomization 
Any type 
x 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
x 
 
Met exclusion 
criterion 
x 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
x 
 
Out of window visit 
x 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
x 
 
Missed treatment 
administration 
x 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
x 
 
Out of window visit 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Category 
Deviation Type 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
All Subjects 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All Subjects 
(N=X)a 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All Subjects 
(N=X)a 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All Subjects 
(N=X)a 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
 
Missed visit/visit not 
conducted 
x 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
x 
Protocol 
procedure/ 
assessment 
Any type 
x 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
x 
 
Blood not collected 
x 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
x 
 
Other specimen not 
collected 
x 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
x 
 
Required procedure 
not conducted 
x 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
x 
 
Study product 
temperature excursion 
x 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
x 
 
Stratification error 
x 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Category 
Deviation Type 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
All Subjects 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All Subjects 
(N=X)a 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All Subjects 
(N=X)a 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All Subjects 
(N=X)a 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
# of 
Subj. 
# of 
Dev. 
Treatment 
administration 
Any type 
x 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
x 
 
Study product 
temperature excursion 
x 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
x 
Blinding 
policy/procedure 
Any type 
x 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
a [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 
Table with similar format: 
Table 14: 
Distribution of Major Subject Specific Protocol Deviations by Category, Type, Treatment Group, and Actual Baseline Ordinal 
Score – mITT Population 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 15: 
Mechanical Ventilation-free Survival by Day 29 by Treatment Group and Actual Baseline Ordinal Score 
Analysis 
Population 
Treatment Group 
Actual Baseline 
Ordinal Score 
Number Subjects 
requiring Mechanical 
Ventilation by Day 29 
Number 
Subjects Dying 
by Day 29 
Day 29 Mechanical 
Ventilation-Free Survival 
HR 
P-value 
Estimate 
95% CI 
Estimate 
95% CI 
mITT Population 
Baricitinib + PBO + RDV (N=X) 
5 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, 
x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Baricitinib + PBO + RDV (N=X) 
6 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, 
x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Baricitinib + PBO + RDV (N=X) 
Baseline Clinical 
Status 5 or 6 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, 
x.xx 
0.xxx 
PBO + Dexamethasone + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Baricitinib + PBO + RDV (N=X) 
Any Baseline 
Ordinal Score 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, 
x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Repeat for the As Treated Population and ITT population. 
N= Number of subjects in the specified treatment group, actual baseline ordinal score, and analysis population.  
n = Number of subjects.  
Mechanical Ventilation-Free Survival are Kaplan-Meier Estimates at Day 29 study visit 
HR is the ratio of the hazard of mechanical ventilation or death in each treatment group estimated from the Cox model. The ratio is to PBO + Dexamethasone + RDV to Baricitinib + PBO + RDV. 
HRs for the ‘combined ordinal score groups are the hazard ratio from the stratified Cox Model.  
P-value calculated using a stratified Chi-square test as in Klein 2007 
a [X] additional subjects are included in the ‘Any Baseline Ordinal Score’ row that were enrolled with an actual baseline ordinal score of 4. [Include as applicable] 
 
Programming note: Subject may be listed in both Mechanical Ventilation by Day 29 and Dying by Day 29 columns if they required ventilation at any 
point prior to death. If Dying without ventilation, not included in both. 
 


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Table 16: 
Mechanical Ventilation Free Survival by Day 29 by Treatment Group and Actual Baseline Ordinal Score: Sensitivity and 
Exploratory Analyses – mITT Population, Actual Baseline Ordinal Score 5 or 6 
Model 
Treatment Group 
Actual Baseline 
Ordinal Score 
HR 
Interaction P-valuea 
Estimate 
95% CI 
Covariate-Adjusted 
Baricitinib + PBO + RDV (N=X) 
Baseline Ordinal 
Score 5 or 6 
x.xx 
x.xx, x.xx 
0.xxx 
PBO + Dexamethasone + RDV (N=X) 
x.xx 
x.xx, x.xx 
Treatment Arm-Baseline Ordinal Score Interaction 
Baricitinib + PBO + RDV (N=X) 
5 
x.xx 
x.xx, x.xx 
0.xxx 
PBO + Dexamethasone + RDV (N=X) 
Baricitinib + PBO + RDV (N=X) 
6 
x.xx 
x.xx, x.xx 
PBO + Dexamethasone + RDV (N=X) 
Baricitinib + PBO + RDV (N=X) 
Baseline Ordinal 
Score 5 or 6 
x.xx 
x.xx, x.xx 
PBO + Dexamethasone + RDV (N=X) 
HR is the ratio of the hazard of mechanical ventilation or death in each treatment group estimated from the indicated model. The ratio is PBO + Dexamethasone + RDV to 
Baricitinib + PBO + RDV. 
HR for the Baseline Ordinal Score 5 or 6’ group is the hazard ratio from the stratified Cox Model. 
Covariate adjustment is by age, duration of symptoms prior to randomization, baseline d-dimer, and baseline CRP values as continuous covariates. High-sensitivity CRP values are 
excluded from this analysis. 
Estimates are HR and CIs from interaction Cox models.  For the interaction models, HRs are calculated at the level of each individual ordinal score category. 
a P-values are from the likelihood ratio test. 
 
Programming Notes: 
For the “Treatment Arm-Actual Baseline Ordinal Score Interaction”, the ordinal score covariate will be treated as a categorical variable. 


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Tables with similar format: 
Table 17: 
Mechanical Ventilation Free Survival by Day 29 by Treatment Group within Subgroups – mITT Population, Actual Baseline 
Ordinal Score 5 or 6 
Table 18: 
Mechanical Ventilation Free Survival by Day 29 by Treatment Group: Prior Corticosteroid Use – mITT Population, Actual 
Baseline Ordinal Score 5 or 6 
Table 19: 
Mechanical Ventilation Free Survival by Day 29 by Treatment Group: Medications of Interest Sensitivity Analysis – mITT 
Population, Actual Baseline Ordinal Score 5 or 6 
Programming Notes for Table 17: 
A “Subgroup” column will replace the “Model” column to the left of the “Treatment Group” column. Actual baseline ordinal score subgroups, prior 
corticosteroid use and medications of interest will not be included in this table. This table will include all other subgroups (see Section 6.4). P-values will 
not be included in this table.  
Programming Notes for Table 18 and Table 19: 
P-values will not be included in these tables. 
A “Subgroup” column will replace the “Model” column to the left of the “Treatment Group” column. Actual Baseline Ordinal Score subgroups will not 
be included in this table.    
A “Subgroup” column will replace the “Model” column to the left of the “Treatment Group” column. Actual Baseline Ordinal Score subgroups will not 
be included in this table. Separate models will be fit with censoring based on  the first date of use for each of the following categories of medications (see 
Section 6.4). 
• Any Medication of Interest 
• Antivirals 
• COVID-19 Vaccination 
• Treatments for COVID-19 
• Monoclonal antibodies targeting the spike protein of SARS-CoV-2 including casirivimab, imdevimab, and bamlanivimab. 
• Renin-angiotensin system (RAS) Inhibitors and HMG-CoA reductase inhibitors (Statins) 
• Corticosteroids 
• Other Anti-Inflammatory Drugs 


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The table will include the following footnote: “In this analysis, subjects that reported use of the specified medications of interest are censored at time of 
medication receipt.”   


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Table 20: 
Summary of Recoveries, Ventilator/ECMO Requirement, and Deaths by Day 29 – mITT Population  
Grouping Variable 
Actual Baseline Ordinal Score 
Treatment Group 
Recovered 
Not Recovered and do 
not Require 
Mechanical 
Ventilation or ECMO 
Require 
ECMO 
Require 
Mechanical 
Ventilation 
Require 
Mechanical 
Ventilation 
or ECMO 
Deaths 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Actual Baseline 
Ordinal Score 
5 
Baricitinib + PBO + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PBO + Dexamethasone + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
6 
Baricitinib + PBO + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PBO + Dexamethasone + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Baseline Ordinal Score 5 or 6 
Baricitinib + PBO + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PBO + Dexamethasone + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Any Baseline Ordinal Scorea 
Baricitinib + PBO + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PBO + Dexamethasone + RDV (N=X) 
x 
x 
x 
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 mITT Population.  
a [X] additional subjects are included in the ‘Any Baseline Ordinal Score’ row that were enrolled with an actual baseline clinical status of 4. [Include as applicable] 
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 21: 
Odds Ratio for Better (Lower) Clinical Status Score at Study Visit Day 15 by Treatment 
Using a Proportional Odds Model, Baricitinib + PBO + RDV Relative to PBO + 
Dexamethasone + RDV – mITT Population, Actual Baseline Ordinal Score 5 or 6 
Analysis/Subgroup 
Treatment Group 
Odds Ratio 
P-value 
Estimate 
95% CI 
Main Analysis of Key Secondary Endpoint 
Analysis of Key Secondary Endpointa 
Baricitinib + PBO + RDV (N=X) 
x.xx 
x.xx, x.xx 
0.xxx 
PBO + Dexamethasone + RDV (N=X) 
Subgroup Analyses of Key Secondary Endpoint  
[Repeat for each Section 6.4 subgroups] 
Baricitinib + PBO + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
Medications of Interest Subgroup Analyses 
Any Medication of Interest 
Baricitinib + PBO + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
Antivirals 
Baricitinib + PBO + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
COVID-19 Vaccination 
Baricitinib + PBO + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
Treatments for COVID-19 
Baricitinib + PBO + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
Monoclonal Antibodies to COVID-19 
spike protein 
Baricitinib + PBO + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
RAS inhibitors and HMG-CoA reductase 
inhibitors 
Baricitinib + PBO + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
Corticosteroids 
Baricitinib + PBO + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
Other Anti-Inflammatory Drugs 
Baricitinib + PBO + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
Covariate-Adjusted Model 
Covariate-Adjusted  
Baricitinib + PBO + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
Interaction Models 
Treatment-Continuous Actual Baseline 
Ordinal Score (5 or 6) Interaction 
Baricitinib + PBO + RDV (N=X) 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
x.xx 
x.xx, x.xx 
aAnalysis of key secondary endpoint using those subjects in the mITT Population with actual baseline ordinal score of 5 or 6 with actual baseline 
ordinal score as a model covariate.   
Odds ratios for interaction models are calculated at the level of each actual baseline ordinal score. 
 
Programming Notes:  
For the Main Analysis, the p-value will only be reported if the p-value from the primary analysis mechanical 
ventilation free survival is significant. If the p-value will not be reported, then the columns will be removed. 


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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 actual 
baseline ordinal score interaction term was 0.xxx.” or “The p-value for the treatment by continuous baseline 
ordinal score interaction term was 0.xxx.”.  
For the covariate-adjusted model, the model will be run with age, duration of symptoms prior to 
randomization, baseline d-dimer, and baseline CRP values included as continuous covariates.  High sensitivity 
CRP values are excluded from this analysis (denote this in a footnote). 
 
Table with similar format: 
Table 22: 
Odds Ratio for Better (Lower) Clinical Status Score at Study Visit Day 15 by Treatment 
Using a Proportional Odds Model, Baricitinib + PBO + RDV Relative to PBO + 
Dexamethasone + RDV – As Treated Population, Actual Baseline Ordinal Score 5 or 6 
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 actual baseline ordinal score interaction term was 0.xxx.” or “The p-value for the treatment 
by continuous baseline ordinal score interaction term was 0.xxx.”. 
 


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Table 23: 
Proportion of Subjects Not Progressing to Clinical Status Ordinal Score 6, 7, or 8 by Day 29 by Treatment Group, Actual 
Baseline Ordinal Score 5 
Analysis 
Population 
Treatment Group 
Actual Baseline 
Ordinal Score  
Number Subjects 
Progressing to Clinical 
Status Ordinal Score 6, 7, 
or 8 by Day 29 
Number 
Subjects Dying 
by Day 29 
Proportion Not 
Progressing to Clinical 
Status 6, 7, or 8 by Day 29 
HR 
P-value 
Estimate 
95% CI 
Estimate 
95% CI 
mITT 
Population 
Baricitinib + PBO + RDV (N=X) 
5 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, 
x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Repeat for the As Treated Population. 
N= Number of subjects in the specified treatment group, actual baseline ordinal score, and analysis population.  
n = Number of subjects.  
Proportions Not Progressing to Clinical Status 6, 7, or 8 by Day 29 are Kaplan-Meier Estimates at Day 29 study visit 
HR is the ratio of the hazard of mechanical ventilation or death in each treatment group estimated from the Cox model. The ratio is to PBO + Dexamethasone + RDV to Baricitinib + PBO + RDV. 
P-value calculated using a stratified Chi-square test as in Klein 2007 
 
Programming Notes:  
If performed, the p-value is from the stratified Chi-square test as in Klein 2007, and will only be reported contingent on results from the hierarchical 
testing procedure (see Section 6.8). 


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Table 24: 
Proportion of Subjects Not Progressing to Clinical Status Ordinal Score 6, 7, or 8 by Day 29 by Treatment Group and Actual 
Baseline Ordinal Score: Sensitivity and Exploratory Analyses – mITT Population, Actual Baseline Ordinal Score 5  
Model 
Treatment Group 
HR 
Interaction P-valuea 
Estimate 
95% CI 
Covariate-Adjusted 
Baricitinib + PBO + RDV (N=X) 
x.xx 
x.xx, x.xx 
0.xxx 
PBO + Dexamethasone + RDV (N=X) 
x.xx 
x.xx, x.xx 
HR is the ratio of the hazard of high flow oxygen, ventilation or death in each treatment group estimated from the indicated model. The ratio is PBO + Dexamethasone + RDV to Baricitinib + PBO + 
RDV. 
Covariate adjustment is by age, duration of symptoms prior to randomization, baseline d-dimer, and baseline CRP values as continuous covariates.  High-sensitivity CRP values are excluded from this 
analysis. 
Estimates are HR and CIs interaction Cox models.   
a P-values are from the likelihood ratio test. 
 
Tables with similar format: 
Table 25: 
Proportion of Subjects Not Progressing to Clinical Status Ordinal Score 6, 7, or 8 by Day 29 by Treatment Group within 
Subgroups  – mITT Population, Actual Baseline Ordinal Score 5 
Table 26: 
Proportion of Subjects Not Progressing to Clinical Status Ordinal Score 6, 7, or 8 by Day 29 by Treatment Group: Prior 
Corticosteroid Use – mITT Population, Actual Baseline Ordinal Score 5 
Table 27: 
Proportion of Subjects Not Progressing to Clinical Status Ordinal Score 6, 7, or 8 by Day 29 by Treatment Group: Medications of 
Interest Sensitivity Analysis – mITT Population, Actual Baseline Ordinal Score 5 
Programming Notes for Table 25: 
A “Subgroup” column will be replace the “Model” to the left of the “Treatment Group” column. Actual baseline ordinal score subgroups will not be 
included in this table. This table will allsubgroups (see Section 6.4) other than actual baseline ordinal score, corticosteroids and medications of interest. 
P-values will not be included in this table. baseline ordinal scoreSubGroups of prior Corticosteroid Use (Section 6.4) will be presented in Table 25. 
Programming Notes for Table 26 and Table 27 
P-values will not be included in these tables. 
A “Subgroup” column will be replace the “Model” to the left of the “Treatment Group” column. Actual Baseline Ordinal Score subgroups will not be 
included in this table.  
A “Subgroup” column will replace the “Model” to the left of the “Treatment Group” column. Clinical Status subgroups will not be included in this table. 
Separate models will be fit with censoring based on  the first date of use for each of the following categories of medications (see Section 6.4). 


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• Any Medication of Interest 
• Antivirals 
• COVID-19 Vaccination 
• Treatments for COIVD-19 
• Monoclonal antibodies targeting the spike protein of SARS-CoV-2 including casirivimab, imdevimab, and bamlanivimab 
• Renin-angiotensin system (RAS) Inhibitors and HMG-CoA reductase inhibitors (Statins) 
• Corticosteroids 
• Other Anti-Inflammatory Drugs 
The table will include the following footnote: “In this analysis, subjects that reported use of the specified medications of interest are censored at time of 
medication receipt.”   


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Table 28: 
Time to Recovery by Day 29 by Treatment Group and Actual Baseline Ordinal Score 
Analysis 
Population 
Treatment Group 
Actual Baseline 
Ordinal Score 
n 
First Quartile Time 
to Recovery (Days) 
Median Time to 
Recovery (Days) 
Third Quartile Time 
to Recovery (Days) 
HR 
P-value 
Estimate 
95% CI 
Estimate 
95% CI 
Estimate 
95% CI 
Estimate 
95% CI 
mITT 
Population 
Baricitinib + PBO + RDV (N=X) 
5 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
Baricitinib + PBO + RDV (N=X) 
6 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
Baricitinib + PBO + RDV (N=X) 
Baseline Clinical 
Status 5 or 6 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
0.xxx 
PBO + Dexamethasone + RDV (N=X) 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
Baricitinib + PBO + RDV (N=X) 
Any Baseline 
Ordinal Scorea 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
Repeat for the As Treated Population. 
N= Number of subjects in the specified treatment group, actual baseline ordinal score, 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 PBO + Dexamethasone + RDV to Baricitinib + PBO + RDV. 
HRs for the ‘Baseline Clinical Status 5 or 6’ and ‘Any Baseline Clinical Status’ groups are the hazard ratios from the stratified Cox Model.  
P-value calculated using the stratified log-rank test 
a [X] additional subjects are included in the ‘Any Baseline Ordinal Score’ row that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 
Programming Notes:  
The p-value for the stratified log-rank test in the (5 or 6) subgroup will only be reported if the p-value for the “Baseline Ordinal Score 5 or 6” analysis is 
significant (see Section 6.8). 
 


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Table 29: 
Time to Recovery by Day 29 by Treatment Group and Baseline Ordinal Score: Sensitivity and Exploratory Analyses – mITT 
Population, Actual Baseline Ordinal Score 5 or 6 
Model 
Treatment Group 
Actual Baseline Ordinal Score 
HR 
Interaction P-valuea 
Estimate 
95% CI 
Fine-Gray  
Baricitinib + PBO + RDV (N=X) 
5 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
Baricitinib + PBO + RDV (N=X) 
6 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
Baricitinib + PBO + RDV (N=X) 
Baseline Ordinal Score 5 or 6 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
Covariate-Adjusted 
Baricitinib + PBO + RDV (N=X) 
Baseline Ordinal Score 5 or 6 
x.xx 
x.xx, x.xx 
0.xxx 
PBO + Dexamethasone + RDV (N=X) 
x.xx 
x.xx, x.xx 
Treatment Arm-Continuous Actual Baseline Status 
Interaction 
Baricitinib + PBO + RDV (N=X) 
5 
x.xx 
x.xx, x.xx 
0.xxx 
PBO + Dexamethasone + RDV (N=X) 
Baricitinib + PBO + RDV (N=X) 
6 
x.xx 
x.xx, x.xx 
PBO + Dexamethasone + RDV (N=X) 
HR is the ratio of the hazard of recovery in each treatment group estimated from the indicated model. The ratio is PBO + Dexamethasone + RDV to Baricitinib + PBO + RDV. 
HR for the ’Baseline Ordinal Score 5 or 6) group is the hazard ratio from the stratified Cox Model. 
For the Fine-Gray model, subjects who die prior to any observed recovery as coded as experiencing a competing risk. 
Covariate adjustment is by age, duration of symptoms prior to randomization, baseline d-dimer, and baseline CRP values as continuous covariates. High-sensitivity CRP values are excluded from this 
analysis. 
Estimates are HR and CIs from Fine-Gray or interaction Cox models.  For the interaction models, HRs are calculated at the level of each individual actual baseline ordinal score. 
a P-values are from the likelihood ratio test. 
 
Programming Notes: 
For the “Treatment Arm-Actual Baseline Ordinal Score Interaction”, the covariate will be treated as a categorical variable. 


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Tables with similar format: 
Table 30: 
Time to Recovery by Day 29 by Treatment Group within Subgroups – mITT Population, Actual Baseline Ordinal Score of 5 or 6 
Table 31: 
Time to Recovery by Day 29 by Treatment Group and Actual Baseline Ordinal Score: Readmittance Sensitivity Analysis – mITT 
Population, Actual Baseline Ordinal Score of 5 or 6 
Table 32: 
Time to Recovery by Day 29 by Treatment Group and Actual Baseline Ordinal Score: Medications of Interest Sensitivity Analysis 
– mITT Population, Actual Baseline Ordinal Score of 5 or 6 
Table 33: 
Time to Recovery by Day 29 by Treatment Group using Modified Recovery Scale Sensitivity Analysis – mITT Population, Actual 
Baseline Ordinal Score of 5 or 6 
Programming Notes for Table 30: 
The “Actual Baseline Ordinal Score” and “Analysis Population” columns will be removed.  A “Subgroup” column will be inserted to the left of the 
“Treatment Group” column. This table will not display the “Any…” rows. The elements for the “n” and “Median Time to Recovery” columns will 
display “-“. This table will include subgroups (see Section 6.4), except for actual baseline ordinal score. 
Programming Notes for Table 31 and Table 32: 
P-values will not be included in these tables. 
Table 31 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 will include the following footnote: “In this analysis, subjects that recover and are subsequently readmitted for COVID-19 are 
censored at 28 days”.   
Table 32 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 a 
medication of interest.” The “Analysis Population” column will be replaced by a column labeled “Medication of Interest”. Separate models will be fit 
with censoring based on  the first date of use for each of the following categories of medications (see Section 6.4): 
• Any Medication of Interest 
• Antivirals 
• COVID-19 Vaccination 
• Treatments for COVID-19 
• Monoclonal antibodies targeting the spike protein of SARS-CoV-2 including casirivimab, imdevimab, and bamlanivimab 
• Renin-angiotensin system (RAS) Inhibitors and HMG-CoA reductase inhibitors (Statins) 


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• Corticosteroids 
• Other Anti-Inflammatory Drugs 
The table will include the following footnote: “In this analysis, subjects that reported use of the specified medications of interest are censored at time of 
medication receipt.”   


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Table 34: 
Time to Recovery by Day 29 by Treatment Group and Actual Baseline Ordinal Score: Restricted Mean Survival Time Analysis, 
Actual Baseline Ordinal Score 5 or 6 
Analysis Population 
Treatment Group 
Actual Baseline Ordinal Score 
n 
Taua 
Restricted Mean Recovery Time 
(Days) 
Difference 
Estimate 
95% CI 
Estimate 
95% CI 
mITT Population 
Baricitinib + PBO + RDV (N=X) 
5 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
PBO + Dexamethasone + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Baricitinib + PBO + RDV (N=X) 
6 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
PBO + Dexamethasone + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Baricitinib + PBO + RDV (N=X) 
Baseline Ordinal Score 5 or 6 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
PBO + Dexamethasone + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Repeat for the As Treated Population. 
N= Number of subjects in the specified treatment group, actual baseline ordinal score, and analysis population.  
n = Number of recovered subjects.  
Difference is the difference in the restricted mean recovery time between PBO + Dexamethasone + RDV to Baricitinib + PBO + RDV.  
a Tau is the truncation time point for the Restricted Mean Survival Time analysis and is equal to the minimum of the largest observed times in each group 
 
Programming Notes: 
Within an actual baseline ordinal score 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 actual Baseline Ordinal Score (“Baseline Ordinal Score 5 or 6” 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; 


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Table 35: 
Summary of Recoveries and Deaths by Day 29 – mITT Population  
Grouping 
Variable 
Actual Baseline 
Ordinal Score 
Treatment Group 
Recoveredb 
Did Not Recover 
Deathsb 
Died or Not Recovered  
n 
% 
n 
% 
n 
% 
n 
% 
Actual Baseline 
Ordinal Score 
5 
Baricitinib + PBO + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
PBO + Dexamethasone + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
6 
Baricitinib + PBO + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
PBO + Dexamethasone + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
Baseline Ordinal 
Score 5 or 6 
Baricitinib + PBO + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
PBO + Dexamethasone + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
Any Baseline 
Ordinal Scorea 
Baricitinib + PBO + RDV (N=X) 
x 
x 
x 
x 
x 
x 
x 
x 
PBO + Dexamethasone + 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 mITT Population.  
a [X] additional subjects are included in the ‘Any Baseline Ordinal Score’ row that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
b [Number] subjects recovered but subsequently died. These X subjects are included in both the recoveries and also in the deaths counts. 
 
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, footnote b will be added. 
 


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Table 36: 
Time to One or Two Category Improvement on the 8-Point Ordinal Scale by Treatment 
Group, Actual Baseline Ordinal Score 5 or 6 
Analysis Population 
Treatment Group 
 
Median Time 
HR 
n 
Estimate 
95% CI 
Estimate 
95% CI 
 
Improvement by at Least One Category 
mITT Population 
Baricitinib + PBO + RDV (N=X) 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
PBO + Dexamethasone + RDV (N=X) 
x 
x.x 
x.x, x.x 
As Treated Population 
Baricitinib + PBO + RDV (N=X) 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
PBO + Dexamethasone + RDV (N=X) 
x 
x.x 
x.x, x.x 
 
Improvement by at Least Two Categories 
mITT Population 
Baricitinib + PBO + RDV (N=X) 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
PBO + Dexamethasone + RDV (N=X) 
x 
x.x 
x.x, x.x 
As Treated Population 
Baricitinib + PBO + RDV (N=X) 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
PBO + Dexamethasone + RDV (N=X) 
x 
x.x 
x.x, x.x 
N = Number of subjects in the specified treatment group, analysis population, and actual baseline ordinal score of 5 or 6.  
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 + PBO + RDV to 
PBO + Dexamethasone + RDV.  
 
Tables with similar format: 
Table 37: 
Time to Improvement on the 8-Point Ordinal Scale by Treatment Group: Modified 
Ordinal Scale, Actual Baseline Ordinal Score 5 or 6 
Table 38: 
Time to Improvement on the 8-Point Ordinal Scale by Treatment Group and Duration of 
Symptoms at Baseline – mITT Population, Actual Baseline Ordinal Score 5 or 6 
Programming notes for Table 37: 
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, but new or increased limitation on activities and/or requiring new or increased 
home oxygen” was given the score 3. 
Programming notes for Table 38: 
The “Analysis Population” column will be re-labeled “Duration of Symptoms at Baseline”.  The “Actual 
Baseline Ordinal Score” column will be removed. Rows will be generated for each subgroup defined by 
duration above/below the median. Only subjects with baseline ordinal score 5 or 6 will be included in the 
table. The footnote for “N” will read “N = Number of subjects in the specified treatment group and analysis 
population with an actual baseline ordinal score of 5 or 6.”  


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Table 39: 
Clinical Status Scores by Treatment Group and Study Visit, Imputed – mITT Population, Actual Baseline Ordinal Score 5 or 6 
Study 
Visit 
Ordinal Scale Measure 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
Risk Difference 
n 
% 
95% CI 
n 
% 
95% CI 
% 
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, but new or increased limitation on activities and/or requiring 
new or increased 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 
[Repeat for Study Visit Days 3, 5, 8, 11, 15, 22, and 29] 
N = Number of Subject in the mITT Population.  
n = Number of subjects who reported the respective score 
95% CI calculated using Wilson CIs 
 
Programming Note: 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. 
 


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Table 40: 
Summary of Clinical Status Score by Treatment Group and Study Visit – mITT Population, Actual Baseline Ordinal Score 5 or 6 
Study Visit 
Statistic 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
Difference 
Baseline 
Number of reported clinical scores 
x 
x 
-- 
 
Mean (95% CI) 
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) 
 
Range (Min, Max) 
x, x 
x, x 
-- 
Day 3 
Number of reported clinical scores 
x 
x 
-- 
 
Mean (95% CI) 
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) 
 
Range (Min, Max) 
x, x 
x, x 
-- 
 
Change from Baseline Mean (95% CI) 
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 mITT Population. 
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. 
 


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Table 41: 
DOOR Category by Treatment Group and Study Visit, Imputed – mITT Population, Actual Baseline Ordinal Score 5 or 6 
Study 
Visit 
DOOR Category 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
Risk Difference 
n 
% 
95% CI 
n 
% 
95% CI 
% 
95% CI 
Day 15 
1 - Recovered (Category 1, 2 or 3 Clinical Status) 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x.x 
x.x, x.x 
2 - Improved (≥ 1 category improvement in Clinical Status compared with 
baseline) & no SAE 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x.x 
x.x, x.x 
3 - Improved (≥ 1 category improvement in Clinical Status compared with 
baseline) & SAE (related or unrelated) 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x.x 
x.x, x.x 
4 - No change in Clinical Status from baseline & no SAE 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x.x 
x.x, x.x 
5 - No change in Clinical Status from baseline & SAE (related or unrelated) 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x.x 
x.x, x.x 
6 - Worsening (≥ 1 category worse in Clinical Status compared with baseline)  
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x.x 
x.x, x.x 
7 - Death  
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x.x 
x.x, x.x 
[Repeat for Study Visit Day 29] 
N = Number of Subject in the mITT Population.  
n = Number of subjects with the respective score 
95% CI calculated using Wilson CIs 
 


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Table 42: 
Summary of DOOR by Treatment Group and Study Visit, Imputed  – mITT Population, Actual Baseline Ordinal Score 5 or 6 
Study Visit 
Statistic 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
Difference 
P-value 
Day 15 
n 
x 
x 
-- 
 
Mean (95% CI) 
x.x (x.x, x.x) 
x.x (x.x, x.x) 
x.x (x.x, x.x) 
0.xxx 
Median 
x.x 
x.x 
x.x (x.x, x.x) 
 
Range (Min, Max) 
x, x 
x, x 
-- 
 
Day 29 
n 
x 
x 
-- 
 
Mean (95% CI) 
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) 
 
Range (Min, Max) 
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 the time point being summarized. 
 
Programming Notes: 
P-value calculated using a Mann-Whitney U statistic 
 


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Table 43: 
Oxygen Use Through Day 29 by Treatment Group – Actual Baseline Ordinal Score of 5 
or 6 
Analysis 
Population 
Oxygen Use 
Statistic 
Treatment Group 
Baricitinib + PBO + 
RDV 
PBO + Dexamethasone 
+ RDV 
mITT Population 
On Oxygen at Baseline (N = x) 
Days on Oxygen (Including 
imputations for subjects who 
died) 
N 
x 
x 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
Q1 
x.x 
x.x 
Median 
x.x 
x.x 
Q3 
x.x 
x.x 
Difference in Medians (95% CI) 
x.x (x.x, x.x) 
Days of Oxygen (Among 
subjects who did not die) 
N 
x 
x 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
Q1 
x.x 
x.x 
Median 
x.x 
x.x 
Q3 
x.x 
x.x 
Difference in Medians (95% CI) 
x.x (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 95% CI 
x.x, x.x 
x.x, x.x 
Difference in Rates (95% CI) 
x.x (x.x, x.x) 
Days on Oxygen (Including 
imputations for subjects who 
died) 
N 
x 
x 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
Q1 
x.x 
x.x 
Median 
x.x 
x.x 
Q3 
x.x 
x.x 
Difference in Medians (95% CI) 
x.x (x.x, x.x) 
Days of Oxygen (Among 
subjects who did not die) 
N 
x 
x 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
Q1 
x.x 
x.x 
Median 
x.x 
x.x 
Q3 
x.x 
x.x 
Difference in Medians (95% CI) 
x.x (x.x, x.x) 
Repeat for As Treated Population. 


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N = Number of subjects in the specified analysis population and oxygen use category.  
Q1 and Q3 are the first and third quartiles, respectively. 
 
Programming Note: For the “Days on Oxygen” statistics within the “Not on Oxygen at Baseline” subgroup, 
only summarize days for subjects who reported new use. 
Tables with similar format: 
Table 44: 
Oxygen Use Through Day 29 by Treatment Group and Duration of Symptoms at 
Baseline – Actual Baseline Ordinal Score of 5 or 6 
Table 45: 
Non-invasive Ventilation/High-Flow Oxygen Use Through Day 29 by Treatment Group – 
Actual Baseline Ordinal Score of 5 or 6 
Table 46: 
Non-invasive Ventilation/High-Flow Oxygen Use Through Day 29 by Treatment Group 
and Duration of Symptoms at Baseline – Actual Baseline Ordinal Score of 5 or 6 
Table 47: 
Ventilation/ECMO Use Through Day 29 by Treatment Group – Actual Baseline Ordinal 
Score of 5 or 6 
Table 48: 
Ventilation/ECMO Use Through Day 29 by Treatment Group and Duration of 
Symptoms at Baseline – Actual Baseline Ordinal Score of 5 or 6 
Programming notes for Table 44, Table 46, and Table 48: 
“Analysis Population” will be replaced by “Duration of Symptoms at Baseline” column. The tables will 
consider the duration above/below median subgroup.  Summaries will only be generated for mITT population. 
Programming notes for Table 47, Table 48: 
The “On Ventilation/ECMO at Baseline” section of the table will not be generated. 
Programming notes for Table 43 and Table 44: 
The “New Use” section of the table will not be generated. 
Programming notes for Tables 43, 44, 45, 46, 47, 48 
When subjects died without new use of the specified oxygen type, split the “N” row for the “Days on Oxygen 
(including imputations for subjects who died” into: 
- 
“N (Observed New Use)” which includes subjects who were observed to have new use 
- 
“Deaths (imputed No new use Observed)” including the subjects who died without observed new use. 
 


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Table 49: 
Hospitalization Through Day 29 by Treatment Group – Actual Baseline Ordinal Score of 
5 or 6 
Analysis 
Population 
Summary 
Statistic 
Treatment Group 
Baricitinib + PBO + 
RDV 
PBO + Dexamethasone 
+ RDV 
mITT Population 
Number of Subjects 
N 
x 
x 
Days of Hospitalization 
(including imputation for 
subjects who died) 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
Q1 
x.x 
x.x 
Median 
x.x 
x.x 
Q3 
x.x 
x.x 
Difference in Medians (95% CI) 
x.x (x.x, x.x) 
Days of Hospitalization 
(among subjects who did not 
die) 
Q1 
x 
x 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
Median 
x 
x 
Q3 
x.x, x.x 
x.x, x.x 
Difference in Medians (95% CI) 
x.x (x.x, x.x) 
Readmittance for 
COVID-19 
N 
x 
x 
n 
x 
x 
Percentage 
x 
x 
Percentage 95% CI 
x.x, x.x 
x.x, x.x 
Difference in Percentages (95% CI) 
x.x (x.x, x.x) 
Readmittance for Any 
Reason 
N 
x 
x 
n 
x 
x 
Percentage 
x 
x 
Percentage 95% CI 
x.x, x.x 
x.x, x.x 
Difference in Percentages (95% CI) 
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 that discharged 
 
Table with similar format: 
Table 50: 
Hospitalization Through Day 29 by Treatment Group and Duration of Symptoms at 
Baseline – Actual Baseline Ordinal Score of 5 or 6 
Programming Note for Table 50: 
“Analysis Population” will be replaced by “Duration of Symptoms at Baseline” column. The table will 
consider the duration above/below median subgroup. Summaries will only be generated for mITT population 


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Table 51: 
Summary Statistics of Laboratory Efficacy Results by Study Visit Day, and Treatment Group – mITT Population, Actual 
Baseline Ordinal Score of 5 or 6 
Laboratory 
Parameter 
Study Visit Day 
Treatment Group 
Absolute 
Change from Baseline 
N 
Mean 
95% CI 
Median 
Min, Max 
N 
Mean 
95% CI 
Median 
Min, Max 
D-dimer 
Baseline 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
--- 
--- 
--- 
--- 
--- 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
--- 
--- 
--- 
--- 
--- 
Day 3 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
Day 5 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
Day 8 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
Day 11 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
Day 15 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
Day 29 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
CRP 
Baseline 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
--- 
--- 
--- 
--- 
--- 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
--- 
--- 
--- 
--- 
--- 
Day 3 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
Day 5 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
Day 8 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
Day 11 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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Laboratory 
Parameter 
Study Visit Day 
Treatment Group 
Absolute 
Change from Baseline 
N 
Mean 
95% CI 
Median 
Min, Max 
N 
Mean 
95% CI 
Median 
Min, Max 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
Day 15 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
Day 29 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
N = Number of subjects in the As Treated Population with laboratory data available for the parameter at the specified study visit. 
High-sensitivity CRP values are excluded from the summaries. 
 
Programming notes: 
Use imputed results for missing data, see Section 6.5. 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
Version 2.0 
09JUN2021 
- 106 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 52: 
Day 60 Ordinal Scores by Treatment Group and Actual Baseline Ordinal Score – mITT Population 
Subject Ordinal Score 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
All Subjects 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N = X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N = X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N = X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Death at or before Study Visit (8) 
x 
xx 
x 
Xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Hospitalized, on invasive mechanical ventilation 
or ECMO (7) 
x 
xx 
x 
Xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Hospitalized, on non-invasive ventilation or high 
flow oxygen devices (6) 
x 
xx 
x 
Xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Hospitalized, requiring supplemental oxygen (5) 
x 
xx 
x 
Xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Hospitalized, not requiring supplemental oxygen 
- requiring ongoing medical care (COVID-19 
related or otherwise) (4) 
x 
xx 
x 
Xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Hospitalized, not requiring supplemental oxygen 
- no longer requires ongoing medical care (3) 
x 
xx 
x 
Xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Not hospitalized, but new or increased limitation 
on activities and/or requiring new or increased 
home oxygen (2) 
x 
xx 
x 
Xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Not hospitalized, no limitations on activities (1) 
x 
xx 
x 
Xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
N = Number of subjects in the mITT Population with a Day 60 ordinal score. 
n = Number of subjects with the reported ordinal score at Day 60.  
a [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
Version 2.0 
09JUN2021 
- 107 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 53: 
Day 60 Change in Ordinal Score from Day 29 by Treatment Group and Actual Baseline Ordinal Score – mITT Population 
Status at Day 29  
Ordinal Score Change 
at Day 60 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
All Subjects 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N = X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N = X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N = X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Recovered 
Maintained Recovery 
Status (OS 1, 2 or 3)  
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Worsened to OS 4 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Worsened to OS 5 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Worsened to OS 6 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Worsened to OS 7 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Died 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Not Recovered 
Recovered (OS 1, 2 or 3) 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Not Recovered but 
Improved by 1 or More 
OS Categories 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
No Change from Last 
Observed OS  
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Worsened by 1 or More 
OS Categories  
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Died 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
All Subjects 
Recovered (OS 1, 2, 3) 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Progressed to OS 7 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Died 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
N = Number of subjects in the mITT Population with a Day 60 ordinal score. 
n = Number of subjects meeting the criteria.  
a [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
Version 2.0 
09JUN2021 
- 108 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 54: 
Categorical Demographic and Baseline Characteristics by Actual Baseline Ordinal Score and Treatment Group – mITT 
Population 
Demographic 
Category 
Characteristic 
Baricitinib + PBO + RDV 
PBO + Dexamethasone + RDV 
All Subjects 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(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 
Country 
Country 1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
…Continue for all countries 
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 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
Version 2.0 
09JUN2021 
- 109 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Demographic 
Category 
Characteristic 
Baricitinib + PBO + RDV 
PBO + Dexamethasone + RDV 
All Subjects 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Blood Type 
A+ 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
A- 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
…Continue for all blood types 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Duration of 
Symptoms prior to 
randomization 
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 
COVID 
Vaccination 
Yes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pre-COVID-19 
Use of 
Supplemental 
Oxygen 
Yes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
a [X] additional subjects are included in the ‘Any Clinical Status’ row that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
Version 2.0 
09JUN2021 
- 110 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 55: 
Continuous Demographic and Baseline Characteristics by Actual Baseline Ordinal Score and Treatment Group – mITT 
Population 
Variable 
Statistic 
Baricitinib + PBO + RDV 
PBO + Dexamethasone + RDV 
All Subjects 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(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 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
Version 2.0 
09JUN2021 
- 111 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Variable 
Statistic 
Baricitinib + PBO + RDV 
PBO + Dexamethasone + RDV 
All Subjects 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N=X) 
Maximum 
x 
x 
x 
x 
x 
x 
x 
x 
X 
Duration of Symptoms prior to 
Randomization (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 
a [X] additional subjects are included in the ‘Any Baseline Ordinal Score’ row that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
Version 2.0 
09JUN2021 
- 112 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 56: 
Summary of Subjects with Pre-Existing Medical Conditions Treatment Group - As Treated Population 
Condition 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
All Subjects 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N = X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N = X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N = X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Any Condition 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Diabetes I 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Diabetes II 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
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. 
a [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 
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. 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
Version 2.0 
09JUN2021 
- 113 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 57: 
Number and Percentage of Subjects with Prior and Concurrent Medications by WHO Drug Classification, Actual Baseline 
Ordinal Score, and Treatment Group – As Treated Population 
WHO Drug Code 
Level 1, Anatomic 
Group 
WHO Drug Code 
Level 2, Therapeutic 
Subgroup 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
All Subjects 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All Subjects 
(N = X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All Subjects 
(N = X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All Subjects 
(N = X) 
n 
% 
n 
% 
n 
% 
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 
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 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 1] 
x 
xx 
x 
xx 
x 
xx 
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 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 3] 
x 
xx 
x 
xx 
x 
xx 
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 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 2] 
x 
xx 
x 
xx 
x 
xx 
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 
x 
xx 
x 
xx 
x 
xx 
a [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 
Programming Note: Only include medications with missing end dates (i.e. ongoing) or end dates on or after the enrollment date. 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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Table 58: 
Number and Percentage of Subjects Reporting On-Study Use of Medications of Interest by Actual Baseline Ordinal Score, and 
Treatment Group – As Treated Population 
Medication/Therapies 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
All Subjects 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Statins/ARBs/ACEIs 
x 
xx 
x 
xx 
x 
xx 
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 
x 
xx 
x 
xx 
x 
xx 
Polymerase inhibitors 
x 
xx 
x 
xx 
x 
xx 
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 
x 
xx 
x 
xx 
x 
xx 
   Chloroquine/Hydroxychloroquine 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
   Aplidin (plitidepsin) 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
   Colchicine (Colcyrs) 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
   Ivermectin (stromectol, Soolantra, Sklice) 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
   Monoclonal antibodies targeting the spike protein of SARS-CoV-2 
including casirivimab, imdevimab, and bamlanivimab 
x 
xx 
x 
xx 
x 
xx 
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 
x 
xx 
x 
xx 
x 
xx 
Corticosteroids 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
RAS Inhibitors and HMG-CoA reductase inhibitors 
x 
xx 
x 
xx 
x 
xx 
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 
x 
xx 
x 
xx 
x 
xx 
  Monoclonal Antibodies Targeting Cytokines 
x 
xx 
x 
xx 
x 
xx 
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 
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. 
a [X] addtional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 
Programming Note: only include medications where the end date is missing (i.e. ongoing) or end date is on or after enrollment date 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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Table 59: 
On-Study Use of Medications of Interest by Study Day, Actual Baseline Ordinal Score, and Treatment Group – As Treated 
Population 
Study Day 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
All Subjects 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All Subjectsa 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All Subjectsa 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All Subjectsa 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Statins/ARBs/ACEIs 
Day 1 
x 
xx 
x 
xx 
x 
xx 
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 
x 
xx 
x 
xx 
x 
xx 
Day 5 
x 
xx 
x 
xx 
x 
xx 
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 
x 
xx 
x 
xx 
x 
xx 
Day 11 
x 
xx 
x 
xx 
x 
xx 
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. 
a [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 
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. 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 60: 
Overall Summary of Adverse Events – As Treated Population 
Subjectsa with 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsc 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsc 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
At least one adverse event 
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 
 
At least one related adverse eventb 
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 
  Severe (Grade 3)  
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 
  Severe or Life-Threatening (Grade 3 or 4)  
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 
 
At least one not related adverse eventb 
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 
  Severe (Grade 3)  
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 
  Death (Grade 5) 
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 
At least one serious adverse event with fatal outcome 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one related serious adverse eventb 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one related serious adverse event with fatal outcomeb 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one adverse event leading to study drug temporary 
holdb 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one related adverse event leading to study drug 
temporary holdb 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one adverse event leading to study drug 
discontinuationb 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one related adverse event leading to study drug 
discontinuationb 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one adverse event leading to early terminationb 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one Unanticipated Problem 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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Subjectsa with 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsc 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsc 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
N = Number of subjects in the actual baseline ordinal score stratum and As Treated Population 
a Subjects are counted once for each category regardless of the number of events.  
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.  
b Relationship, discontinuation and drug hold are defined as occurring for any study product (remdesivir, baricitinib/placebo or 
dexamethasone/placebo).  
c[X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
Table 61: 
Subject-Level Rates of Adverse Events and Differences between Treatment Groups – As 
Treated Population 
Subjectsa with at least one: 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
Risk Difference (95% CI) 
n 
% 
n 
% 
AE 
x 
x 
x 
x 
x.x (x.x, x.x) 
Related AEb 
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 AEb 
x 
x 
x 
x 
x.x (x.x, x.x) 
SAE 
x 
x 
x 
x 
x.x (x.x, x.x) 
Related SAEb 
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 outcomeb 
x 
x 
x 
x 
x.x (x.x, x.x) 
AE leading to discontinuation of study drugb 
x 
x 
x 
x 
x.x (x.x, x.x) 
Related AE leading to discontinuation of 
study drugb 
x 
x 
x 
x 
x.x (x.x, x.x) 
N = Number of subjects in the As Treated Population. 
a Subjects are counted once for each category regardless of the number of events. 
b Relationship and discontinuation are defined as occurring for any study product (remdesivir, baricitinib/placebo or dexamethasone/placebo).  
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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Table 62: 
Serious Adverse Events by MedDRA System Organ Class and Preferred Term, and 
Treatment Group - As Treated Population 
MedDRA System Organ 
Class 
Preferred Term 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
Risk Difference 
 
 
n 
% 
Events 
n 
% 
Events 
% 
95% CI 
SOC1 
PT1 
x 
x 
x 
x 
x 
x 
x.x 
x.x, x.x 
Etc. 
Etc. 
x 
x 
x 
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. 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 63: 
Non-Serious 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 
MedDRA System 
Organ Class 
Preferred 
Term 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
Risk Difference 
 
 
n 
% 
Events 
n 
% 
Events 
% 
95% CI 
SOC1 
PT1 
x 
x 
x 
x 
x 
x 
x.x 
x.x, x.x 
Etc. 
Etc. 
x 
x 
x 
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 Note: Select all preferred terms/system organ classes among non-serious AEs where the % for 
any treatment group or overall is >= 5%. For both sections, sort preferred terms by descending order of 
frequency. 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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09JUN2021 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 64: 
Renal Adverse Events by Preferred Term and Treatment Group – As Treated Population 
Preferred Term 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
Risk Difference 
n 
% 
Events 
n 
% 
Events 
% 
95% CI 
Any renal adverse event 
x 
x 
x 
x 
x 
x 
x.x 
x.x, x.x 
PT 1 
x 
x 
x 
x 
x 
x 
x.x 
x.x, x.x 
PT 2 
x 
x 
x 
x 
x 
x 
x.x 
x.x, x.x 
Etc. 
x 
x 
x 
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. 
Renal adverse events determined through a Standardized MedDRA Query (SMQ) of acute renal failures. 
 
Table with similar format: 
Table 65: 
Hepatic Adverse Events by Preferred Term and Treatment Group – As Treated 
Population 
 
Programming Note:  
Update footnote to be: Hepatic adverse events determined through a Standardized MedDRA Query (SMQ) of 
hepatic disorders. 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 66: 
Related Adverse Events by MedDRA System Organ Class and Preferred Term, and 
Treatment Group - As Treated Population 
Related Study 
Product 
MedDRA System 
Organ Class 
Preferred 
Term 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
Risk 
Difference 
n 
% 
Events 
n 
% 
Events 
% 
95% CI 
Remdesivir 
Any SOC 
Any PT 
x 
x 
x 
x 
x 
x 
x.x 
x.x, x.x 
 
SOC1 
PT1 
x 
x 
x 
x 
x 
x 
x.x 
x.x, x.x 
 
Etc. 
Etc. 
… 
… 
… 
… 
… 
… 
… 
… 
Repeat for Dexamethasone/Placebo, Baricitinib/Placebo, Any Study Product (Remdesivir, Dexamethasone/Placebo or Baricitinib/Placebo) 
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-4) 
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09JUN2021 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 67: 
Day 60 New Diagnoses Since Day 29 by Treatment Group and Actual Baseline Ordinal Score – As Treated Population 
Condition 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
All Subjects 
(N=X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N = X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N = X) 
Baseline 
Ordinal 
Score 5 
(N=X) 
Baseline 
Ordinal 
Score 6 
(N=X) 
All 
Subjectsa 
(N = X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Infection 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Chronic Respiratory Disease  
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Pulmonary Emboli 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Deep Venous Thrombosis 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Cardiac Arrhythmia 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Myocardial Infarction 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Stroke 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Major Depression 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Anxiety 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Post-traumatic Stress Disorder 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Other New Diagnosis 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
N = Number of subjects in the As Treated Population with a Day 60 visit. 
n = Number of subjects reporting the condition.  
a [X] additional subjects are included in the ‘All Subjects’ column that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 


Statistical Analysis Plan - DMID Protocol: 20-0006 (ACTT-4) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 68: 
Deaths by Day 15, Day 29, or Day 60 by Treatment Group and Actual Baseline Ordinal Score – mITT Population 
Study Day 
Actual Baseline Clinical Status 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
n 
Mortality Ratea 
Rate 95% CI 
n 
Mortality Ratea 
Rate 95% CI 
Day 15 
5 
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 
Baseline Ordinal Score 5 or 6 
X 
x.x 
x.x, x.x 
x 
x.x 
x.x, x.x 
Any Baseline Ordinal Scoreb 
X 
x.x 
x.x, x.x 
x 
x.x 
x.x, x.x 
Day 29 
5 
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 
Baseline Ordinal Score 5 or 6 
X 
x.x 
x.x, x.x 
x 
x.x 
x.x, x.x 
Any Baseline Ordinal Scoreb 
X 
x.x 
x.x, x.x 
x 
x.x 
x.x, x.x 
Day 60 
5 
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 
Baseline Ordinal Score 5 or 6 
X 
x.x 
x.x, x.x 
x 
x.x 
x.x, x.x 
Any Baseline Ordinal Scoreb 
X 
x.x 
x.x, x.x 
x 
x.x 
x.x, x.x 
N = Number of subjects 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.  
b [X] additional subjects are included in the ‘Any Baseline Ordinal Score’ row that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 
Table with similar format: 
Table 69: 
Deaths by Day 15 or Day 29 by Treatment Group and Actual Baseline Ordinal Score – As Treated Population 
 


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Table 70: 
Time to Death through Day 15 and 29 by Treatment Group and Actual Baseline Ordinal Score – mITT Population 
Study Day 
Treatment Group 
Actual Baseline Ordinal Score 
n 
HR 
P-value 
Estimate 
95% CI 
Day 15 
Baricitinib + PBO + RDV (N=X) 
5 
x 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
x 
Baricitinib + PBO + RDV (N=X) 
6 
x 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
x 
Baricitinib + PBO + RDV (N=X) 
Baseline Ordinal Score 5 or 6 
x 
x.xx 
x.xx, x.xx 
x.xxx 
PBO + Dexamethasone + RDV (N=X) 
x 
Baricitinib + PBO + RDV (N=X) 
Any Baseline Ordinal Scorea 
x 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
x 
Day 29 
Baricitinib + PBO + RDV (N=X) 
5 
x 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
x 
Baricitinib + PBO + RDV (N=X) 
6 
x 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=X) 
x 
Baricitinib + PBO + RDV (N=X) 
Baseline Ordinal Score 5 or 6 
x 
x.xx 
x.xx, x.xx 
x.xxx 
PBO + Dexamethasone + RDV (N=X) 
x 
Baricitinib + PBO + RDV (N=X) 
Any Baseline Ordinal Scorea 
x 
x.xx 
x.xx, x.xx 
-- 
PBO + Dexamethasone + RDV (N=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 Cox model. The ratio is Baricitinib + PBO + RDV to PBO + Dexamethasone + RDV. 
HR for the ‘Baseline Ordinal Score 5 or 6 and ‘Any Baseline Ordinal Score’ group is the hazard ratio from the stratified Cox Model.  
P-value calculated using the stratified Log-rank test. 
a [X] additional subjects are included in the ‘Any Baseline Ordinal Score’ row that were enrolled with a baseline ordinal score of 4. [Include as applicable] 
 
Programming Notes:  
The p-value for the stratified log-rank test for the ‘Any Baseline Ordinal Score’ will only be reported if the p-value from the preceding elements of the 
hierarchical testing procedure are all < 0.05. Otherwise the p-value from the analysis including the 6 subgroup will be reported. 


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Tables with similar format: 
Table 71: 
Time to Death through Day 15 and 29 by Treatment Group and Actual Baseline Ordinal Score – As Treated Population 
Table 72: 
Time to Death through Day 15 and 29 by Treatment Group within Subgroups – mITT Population, Actual Baseline Ordinal Score 
5 or 6 
Table 73: 
Time to Death through Day 15 and 29 by Treatment Group: Medications of Interest Sensitivity Analysis – mITT Population, 
Actual Baseline Ordinal Score 5 or 6 
Table 74: 
Time to Death through Day 15 and 29 by Treatment Group: Interaction Modeling – mITT Population, Actual Baseline Ordinal 
Score 5 or 6 
 
Programming notes for Table 72: 
Log-rank p-values will not be included in this table so the column will be removed. The Actual Baseline Ordinal Score 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. Actual baseline 
ordinal score will be excluded from this table.  
Programming notes for Table 73: 
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 Actual Baseline Ordinal Score 
column will be removed and a “Medication of Interest” column will be inserted to the left of Study Day. Separate models will be fit with censoring based 
on  the first date of use for each of the following categories of medications (see Section 6.4): 
• Any Medication of Interest 
• Antivirals 
• COVID-19 Vaccination 
• Treatments for COVID-19 
• Monoclonal antibodies targeting the spike protein of SARS-CoV-2 including casirivimab, Imdevimab, and bamlanivimab 
• Renin-angiotensin system (RAS) Inhibitors and HMG-CoA reductase inhibitors (Statins) 
• Corticosteroids 


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• Other 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) are 
censored at time of medication receipt.”  
Programming notes for Table 74: 
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”. The 
following models will be run:  
• “Treatment – Continuous Actual 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 continuous 
baseline ordinal score interaction term was 0.xxxx.”. 
 


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Table 75: 
Time to Death through Day 15 and 29 by Treatment Group: Restricted Mean Survival Time Analysis – mITT Population, Actual 
Baseline Ordinal Score 5 or 6 
Study Day 
Treatment Group 
Actual Baseline Ordinal Score 
n 
Restricted Mean Mortality Time (Days) 
Difference 
Estimate 
95% CI 
Estimate 
95% CI 
Day 15 
Baricitinib + PBO + RDV (N=X) 
5 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
PBO + Dexamethasone + RDV (N=X) 
x 
x.x 
x.x, x.x 
Baricitinib + PBO + RDV (N=X) 
6 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
PBO + Dexamethasone + RDV (N=X) 
x 
x.x 
x.x, x.x 
Baricitinib + PBO + RDV (N=X) 
Baseline Clinical Status 5 or 6 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
PBO + Dexamethasone + RDV (N=X) 
x 
x.x 
x.x, x.x 
Repeat for Day 29 
N= Number of subjects in the specified treatment group, actual baseline ordinal score, 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 + PBO + RDV and PBO + Dexamethasone + RDV.   
 


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Table 76: 
Subjects Experiencing Grade 3 or 4 AEs and SAEs through Day 29 by Treatment Group 
and Actual Baseline Ordinal Score – As Treated Population 
Safety Event Outcome 
Baricitinib + PBO + RDV 
PBO + Dexamethasone + RDV 
n 
% 
95% CI 
n 
% 
95% CI 
Baseline Ordinal Score 5  
(N = X) 
Grade 3 or 4 AE 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
SAE 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
Baseline Ordinal Score 6  
(N = X) 
Grade 3 or 4 AE 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
SAE 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
Baseline Ordinal Score 5 or 6 
(N = X) 
Grade 3 or 4 AE 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
SAE 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
Any Baseline Ordinal Scorea 
(N = X) 
Grade 3 or 4 AE 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
SAE 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
N = Number of subjects in the As Treated Population and specified actual baseline ordinal score 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. 
a [X] additional subjects are included in the ‘Any Baseline Ordinal Score’ row that were enrolled with a baseline ordinal score of 4. [Include as 
applicable] 
 


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Table 77: 
Analysis of Time to Death, SAEs, or Grade 3 or 4 AEs by Treatment Group – As Treated 
Population 
Actual Baseline Ordinal Score 
Treatment Group 
n 
HR 
Estimate 
95% CI 
Baseline Ordinal Score 5  
(N=X) 
Baricitinib + PBO + RDV (N=X) 
X 
x.xx 
x.xx, x.xx 
PBO + Dexamethasone + RDV (N=X) 
X 
Baseline Ordinal Score 6 
(N=X) 
Baricitinib + PBO + RDV (N=X) 
X 
x.xx 
x.xx, x.xx 
PBO + Dexamethasone + RDV (N=X) 
X 
Baseline Ordinal Score 5 or 6 
(N=X) 
Baricitinib + PBO + RDV (N=X) 
X 
x.xx 
x.xx, x.xx 
PBO + Dexamethasone + RDV (N=X) 
X 
N= Number of subjects in the As Treated Population and specified actual baseline ordinal score 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 Cox model. The ratio is Baricitinib + 
PBO + RDV to PBO + Dexamethasone + RDV.  
HRs for the ‘Baseline Ordinal Score 5 or 6’ are the hazard ratios from the stratified Cox Model.  
P-value calculated using the Log-rank test 
 


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Table 78: 
Culture Results by Treatment Group and Infection AE Severity – As Treated Population 
Anatomical 
Location 
Pathogen 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + 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.  
N=Number of participants randomized to Treatment group.  
n=Number of participants with infection.  
 


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Table 79: 
New Infections by Treatment Group – As Treated Population, Actual Baseline Ordinal 
Score 5 
Preferred Term 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
Risk Difference 
n 
% 
Events 
n 
% 
Events 
% 
95% CI 
Any New Infection 
x 
x 
x 
x 
x 
x 
x.x 
x.x, x.x 
PT 1 
x 
x 
x 
x 
x 
x 
x.x 
x.x, x.x 
PT 2 
x 
x 
x 
x 
x 
x 
x.x 
x.x, x.x 
Etc. 
x 
x 
x 
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. 
New infections were identified by the site. 
 
Tables with similar format: 
Table 80: 
Opportunistic New Infections by Treatment Group – As Treated Population, Actual 
Baseline Ordinal Score 5 
Table 81: 
New Infections by Treatment Group – As Treated Population, Actual Baseline Ordinal 
Score 6 
Table 82: 
Opportunistic New Infections by Treatment Group – As Treated Population, Actual 
Baseline Ordinal Score 6 
Table 83: 
New Infections by Treatment Group – As Treated Population, Actual Baseline Ordinal 
Score 5 or 6 
Table 84: 
Opportunistic New Infections by Treatment Group – As Treated Population, Actual 
Baseline Ordinal Score 5 or 6 
Table 85: 
New Infections by Treatment Group by Dexamethasone Prior to Enrollment – As 
Treated Population, Actual Baseline Ordinal Score 5 or 6 
Table 86: 
Opportunistic New Infections by Treatment Group by Dexamethasone Prior to 
Enrollment – As Treated Population, Actual Baseline Ordinal Score 5 or 6 
Programming Notes for Table 80, Table 82, Table 84, and Table 86:  
Opportunistic infections will be identified by a Standardized MedDRA Query among the new infections 
identified by the site.  


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Table 87: 
VTEs by Treatment Group – As Treated Population, Actual Baseline Ordinal Score 5 
or 6 
Preferred Term 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + RDV 
(N=X) 
Risk Difference 
n 
% 
Events 
n 
% 
Events 
% 
95% CI 
Any VTE 
x 
x 
x 
x 
x 
x 
x.x 
x.x, x.x 
PT 1 
x 
x 
x 
x 
x 
x 
x.x 
x.x, x.x 
PT 2 
x 
x 
x 
x 
x 
x 
x.x 
x.x, x.x 
Etc. 
x 
x 
x 
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. 
New infections were identified by the site. 
 
Programming note: superficial venous thrombosis is not included as a VTE. 
 


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Table 88: 
Abnormal Laboratory Results of Grade 3 or 4 by Parameter, Maximum Severity, Time Point, and Treatment Group – As 
Treated Population, Actual Baseline Ordinal Score of 5 or 6 
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 + PBO + RDV 
x 
x 
x 
x 
x 
x 
x 
 
PBO + Dexamethasone + RDV 
x 
x 
X 
x 
x 
x 
x 
Day 3 
Baricitinib + PBO + RDV 
x 
x 
X 
x 
x 
x 
x 
 
PBO + Dexamethasone + RDV 
x 
x 
X 
x 
x 
x 
x 
Day 5 
Baricitinib + PBO + RDV 
x 
x 
X 
x 
x 
x 
x 
 
PBO + Dexamethasone + RDV 
x 
x 
X 
x 
x 
x 
x 
Day 8 
Baricitinib + PBO + RDV 
x 
x 
X 
x 
x 
x 
x 
 
PBO + Dexamethasone + RDV 
x 
x 
X 
x 
x 
x 
x 
Day 11 
Baricitinib + PBO + RDV 
x 
x 
X 
x 
x 
x 
x 
 
PBO + Dexamethasone + RDV 
x 
x 
X 
x 
x 
x 
x 
Day 15 
Baricitinib + PBO + RDV 
x 
x 
X 
x 
x 
x 
x 
 
PBO + Dexamethasone + RDV 
x 
x 
X 
x 
x 
x 
x 
Day 29 
Baricitinib + PBO + RDV 
x 
x 
X 
x 
x 
x 
x 
 
PBO + Dexamethasone + RDV 
x 
x 
X 
x 
x 
x 
x 
Maximum Severity Post Baseline 
Baricitinib + PBO + RDV 
x 
x 
X 
x 
x 
x 
x 
 
PBO + Dexamethasone + 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: Vitamin D, 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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Table 89: 
Treatment-Emergent Laboratory Abnormalities - As Treated Population, Actual 
Baseline Ordinal Score of 5 or 6 
Laboratory 
Parameter 
Maximum Post 
Baseline Grade 
Baricitinib + PBO + RDV 
(N=X) 
PBO + Dexamethasone + 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 90: 
Summary Statistics of Laboratory Results by Parameter, Study Visit Day, and Treatment Group – As Treated Population, Actual 
Baseline Ordinal Score 5 or 6 
Laboratory 
Parameter 
Study Visit Day 
Treatment Group 
Absolute 
Change from Baseline 
N 
Mean 
95% CI 
Median 
Min, Max 
N 
Mean 
95% CI 
Median 
Min, Max 
Parameter 1 
Baseline 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
--- 
--- 
--- 
--- 
--- 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
--- 
--- 
--- 
--- 
--- 
Day 3 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
Day 5 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
Day 8 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
Day 11 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
Day 15 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
Day 29 
Baricitinib + PBO + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
 
PBO + Dexamethasone + RDV 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x, xx.x 
Continue for all parameters…Table  
N = Number of subjects in the As Treated Population with laboratory data available for the parameter at the specified study visit. 
 
Programming Note:  Include all lab parameters in this table except d-dimer and CRP which are in table. 
 


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APPENDIX 2. FIGURE MOCK-UPS 
General Programming Notes for figures: 
• Treatment group labeling will be the following: 
o Baricitinib + PBO + RDV 
o PBO + Dexamethasone + RDV 
• If the treatment group labels need to be abbreviated to improve fit, the following abbreviations will be used: 
o B + R 
o D + R 
• Use the same color for a treatment on the different graphs (SAS standard colors): 
o Baricitinib + PBO + RDV = Blue 
o PBO + Dexamethasone + RDV = Red 
• For severity graphs (SAS standard colors): 
o Mild = yellow 
o Moderate = orange 
o Severe = red 
o Life-threatening = brown 
o Death = black 
 


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LIST OF FIGURES 
Figure 1: 
Elements of the fixed-sequence hierarchical testing procedure .................................35 
Figure 2: 
CONSORT Flow Diagram .......................................................................................140 
Figure 3: 
Number of Subjects that Early Terminated from the Study by Study Day and 
Hospitalization Status for Last Ordinal Score Collected, Actual Baseline 
Ordinal Score – mITT Population ............................................................................141 
Figure 4: 
Kaplan-Meier Curve of Mechanical Ventilation Free Survival through Day 
29 by Treatment Group – mITT Population .............................................................142 
Figure 5: 
Kaplan-Meier Curve of Mechanical Ventilation Free Survival through Day 
29 by Treatment Group – As Treated Population .....................................................143 
Figure 6: 
Kaplan-Meier Curve of Mechanical Ventilation Free Survival through Day 
29 by Treatment Group – mITT Population, Actual Baseline Clinical Status 
of 5 ............................................................................................................................143 
Figure 7: 
Kaplan-Meier Curve of Mechanical Ventilation Free Survival through Day 
29 by Treatment Group – mITT Population, Actual Baseline Clinical Status 
of 6 ............................................................................................................................143 
Figure 8: 
Forest Plot of Hazard Ratios of Mechanical Ventilation Free Survival by 
Subgroup - mITT Population ....................................................................................144 
Figure 9: 
Forest Plot of Hazard Ratios of Mechanical Ventilation Free Survival by 
Subgroup - mITT Population, Actual Baseline Clinical Status of 5 .........................144 
Figure 10: Forest Plot of Hazard Ratios of Mechanical Ventilation Free Survival by 
Subgroup - mITT Population, Actual Baseline Clinical Status of 6 .........................144 
Figure 11: Forest Plot of Hazard Ratios of Mechanical Ventilation Free Survival by 
Comorbidity - mITT Population ...............................................................................144 
Figure 12: Forest Plot of Hazard Ratios of Mechanical Ventilation Free Survival: Leave 
One Site Out Sensitivity Analysis - mITT Population .............................................144 
Figure 13: Study Visit Day 15 Clinical Status Score by Baseline Ordinal Score and 
Treatment Group – mITT Population .......................................................................145 
Figure 14: Kaplan-Meier Curves of Time to Improvement by at Least One Category of 
Clinical Status Score by Treatment Group – mITT Population, Actual 
Baseline Ordinal Score 5 or 6 ...................................................................................146 
Figure 15: Kaplan-Meier Curves of Time to Recovery by Day 29 by Treatment Group – 
mITT Population .......................................................................................................147 
Figure 16: Kaplan-Meier Curve of Time to Recovery by Day 29 by Treatment Group – 
mITT Population, Actual Baseline Ordinal Score of 5 .............................................147 
Figure 17: Kaplan-Meier Curve of Time to Recovery by Day 29 by Treatment Group – 
mITT Population, Actual Baseline Ordinal Score of 6 .............................................147 


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Figure 18: Forest Plot of Hazard Ratios of Time to Recovery by Day 29 by Subgroup - 
mITT Population .......................................................................................................148 
Figure 19: Forest Plot of Hazard Ratios of Time to Recovery by Day 29 by 
Comorbidity - mITT Population ...............................................................................148 
Figure 20: Mean DOOR by Day and Treatment Group – mITT Population, Actual 
Baseline Ordinal Score of 5 or 6...............................................................................149 
Figure 21: Bee Swarm Plot of Oxygen Days by Treatment Group – mITT Population, 
Actual Baseline Ordinal Score of 5 or 6 ...................................................................150 
Figure 22: Bee Swarm Plot of Non-Invasive Ventilation/High-Flow Oxygen Days by 
Treatment Group – mITT Population, Actual Baseline Ordinal Score of 5 or 
6 ................................................................................................................................150 
Figure 23: Bee Swarm Plot of Invasive Mechanical Ventilation/ECMO Days by 
Treatment Group – mITT Population, Actual Baseline Ordinal Score of 5 or 
6 ................................................................................................................................150 
Figure 24: Bee Swarm Plot of Hospitalization Days by Treatment Group – mITT 
Population, Actual Baseline Ordinal Score of 5 or 6 ................................................150 
Figure 25: Frequency of Non-Serious Related Adverse Events by MedDRA System 
Organ Class, Severity, and Treatment Group - As Treated Population, Actual 
Baseline Ordinal Score .............................................................................................151 
Figure 26: Incidence of Non-Serious Related Adverse Events by MedDRA System 
Organ Class, Severity, and Treatment Group - As Treated Population, Actual 
Baseline Ordinal Score .............................................................................................152 
Figure 27: Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group 
– mITT Population ....................................................................................................153 
Figure 28: Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group 
– As Treated Population ...........................................................................................153 
Figure 29: Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group 
– mITT Population, Actual Baseline Ordinal Score of 5 ..........................................153 
Figure 30: Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group 
– mITT Population, Actual Baseline Ordinal Score of 6 ..........................................153 
Figure 31: Kaplan-Meier Curve of Time to Death or Progression to Clinical Status 6, 7, 
or 8 through Day 29 by Treatment Group – mITT Population, Actual 
Baseline Ordinal Score of 5 ......................................................................................153 
Figure 32: Kaplan-Meier Curve of Time to Death or Progression to Clinical Status 6, 7, 
or 8 through Day 29 by Treatment Group – As Treated Population, Actual 
Baseline Ordinal Score of 5 ......................................................................................153 
Figure 33: Kaplan-Meier Curve of Time to Death, SAE, or Grade 3 or 4 AE through 
Day 29 by Treatment Group – As Treated Population .............................................154 


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Figure 34: [Parameter X] Results by Scheduled Visits: Change from Baseline by 
Treatment Group – As Treated Population ...............................................................155 
 


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Figure 2: 
CONSORT Flow Diagram 
 
 
Programming Note: 
Diagram will collapse across baseline ordinal score strata. Content of individual boxes may be altered from the 
shell. 
 


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Figure 3: 
Number of Subjects that Early Terminated from the Study by Study Day and Hospitalization 
Status for Last Ordinal Score Collected, Actual Baseline Ordinal Score – mITT Population 
 
 
Programming Notes: 
The shell above is a generic shell. For the panels, the rows will be, going top to bottom, “All Subjects”, “Baricitinib 
+ PBO + RDV” and “PBO + Dexamethasone + RDV”. The columns will be, going left to right, “Ordinal Score 5”, 
and “Ordinal Score 6”. Within each panel, the x-axis will be labeled “Study Day of Last Ordinal Score” and will 
have a tick at each Study Day. The blue bars will be “Hospitalized” and the red bars will be “Not Hospitalized”.  
PBO + Dexamethasone + RDV
Baricitinib + PBO + RDV
Group
Ordinal Scale Score
Percent of Total Frequency
Day = 29
Day = 15
Day = 11
Day = 8
Day = 5
Day = 3
Day = 1
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
0
20
40
60
0
20
40
60
0
20
40
60


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Figure 4: 
Kaplan-Meier Curve of Mechanical Ventilation Free Survival through Day 29 by Treatment 
Group – mITT Population 
 
 
Programing Note: 
Include p-value from stratified Chi-Square test as in Klein (2007). 
 
Figures with similar format: 


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Figure 5: 
Kaplan-Meier Curve of Mechanical Ventilation Free Survival through Day 29 by Treatment 
Group – As Treated Population 
Figure 6: 
Kaplan-Meier Curve of Mechanical Ventilation Free Survival through Day 29 by Treatment 
Group – mITT Population, Actual Baseline Clinical Status of 5 
Figure 7: 
Kaplan-Meier Curve of Mechanical Ventilation Free Survival through Day 29 by Treatment 
Group – mITT Population, Actual Baseline Clinical Status of 6 
 


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Figure 8: 
Forest Plot of Hazard Ratios of Mechanical Ventilation Free Survival by Subgroup - mITT 
Population 
 
 
Figures with similar format: 
Figure 9: 
Forest Plot of Hazard Ratios of Mechanical Ventilation Free Survival by Subgroup - mITT 
Population, Actual Baseline Clinical Status of 5 
Figure 10: 
Forest Plot of Hazard Ratios of Mechanical Ventilation Free Survival by Subgroup - mITT 
Population, Actual Baseline Clinical Status of 6 
Figure 11: 
Forest Plot of Hazard Ratios of Mechanical Ventilation Free Survival by Comorbidity - mITT 
Population  
Figure 12: 
Forest Plot of Hazard Ratios of Mechanical Ventilation Free Survival: Leave One Site Out 
Sensitivity Analysis - mITT Population 
 
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
Hazard Ratio
Region 2
Region 1
Geographic Region
Category 4
Category 5
Category 6
Disease Status
Female
Male
Sex
> 65 Yr
40-64 Yr
< 40 Yr
Age
Overall


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Figure 13: 
Study Visit Day 15 Clinical Status Score by Baseline Ordinal Score and Treatment Group – 
mITT Population 
 
 


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Figure 14: 
Kaplan-Meier Curves of Time to Improvement by at Least One Category of Clinical Status 
Score by Treatment Group – mITT Population, Actual Baseline Ordinal Score 5 or 6 
 
 


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Figure 15: 
Kaplan-Meier Curves of Time to Recovery by Day 29 by Treatment Group – mITT Population 
 
 
Programming Note:  
For Subjects at risk counts, only display Days 1, 3, 5, 8, 11, 15, 22, 29. 
 
Figures with similar format: 
Figure 16: 
Kaplan-Meier Curve of Time to Recovery by Day 29 by Treatment Group – mITT Population, 
Actual Baseline Ordinal Score of 5 
Figure 17: 
Kaplan-Meier Curve of Time to Recovery by Day 29 by Treatment Group – mITT Population, 
Actual Baseline Ordinal Score of 6 
 


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Figure 18: 
Forest Plot of Hazard Ratios of Time to Recovery by Day 29 by Subgroup - mITT Population 
 
 
Figure with similar format: 
Figure 19: 
Forest Plot of Hazard Ratios of Time to Recovery by Day 29 by Comorbidity - mITT 
Population  
 
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
Hazard Ratio
Region 2
Region 1
Geographic Region
Severity 4
Severity 5
Severity 6
Severity 7
Disease Severity
Female
Male
Sex
> 65 Yr
40-64 Yr
< 40 Yr
Age
Overall


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Figure 20: 
Mean DOOR by Day and Treatment Group – mITT Population, Actual Baseline Ordinal 
Score of 5 or 6 
 
 
Programming Note: 
Bars reflect the CIs. No Day 0 will be available. 
 
0
5
10
15
20
25
30
Study Day
3
4
5
6
7
DOOR
PBO + Dexamethasone + RDV
Baricitinib + PBO + RDV
PBO + Dexamethasone + RDV
Baricitinib + PBO + RDV
Treatment Group


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Figure 21: 
Bee Swarm Plot of Oxygen Days by Treatment Group – mITT Population, Actual Baseline 
Ordinal Score of 5 or 6 
 
 
Programming Note: 
Use the format used for ACTT-1 which incorporated summary statistics. 
 
Figures with similar format: 
Figure 22: 
Bee Swarm Plot of Non-Invasive Ventilation/High-Flow Oxygen Days by Treatment Group – 
mITT Population, Actual Baseline Ordinal Score of 5 or 6 
Figure 23: 
Bee Swarm Plot of Invasive Mechanical Ventilation/ECMO Days by Treatment Group – 
mITT Population, Actual Baseline Ordinal Score of 5 or 6 
Figure 24: 
Bee Swarm Plot of Hospitalization Days by Treatment Group – mITT Population, Actual 
Baseline Ordinal Score of 5 or 6 
 
 
0
Baricitinib + PBO + RDV
PBO + Dexamethasone + RDV
Treatment Group
0
5
10
15
20
25
30
Number of Days of Oxygenation


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Figure 25: 
Frequency of Non-Serious Related Adverse Events by MedDRA System Organ Class, Severity, 
and Treatment Group - As Treated Population, Actual Baseline Ordinal Score 
 
 
Programming Note: 
Two separate sub-figures will be generated for each actual baseline ordinal score.  
 
 


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Figure 26: 
Incidence of Non-Serious Related Adverse Events by MedDRA System Organ Class, Severity, 
and Treatment Group - As Treated Population, Actual Baseline Ordinal Score 
 
 
Programming Note: 
Two separate sub-figures will be generated for each actual baseline ordinal score. Add footnote that Relationship is 
defined as related to any study product (remdesivir, baricitinib/placebo, dexamethasone/placebo).  
 


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Figure 27: 
Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group – mITT 
Population 
 
 
Figures with similar format: 
Figure 28: 
Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group – As Treated 
Population 
Figure 29: 
Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group – mITT 
Population, Actual Baseline Ordinal Score of 5 
Figure 30: 
Kaplan-Meier Curve of Time to Death through Day 29 by Treatment Group – mITT 
Population, Actual Baseline Ordinal Score of 6 
Figure 31: 
Kaplan-Meier Curve of Time to Death or Progression to Clinical Status 6, 7, or 8 through Day 
29 by Treatment Group – mITT Population, Actual Baseline Ordinal Score of 5 
Figure 32: 
Kaplan-Meier Curve of Time to Death or Progression to Clinical Status 6, 7, or 8 through Day 
29 by Treatment Group – As Treated Population, Actual Baseline Ordinal Score of 5 


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Figure 33: 
Kaplan-Meier Curve of Time to Death, SAE, or Grade 3 or 4 AE through Day 29 by 
Treatment Group – As Treated Population 
 
 
 


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Figure 34: 
[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 baseline ordinal score (5 or 6). 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 .............................................................158 
Listing 2: Subjects Who Early Terminated or Discontinued Treatment ...................................159 
Listing 3: Subject-Specific Protocol Deviations .......................................................................160 
Listing 4: Non Subject-Specific Protocol Deviations ...............................................................161 
Listing 5: Individual Efficacy Response Data: Ordinal Score Data .........................................162 
Listing 6: Individual Efficacy Response Data: DOOR .............................................................163 
Listing 7: Demographic Data ....................................................................................................164 
Listing 8: Pre-Existing and Concurrent Medical Conditions ....................................................165 
Listing 9: Concomitant Medications .........................................................................................166 
Listing 10: Corticosteroid Use ....................................................................................................167 
Listing 11: Medications of Interest .............................................................................................168 
Listing 12: Compliance Data ......................................................................................................169 
Listing 13: Listing of Non-Serious Adverse Events ...................................................................170 
Listing 14: Listing of Related Adverse Events ...........................................................................171 
Listing 15: Listing of Non-Fatal Serious Adverse Events ..........................................................172 
Listing 16: Listing of Culture Results .........................................................................................173 
Listing 17: Listing of Deaths .......................................................................................................174 
Listing 18: Pregnancy Reports – Maternal Information .............................................................175 
Listing 19: Pregnancy Reports – Gravida and Para ....................................................................176 
Listing 20: Pregnancy Reports – Live Birth Outcomes ..............................................................177 
Listing 21: Pregnancy Reports – Still Birth Outcomes ...............................................................178 
Listing 22: Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion 
Outcomes ..................................................................................................................179 
Listing 23: Clinical Laboratory Results ......................................................................................180 
Listing 24: Vital Signs ................................................................................................................181 
Listing 25: Physical Exam Findings ...........................................................................................182 
Listing 26: Subjects Who Received the Incorrect Treatment .....................................................183 
Listing 27: Subjects Randomized to the Incorrect Clinical Status Stratum ................................184 
Listing 28: Subjects Receiving Supplemental Oxygen Post Discharge ......................................185 


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Listing 29: Subjects Readmitted .................................................................................................186 
Listing 30: Listing of Day 60 Results ..........................................................................................187 


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Listing 1: 
Exclusions from the As Treated Population 
Planned Treatment Group 
Actual Baseline Ordinal Score 
Subject ID 
Baricitinib + PBO + RDV/ 
PBO + Dexamethasone + RDV 
7/6/5/4/3 
XXXXX 
 
Programming Notes: 
Include randomized subjects only. Sort Order = Treatment Group, Actual Baseline Ordinal Score (descending 
order, i.e. 6, then 5 then 4), USUBJID.  
 


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Listing 2: 
Subjects Who Early Terminated or Discontinued Treatment 
Actual Treatment Group 
Actual Baseline Ordinal Score
Subject ID 
Category 
Treatment Discontinued 
Reason for Early Termination or 
Treatment Discontinuation 
Study Day 
Baricitinib + PBO + RDV/ 
PBO + Dexamethasone + RDV 
7/6/5/4/3 
XXXXX 
Early Termination/Treatment 
Discontinuation 
NA/Infusions/Tablets  
Xxxxxx 
xxxx 
 
Programming Notes: 
Sort Order = Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), 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 + Injections” will be displayed in the Treatment 
Discontinued column. If subjects were randomized and not dosed are categorized as “Not Treated” and sorted after PBO + Dexamethasone + RDV if 
applicable. 
 


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Listing 3: 
Subject-Specific Protocol Deviations 
Actual Treatment 
Group 
Actual Baseline 
Ordinal Score 
Subject 
ID 
DV 
Number Deviation 
Deviation 
Classification 
Deviation 
Category 
Study 
Day 
Reason for 
Deviation 
Deviation 
Resulted 
in AE? 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Comments 
Baricitinib + PBO + 
RDV/ 
PBO + Dexamethasone 
+ RDV 
7/6/5/4 
Xxxxx 
xx 
xxx 
Major/Minor 
xxx 
x 
xxxx 
Yes/No 
Yes/No 
Yes/No 
xxxx 
 
Programming Notes: 
Sort Order = Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), 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 Baseline Ordinal 
Score, 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 
Deviation 
Classification 
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: Ordinal Score Data 
Actual Treatment Group  
Actual Baseline Ordinal Score 
Subject ID 
Study Visit Day of Assessment Actual Study Day of Assessment 
Ordinal Score  
Ordinal Status 
Baricitinib + PBO + RDV/ 
PBO + Dexamethasone + 
RDV 
7/6/5/4 
xxxxx 
xx 
xx 
xx 
xxxxx 
 
Programming Notes: 
Sort Order = Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), USUBJID, Study Day. Ordinal status should 
match the wording of the scale definitions in Section 4.3.  


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Listing 6: 
Individual Efficacy Response Data: DOOR 
Actual Treatment Group  
Actual Baseline 
Ordinal Score 
Subject ID 
Study Visit Day of 
Assessment 
Actual Study Day of 
Assessment 
DOOR  
Ordinal Score  
SAE/Death 
Severe AE 
Baricitinib + PBO + RDV/ 
PBO + Dexamethasone + RDV 
7/6/5/4/3 
xxxxx 
xx 
xx 
1/2/3/4/5/6/7 
xxxxx 
Yes/No 
Yes/No 
 
Programming Notes: 
Sort Order = Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), USUBJID, Study Visit Day. SAE/Death and 
Severe AE are No until a subject experiences an event, and Yes for every study visit day thereafter. 
 


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Listing 7: 
Demographic Data 
Actual Treatment Group 
Actual Baseline Ordinal 
Score 
Subject 
ID 
Geographic 
Region 
Sex 
Age at 
Randomization 
(years) 
Ethnicity 
Race 
Duration of Symptoms 
prior to Randomization 
(Days) 
Weight 
(Kg) 
Height 
(Cm) 
BMI 
Baricitinib + PBO + RDV/ 
PBO + Dexamethasone + 
RDV 
7/6/5/4/3 
xxxxx 
xxx 
xxx 
Xx 
xxx 
xxx 
xxx 
xx 
Xx 
Xxx 
 
Programming Notes: 
Sort Order = Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), USUBJID.  
 


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Listing 8: 
Pre-Existing and Concurrent Medical Conditions 
Actual Treatment Group 
Actual Baseline 
Ordinal Score 
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 + PBO + RDV/ 
PBO + Dexamethasone + 
RDV 
7/6/5/4/3 
Xxx001 
Yes/No/Unknown 
Yes/No/Unknown 
Yes/No/Unknown 
01 
xxxxx 
Xxxx 
xxxx 
02 
xxxxx 
Xxxx 
xxxx 
 
Programming Note: 
Sort Order = Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), 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 Baseline Ordinal Score, 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 Baseline 
Ordinal Score 
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 + PBO + RDV/ 
PBO + Dexamethasone + RDV 
7/6/5/4/3 
xxx 
xx 
xxxx 
x 
x 
xxxx 
Yes/No 
Yes/No 
xxxx / xxxx 
 
Programming Notes: 
Sort Order = Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), 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: 
Corticosteroid Use 
Actual Treatment 
Group 
Actual Baseline 
Ordinal Score 
Subject ID 
Medication 
Number 
Medication 
Medication 
Start Day 
Medication 
End Day 
Dose / Route 
Frequency 
Indication 
Taken for an AE? 
(AE Description; 
Number) 
Baricitinib + PBO + 
RDV/ 
PBO + 
Dexamethasone + 
RDV 
7/6/5/4/3 
xxx 
xx 
xxxx 
x 
x 
xx / xx 
xx 
xxxx 
Yes/No 
 
Programming Notes:  
Sort Order = Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), USUBJID, CM number. 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 11: 
Medications of Interest 
Actual Treatment Group 
Actual Baseline 
Ordinal Score 
Subject 
ID 
Medication 
Number 
Medication 
Medication 
Start Day 
Medication 
End Day 
Indication 
Medication of 
Interest 
Category 
Medication 
of Interest 
Subcategory 
ATC Level 1 
(ATC Level 2) 
Baricitinib + PBO + RDV/ 
PBO + Dexamethasone + RDV 
7/6/5/4/3 
xxx 
xx 
xxxx 
x 
x 
xxxx 
xxxx 
xxxx 
xxxx / xxxx 
 
Programming Notes:  Sort Order = Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), 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 12: 
Compliance Data  
Dose Type  
Dose Number 
Dose Administered? 
Number of 
Tablets Received 
Dose Stopped or 
Slowed? 
Reason Dose Missed, Stopped or 
Slowed 
Did the Reason Result in Permanent 
Discontinuation?  
Actual Treatment Group: , Actual Baseline Ordinal Score: , Subject ID: , Study Day of Discharge: , Study Day of Death: 
Remdesivir/IV Push/Tablets  
1 
Yes/No 
1 / 2 / NA 
Yes/No/NA 
Reason / NA 
Yes /No/NA 
  
2 
Yes/No  
1 / 2 / NA 
Yes/No/NA 
Reason / NA 
Yes /No/NA 
… 
… 
  
  
… 
… 
  
 
Programming Notes: 
Sort Order = Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), USUBJID, Dose Type and Dose Number.  
 


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Listing 13: 
Listing of Non-Serious Adverse Events 
Adverse 
Event 
Study Day 
Duration 
(Days) 
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 Baseline Ordinal Score: , Subject ID: , AE Number:  
xxx 
xx 
x 
xxx 
Not 
Related/Related 
to each of 
Remdesivir, 
Baricitinib, 
Dexamethasone, 
or Placebo 
xxxx 
Yes/No 
For each of 
Remdesivir, 
Baricitinib, 
Dexamethasone, 
or Placebo 
Yes/No 
xxxx 
xxxx 
xxxx 
Comments: xxxx 
 
Programming Note: 
Sort order will be Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), USUBJID, AE Number. For relationship to 
study treatment, list either Not Related or each study treatment it is related to. For Action taken, separately list actions for each treatment. 


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Listing 14: 
Listing of Related Adverse Events 
Adverse 
Event 
Study 
Day 
Duration 
(Days) 
Severity 
Unanticipated 
Problem 
Study Treatment  
Action Taken with 
Study Treatment 
Subject Discontinued 
Due to AE 
Outcome 
MedDRA System 
Organ Class 
MedDRA 
Preferred Term 
Actual Treatment Group: Actual Baseline Ordinal Score: , Subject ID: , AE Number:  
xxx 
xx 
x 
xxx 
Yes/No 
Dexamethasone/Baricitinib/
Remdesivir 
xxx 
Yes/No 
xxxx 
xxxx 
xxxx 
Comments: xxx 
 
Programming Note: 
Sort order will be Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), Study Treatment, USUBJID, Study Day. List 
the study treatment the event is associated to, or more than one if multiple. 
 


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Listing 15: 
Listing of Non-Fatal Serious Adverse Events 
Adverse 
Event 
Study 
Day 
Duration 
(Days) 
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 Baseline Ordinal Score: , Subject ID: , AE Number:  
xxxx 
x 
x 
x 
xxxxx 
xxx 
Not 
Related/Related 
to each of 
Remdesivir, 
Baricitinib, 
Dexamethasone, 
or Placebo 
xxxx 
Yes/No 
For each of 
Remdesivir, 
Baricitinib, 
Dexamethasone, 
or Placebo 
Yes/No 
xxxxx 
xxxxx 
xxxxx 
Comments: xxxx 
 
Programming Note: 
Sort order will be Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), USUBJID, Study Day. For relationship to 
study treatment, list either Not Related or each study treatment it is related to. For Action taken, separately list actions for each treatment. 


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Listing 16: 
Listing of Culture Results 
Study Day 
Anatomical Location 
Pathogen 1 
Pathogen 2 
Pathogen 3 
Pathogen 4 
Associated with AE Number 
Secondary AE Number 
Actual Treatment Group:  , Actual Baseline Ordinal Score: , Subject ID: ,  
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Programming Note: 
Sort order will be Treatment Group, Actual Baseline Ordinal Score, USUBJID, Study Day. 
 


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Listing 17: 
Listing of Deaths 
Adverse 
Event 
Study 
Day 
Duration 
(Days) 
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 Baseline Ordinal Score: , Subject ID: , AE Number:  
xxxx 
x 
x 
x 
xxxxx 
xxx 
Not 
Related/Related 
to each of 
Remdesivir, 
Baricitinib, 
Dexamethasone, 
or Placebo 
xxxx 
Yes/No 
For each of 
Remdesivir, 
Baricitinib, 
Dexamethasone, 
or Placebo  
Yes/No 
xxxxx 
xxxxx 
Comments: xxxx 
 
Programming Note: 
Sort by Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), USUBJID. For relationship to study treatment, list 
either Not Related or each study treatment it is related to. For Action taken, separately list actions for each treatment. 
 


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Listing 18: 
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 19: 
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 + 
PBO + RDV/ 
PBO + 
Dexamethasone 
+ RDV 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gravida includes the current pregnancy, para events do not. 
a Preterm Birth 
b Term Birth 
 


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Listing 20: 
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 + 
PBO + RDV/ 
PBO + 
Dexamethasone 
+ RDV 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Congenital Anomalies are included in the Adverse Event listing. 
 


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Listing 21: 
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 + 
PBO + RDV/ 
PBO + 
Dexamethasone 
+ RDV 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 22: 
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 + PBO + RDV/ 
PBO + Dexamethasone + RDV 
 
 
 
 
 
 
 
 
 


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Listing 23: 
Clinical Laboratory Results 
Actual Treatment Group 
Actual 
Baseline 
Ordinal Score 
Subject ID 
Planned 
Study Day  
Actual 
Study Day  
Sex  
Age 
(years) 
Laboratory 
Parameter 
(Units) 
Result 
(Toxicity Grade) 
Change 
from 
Baseline 
Reference 
Range Low 
Reference 
Range High 
Baricitinib + PBO + RDV/ 
PBO + Dexamethasone + RDV 
Category 
7/6/5/4/3 
xxx 
xx 
xx 
Xx 
x 
xxx (xxx) 
xxx (xxxx) 
xxx 
xxxx 
xxxx 
 
Programming Note: 
Sort order will be Treatment Group, Actual Baseline Ordinal Score, USUBJID, Planned Study Day. If subjects were randomized and not dosed “Not 
Treated” will be used for the actual treatment category and will be sorted after PBO + Dexamethasone + RDV. All parameters will be included in the 
listing. 


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Listing 24: 
Vital Signs 
Study Visit 
Day 
Actual Study 
Day 
Respiratory Rate  
O2 Saturation  
Any Supplemental O2 
Temperature  
Systolic BP  
Heart Rate 
Level of 
Consciousness 
Total 
NEW 
Score 
bpm 
Score 
% 
Score 
Yes/No 
Score 
°C 
Score 
mmHg 
Score 
bpm 
Score 
A/V/P/U 
Score 
Actual Treatment Group: , Baseline Ordinal Score: , Subject ID:  
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 


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Listing 25: 
Physical Exam Findings 
Actual Treatment Group 
Actual Baseline Ordinal 
Score 
Subject ID 
Planned Study 
Day 
Actual Study 
Day 
Body System 
Abnormal 
Finding 
Reported as an AE? 
(AE Description; Number) 
Baricitinib + PBO + RDV/ 
PBO + Dexamethasone + RDV 
7/6/5/4 
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 Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), USUBJID, Planned Study Day, and Body 
System. 
 


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Listing 26: 
Subjects Who Received the Incorrect Treatment 
Actual Treatment Group 
Actual Baseline 
Ordinal Score 
Subject ID 
Randomized Treatment Group 
Number of Infusions 
Received 
Number of Doses 
Received 
Number of Incorrect 
Doses Received 
Baricitinib + PBO + RDV/ 
PBO + Dexamethasone + RDV 
7/6/5/4 
xxx 
Baricitinib + PBO + RDV/ 
PBO + Dexamethasone + RDV 
x 
x 
x 
 
Programming Note: 
Sort order will be Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), USUBJID. 
 


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Listing 27: 
Subjects Randomized to the Incorrect Clinical Status Stratum 
Actual Treatment Group 
Actual Baseline Ordinal Score 
Subject ID 
Randomized Stratum 
Baricitinib + PBO + RDV/ 
PBO + Dexamethasone + RDV 
7/6/5/4/3 
xxx 
7/6/5/4/3 
 
Programming Note:  
Sort order will be Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), 
USUBJID. If subjects were randomized and not dosed “Not Treated” will be used for the actual treatment 
category. 


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Listing 28: 
Subjects Receiving Supplemental Oxygen Post Discharge 
Actual Treatment Group 
Actual Baseline Ordinal Score Subject ID Discharge Study Day Oxygen Type 
Is the Oxygen 
New Use? 
Study Day Supplemental 
Oxygen Initiated 
Study Day Supplemental 
Oxygen Stopped 
Baricitinib + PBO + RDV/ 
PBO + Dexamethasone + RDV 
7/6/5/4/3 
xxx 
XXX 
XXXX 
Yes/No 
XXX 
XXX 
 
Programming Note: 
Sort order will be Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), USUBJID. If subjects were randomized and 
not dosed “Not Treated” will be used for the actual treatment category. 


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Listing 29: 
Subjects Readmitted  
Subject ID 
Actual Treatment Group 
Actual Baseline 
Ordinal Score 
Original Discharge 
Study Day 
Study Day 
Readmitted 
Reason for 
Readmission 
Readmission 
Discharge Day 
xxx 
Baricitinib + PBO + RDV/ 
PBO + Dexamethasone + RDV 
7/6/5/4 
XXX 
XXX 
XXX 
XXXX 
 
Programming Note: 
Sort order will be Treatment Group, Actual Baseline Ordinal Score (descending order, i.e. 6, then 5 then 4), 
USUBJID. If subjects were randomized and not dosed “Not Treated” will be used for the actual treatment 
category. 
 


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Listing 30: Listing of Day 60 Results  
Actual Treatment 
Group 
Actual 
Baseline 
Ordinal Score 
Subject 
ID 
Did the 
Visit 
Occur? 
Study 
Day 
Since the Day 29 / Last Study Contact 
Any New 
Infections? 
If New 
Infection, 
Type of 
Infection 
Other New 
Diagnosesa 
Ordinal 
Score 
Was the 
Subject Seen 
by a 
Healthcare 
Provider? 
Was the 
Subject Re-
admitted to 
the Hospital? 
Was it Due to 
Worsening or 
Exacerbation of a Pre-
existing Condition?  
If Yes, Specify 
Associated Pre-
Existing 
Condition 
Baricitinib + PBO + 
RDV/ 
PBO + 
Dexamethasone + 
RDV 
7/6/5/4 
xxx 
Yes/No 
XX 
Yes/No 
Yes/No 
Yes/No/NA 
Condition/NA 
Yes/No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aOther new diagnoses are based on a targeted list of diagnoses (chronic respiratory disease, pulmonary emboli, deep venous thrombosis, cardiac arrhythmia, myocardial infarction, stroke, major 
depression, anxiety, post-traumatic stress disorder) as well as an ‘Other’ option for site staff to specify other diagnoses. 
 
Programming note: Combine all new diagnoses with a “;” separating multiple terms.  Sort order will be Treatment Group, Actual Baseline Ordinal Score 
(descending order, i.e. 6, then 5 then 4), USUBJID.  If subjects were randomized and not dosed “Not Treated” will be used for the actual treatment 
category. 

Prot_001.pdf: 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 1 of 172 
 
 
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: 10.0 
 
18 January 2021 
 
 
 
 


Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 2 of 172 
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 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 3 of 172 
TABLE OF CONTENTS 
 
STATEMENT OF COMPLIANCE ................................................................................................ 2 
TABLE OF CONTENTS ................................................................................................................ 3 
LIST OF TABLES ........................................................................................................................ 11 
LIST OF FIGURES ...................................................................................................................... 11 
1. 
OVERALL PROTOCOL SUMMARY ................................................................................ 12 
1.1 
Synopsis ........................................................................................................................ 12 
1.2 
Stages in the adaptive trial ............................................................................................ 17 
1.3 
Study Schema................................................................................................................ 17 
2. 
INTRODUCTION ................................................................................................................ 17 
2.1 
Study Rationale ............................................................................................................. 18 
2.2 
Background ................................................................................................................... 18 
 
Purpose of Study ................................................................................................... 18 
2.3 
Risk/Benefit Assessment .............................................................................................. 18 
3. 
OBJECTIVES AND ENDPOINTS ...................................................................................... 18 
4. 
STUDY DESIGN.................................................................................................................. 21 
4.1 
Overall Design .............................................................................................................. 22 
4.2 
Scientific Rationale for Study Design ........................................................................... 22 
5. 
STUDY POPULATION ....................................................................................................... 22 
5.1 
Specific Populations ...................................................................................................... 22 
5.2 
Strategies for Recruitment and Retention ..................................................................... 23 
 
Recruitment ........................................................................................................... 23 
 
Retention ............................................................................................................... 23 
 
Compensation Plan for Subjects ........................................................................... 23 
 
Costs ...................................................................................................................... 23 
6. 
STUDY PRODUCT.............................................................................................................. 23 
7. 
STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................................... 24 
7.1 
Halting Criteria and Discontinuation of Study Intervention ......................................... 24 
 
Individual Study Product Halting ......................................................................... 24 
 
Study Halting ........................................................................................................ 24 
7.2 
Withdrawal from the Study ........................................................................................... 24 
7.3 
Lost to Follow-Up ......................................................................................................... 24 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 24 
8.1 
Screening and Efficacy Assessments ............................................................................ 24 
 
Severity and Efficacy Scales ................................................................................. 24 


Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 4 of 172 
 
Ordinal Scale ..................................................................................................... 24 
 
National Early Warning Score (NEWS) ........................................................... 25 
 
Exploratory assessments ....................................................................................... 26 
 
Viral Load and/or Shedding .............................................................................. 26 
8.2 
Adverse Events and Serious Adverse Events ............................................................... 26 
 
Definition of Adverse Event (AE) ........................................................................ 26 
 
Definition of Serious Adverse Event (SAE) ......................................................... 26 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) .............................. 27 
 
Classification of an Adverse Event ....................................................................... 27 
 
Severity of Adverse Events ............................................................................... 27 
 
Relationship to Study Intervention ................................................................... 28 
 
Time Period and Frequency for Event Assessment and Follow-Up ..................... 28 
 
Investigators Reporting of AEs ......................................................................... 28 
 
Serious Adverse Event Reporting ......................................................................... 28 
 
Investigators Reporting of SAEs ...................................................................... 29 
 
Regulatory Reporting of SAEs ......................................................................... 29 
 
Reporting of Pregnancy ........................................................................................ 29 
8.3 
Unanticipated Problems ................................................................................................ 29 
 
Definition of Unanticipated Problems .................................................................. 30 
 
Unanticipated Problem Reporting ......................................................................... 30 
9. 
STATISTICAL CONSIDERATIONS.................................................................................. 30 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....... 30 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................................ 30 
 
Informed Consent Process .................................................................................... 31 
 
Requirements for Permission by Parents/Guardians and Assent by Children 
(in case of a minor) ........................................................................................................... 32 
 
Other Informed Consent Procedures ............................................................. 32 
 
Study Termination and Closure ............................................................................ 32 
 
Confidentiality and Privacy .................................................................................. 33 
 
Secondary Use of Stored Specimens and Data ..................................................... 33 
 
Data Sharing for Secondary Research .......................................................... 34 
 
Key Roles and Study Governance ........................................................................ 34 
 
Safety Oversight.................................................................................................... 34 
 
Protocol team oversight ................................................................................ 34 
 
Data Safety Monitoring Board ...................................................................... 34 
 
Clinical Monitoring ............................................................................................... 35 
 
Data Handling and Record Keeping ..................................................................... 35 
 
Data Collection and Management Responsibilities ...................................... 35 
 
Study Record Retention ................................................................................ 36 
 
Source Records ............................................................................................. 36 
 
Protocol Deviations ............................................................................................... 36 
 Publication and Data Sharing Policy .................................................................... 37 
 Human Data Sharing Plan ..................................................................................... 37 
 Publication ............................................................................................................ 37 
 Conflict of Interest Policy ..................................................................................... 37 


Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 5 of 172 
10.2 
Additional Considerations ............................................................................................ 38 
 
Research Related Injuries ..................................................................................... 38 
 
Public Readiness and Emergency Preparedness Act ............................................ 38 
10.3 
Abbreviations ................................................................................................................ 39 
10.4 
Protocol Amendment History ....................................................................................... 40 
11. REFERENCES ..................................................................................................................... 49 
Appendix A - ACTT-1: Remdesivir vs Placebo ........................................................................... 52 
Appendix B - ACTT-2: Baricitinib/Remdesivir Vs. Remdesivir ................................................. 53 
Appendix C - ACTT-3: Remdesivir + Interferon beta-1a ............................................................ 54 
1. 
PROTOCOL SUMMARY .................................................................................................... 54 
1.1 
ACTT-3 – Synopsis ...................................................................................................... 54 
1.2 
Schedule of Assessments .............................................................................................. 57 
2. 
INTRODUCTION ................................................................................................................ 58 
2.1 
Background ................................................................................................................... 58 
 
ACTT-3 – Interferon beta-1a /Remdesivir vs. Placebo/Remdesivir Trial ............ 58 
2.2 
Risk/Benefit Assessment .............................................................................................. 60 
 
Known Potential Risks .......................................................................................... 60 
 
Remdesivir ............................................................................................................ 61 
 
Potential Risks of Remdesivir ........................................................................... 62 
 
Potential Benefits of Remdesivir ...................................................................... 63 
 
Assessment of Potential Risks and Benefits of Remdesivir ............................. 63 
 
Subcutaneous Interferon beta-1a ........................................................................... 63 
 
Potential Risks of Subcutaneous Interferon beta-1a ......................................... 63 
 
Potential Benefits of Subcutaneous Interferon beta-1a ..................................... 66 
 
Assessment of Potential Risks and Benefits of Subcutaneous Interferon beta-1a
 
66 
3. 
OBJECTIVES AND ENDPOINTS ...................................................................................... 66 
4. 
STUDY DESIGN.................................................................................................................. 70 
4.1 
Overall Design .............................................................................................................. 70 
4.2 
Scientific Rationale for Study Design ........................................................................... 71 
4.3 
Justification for Dose .................................................................................................... 71 
 
Justification for Dose of Remdesivir .................................................................... 71 
 
Justification for Dose of Subcutaneous Interferon beta-1a ................................... 71 
5. 
STUDY POPULATION ....................................................................................................... 72 
5.1 
Inclusion Criteria .......................................................................................................... 72 
5.2 
Exclusion Criteria ......................................................................................................... 73 
 
Exclusion of Specific Populations ........................................................................ 73 
5.3 
Inclusion of Vulnerable Subjects .................................................................................. 74 
5.4 
Lifestyle Considerations ............................................................................................... 74 
5.5 
Screen Failures .............................................................................................................. 75 
5.6 
Strategies for Recruitment and Retention ..................................................................... 75 


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Recruitment ........................................................................................................... 75 
 
Retention ............................................................................................................... 75 
 
Compensation Plan for Subjects ........................................................................... 76 
 
Costs ...................................................................................................................... 76 
6. 
STUDY PRODUCT.............................................................................................................. 76 
6.1 
Study Product(s) and Administration ........................................................................... 76 
 
Study Product Description .................................................................................... 76 
 
Dosing and Administration ................................................................................... 77 
 
Dose Escalation ..................................................................................................... 77 
 
Dose Modifications ............................................................................................... 77 
 
Overdosage ........................................................................................................... 78 
6.2 
Preparation/Handling/Storage/Accountability .............................................................. 78 
 
Acquisition and Accountability ............................................................................ 79 
 
Formulation, Appearance, Packaging, and Labeling ............................................ 79 
 
Product Storage and Stability................................................................................ 80 
 
Preparation ............................................................................................................ 80 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................... 81 
 
Randomization ...................................................................................................... 81 
 
Blinding and Masking Procedures ........................................................................ 82 
6.4 
Study Intervention Compliance .................................................................................... 82 
6.5 
Concomitant Therapy.................................................................................................... 82 
 
Permitted Concomitant Therapy and Procedures ................................................. 82 
 
Prohibited Concomitant Therapy .......................................................................... 83 
 
Rescue Medicine ................................................................................................... 84 
 
Non-Research Standard of Care ............................................................................ 84 
7. 
STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................................... 84 
7.1 
Halting Criteria and Discontinuation of Study Intervention ......................................... 84 
 
Individual Study Product Halting ......................................................................... 84 
 
Remdesivir Halting ........................................................................................... 85 
 
Subcutaneous Interferon beta-1a and Placebo Injections Halting .................... 85 
 
Study Halting ........................................................................................................ 85 
7.2 
Withdrawal from the Study ........................................................................................... 86 
7.3 
Lost to Follow-Up ......................................................................................................... 86 
7.4 
Readmission .................................................................................................................. 86 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 87 
8.1 
Screening and Efficacy Assessments ............................................................................ 87 
 
Screening Procedures ............................................................................................ 87 
 
Efficacy Assessments ............................................................................................ 89 
 
Measures of clinical support, limitations and infection control ........................ 89 
 
Ordinal Scale ..................................................................................................... 90 
 
National Early Warning Score (NEWS) ........................................................... 91 
 
Exploratory Assessments and Secondary Research Samples ............................... 92 
 
SARS-CoV-2 Virology Exploratory Assessment ............................................. 93 


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Immunophenotyping Exploratory Assessment ................................................. 93 
8.2 
Safety and Other Assessments ...................................................................................... 95 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings .................................................................................................. 97 
 
Unscheduled Visits ............................................................................................... 97 
8.3 
Adverse Events and Serious Adverse Events ............................................................... 97 
 
Definition of Adverse Event (AE) ........................................................................ 97 
 
Definition of Serious Adverse Event (SAE) ......................................................... 99 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) ............................ 100 
 
Classification of an Adverse Event ..................................................................... 100 
 
Severity of Adverse Events ............................................................................. 100 
 
Relationship to Study Intervention ................................................................. 101 
 
Time Period and Frequency for Event Assessment and Follow-Up ................... 101 
 
Investigator Reporting of AEs ........................................................................ 101 
 
Serious Adverse Event Reporting ....................................................................... 102 
 
Investigators Reporting of SAEs .................................................................... 102 
 
Regulatory Reporting of SAEs ....................................................................... 102 
 
Reporting of Pregnancy ...................................................................................... 102 
8.4 
Unanticipated Problems .............................................................................................. 103 
 
Definition of Unanticipated Problems ................................................................ 103 
 
Unanticipated Problem Reporting ....................................................................... 103 
9. 
STATISTICAL CONSIDERATIONS................................................................................ 103 
9.1 
Statistical Hypotheses ................................................................................................. 103 
9.2 
Sample Size Determination ......................................................................................... 104 
9.3 
Populations for Analyses ............................................................................................ 108 
9.4 
Statistical Analyses ..................................................................................................... 108 
 
General Approach ............................................................................................... 108 
 
Analysis of the Primary Efficacy Endpoint ........................................................ 108 
 
Analysis of the Secondary Endpoint(s) ............................................................... 108 
 
Analysis of Exploratory Objectives and Endpoints ............................................ 109 
 
Safety Analyses ................................................................................................... 109 
 
Baseline Descriptive Statistics ............................................................................ 109 
 
Planned Interim and Early Analyses ................................................................... 109 
 
Interim Safety Analyses .................................................................................. 110 
 
Interim Efficacy Review ................................................................................. 110 
 
Sub-Group Analyses ........................................................................................... 110 
 
Exploratory Analyses .......................................................................................... 110 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS – ALL 
STAGES ..................................................................................................................................... 111 
Appendix D - ACTT-4: Baricitinib/Remdesivir Vs. Dexamethasone/Remdesivir .................... 112 
1. 
PROTOCOL SUMMARY .................................................................................................. 112 
1.1 
ACTT-4 – Synopsis .................................................................................................... 112 
1.2 
Schedule of Assessments ............................................................................................ 116 
1.3 
Study Schema.............................................................................................................. 117 


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2. 
INTRODUCTION .............................................................................................................. 118 
2.1 
Background ................................................................................................................. 118 
 
ACTT-4 – Baricitinib/Remdesivir vs. Dexamethasone/Remdesivir Trial .......... 118 
2.2 
Risk/Benefit Assessment ............................................................................................ 120 
 
Known Potential Risks ........................................................................................ 120 
 
Remdesivir (Veklury®) ...................................................................................... 121 
 
Potential Risks of Remdesivir ......................................................................... 121 
 
Potential Benefits of Remdesivir .................................................................... 122 
 
Assessment of Potential Risks and Benefits of Remdesivir ........................... 122 
 
Baricitinib ........................................................................................................... 122 
 
Potential Risks of Baricitinib .......................................................................... 122 
 
Potential Benefits of Baricitinib...................................................................... 125 
 
Assessment of Potential Risks and Benefits of Baricitinib ............................. 125 
 
Dexamethasone ................................................................................................... 125 
 
Potential risks of dexamethasone .................................................................... 125 
 
Potential Benefits of Dexamethasone ............................................................. 126 
 
Assessment of Potential Risks and Benefits of Dexamethasone .................... 126 
3. 
OBJECTIVES AND ENDPOINTS .................................................................................... 126 
4. 
STUDY DESIGN................................................................................................................ 130 
4.1 
Overall Design ............................................................................................................ 130 
4.2 
Scientific Rationale for Study Design ......................................................................... 131 
4.3 
Justification for Dose .................................................................................................. 131 
 
Justification for Dose of Remdesivir .................................................................. 131 
 
Justification for Dose of Baricitinib .................................................................... 131 
 
Justification for Dose of Dexamethasone ........................................................... 131 
5. 
STUDY POPULATION ..................................................................................................... 132 
5.1 
Inclusion Criteria ........................................................................................................ 132 
5.2 
Exclusion Criteria ....................................................................................................... 132 
 
Exclusion of Specific Populations ...................................................................... 133 
5.3 
Inclusion of Vulnerable Subjects ................................................................................ 134 
5.4 
Lifestyle Considerations ............................................................................................. 134 
5.5 
Screen Failures ............................................................................................................ 135 
5.6 
Strategies for Recruitment and Retention ................................................................... 135 
 
Recruitment ......................................................................................................... 135 
 
Retention ............................................................................................................. 136 
 
Compensation Plan for Subjects ......................................................................... 136 
 
Costs .................................................................................................................... 136 
6. 
STUDY PRODUCT............................................................................................................ 136 
6.1 
Study Product(s) and Administration ......................................................................... 136 
 
Study Product Description .................................................................................. 137 
 
Dosing and Administration ................................................................................. 138 
Anti-inflammatory Agents (Dexamethasone/IV placebo + Baricitinib/ po placebo) ................. 138 


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Dose Escalation ................................................................................................... 140 
 
Dose Modifications ............................................................................................. 140 
 
Overdosage ......................................................................................................... 141 
6.2 
Preparation/Handling/Storage/Accountability ............................................................ 141 
 
Acquisition and Accountability .......................................................................... 141 
 
Formulation, Appearance, Packaging, and Labeling .......................................... 142 
 
Product Storage and Stability.............................................................................. 143 
 
Preparation .......................................................................................................... 143 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................ 143 
 
Randomization .................................................................................................... 143 
 
Blinding and Masking Procedures ...................................................................... 143 
 
Unblinding at end of study .............................................................................. 143 
 
Unblinding for worsening clinical status ........................................................ 144 
 
Unblinding for adverse event .......................................................................... 144 
6.4 
Study Intervention Compliance .................................................................................. 144 
6.5 
Concomitant Therapy.................................................................................................. 144 
 
Permitted Concomitant Therapy and Procedures ............................................... 144 
 
Prohibited Concomitant Therapy ........................................................................ 145 
 
Assessment of Concomitant Therapies ............................................................... 145 
 
Progression to Intubation/Invasive Mechanical Ventilation. .............................. 146 
 
Non-Research Standard of Care .......................................................................... 147 
7. 
STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ................................................................................... 147 
7.1 
Halting Criteria and Discontinuation of Study Intervention ....................................... 147 
 
Individual Study Product Halting ....................................................................... 147 
 
Remdesivir Halting ......................................................................................... 148 
 
Oral and IV Study Product Halting ................................................................. 148 
 
Study Halting ...................................................................................................... 148 
7.2 
Withdrawal from the Study ......................................................................................... 148 
7.3 
Lost to Follow-Up ....................................................................................................... 149 
7.4 
Readmission ................................................................................................................ 149 
8. 
STUDY ASSESSMENTS AND PROCEDURES .............................................................. 149 
8.1 
Screening and Efficacy Assessments .......................................................................... 150 
 
Screening Procedures .......................................................................................... 150 
 
Efficacy Assessments .......................................................................................... 152 
 
Measures of clinical support, limitations and infection control ...................... 152 
 
Ordinal Scale ................................................................................................... 153 
 
National Early Warning Score (NEWS) ......................................................... 154 
 
Exploratory assessments ..................................................................................... 155 
 
Exploratory Assessments and Secondary Research Samples ............................. 155 
 
SARS-CoV-2 Virology Exploratory Assessment ........................................... 157 
 
Immunophenotyping Exploratory Assessment ............................................... 157 
8.2 
Safety and Other Assessments .................................................................................... 158 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings ................................................................................................ 160 


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Unscheduled Visits ............................................................................................. 160 
8.3 
Adverse Events and Serious Adverse Events ............................................................. 160 
 
Definition of Adverse Event (AE) ...................................................................... 160 
 
Definition of Serious Adverse Event (SAE) ....................................................... 162 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) ............................ 163 
 
Classification of an Adverse Event ..................................................................... 163 
 
Severity of Adverse Events ............................................................................. 163 
 
Relationship to Study Intervention ................................................................. 163 
 
Time Period and Frequency for Event Assessment and Follow-Up ................... 164 
 
Investigator Reporting of AEs ........................................................................ 164 
 
Serious Adverse Event Reporting ....................................................................... 164 
 
Investigators Reporting of SAEs .................................................................... 164 
 
Regulatory Reporting of SAEs ....................................................................... 165 
 
Reporting of Pregnancy ...................................................................................... 165 
8.4 
Unanticipated Problems .............................................................................................. 165 
 
Definition of Unanticipated Problems ................................................................ 165 
 
Unanticipated Problem Reporting ....................................................................... 166 
9. 
STATISTICAL CONSIDERATIONS................................................................................ 166 
9.1 
Statistical Hypotheses ................................................................................................. 166 
9.2 
Sample Size Determination ......................................................................................... 166 
9.3 
Populations for Analyses ............................................................................................ 167 
9.4 
Statistical Analyses ..................................................................................................... 168 
 
General Approach ............................................................................................... 168 
 
Analysis of the Primary Efficacy Endpoint ........................................................ 168 
 
Analysis of the Secondary Endpoint(s) ............................................................... 168 
 
Safety Analyses ................................................................................................... 169 
 
Baseline Descriptive Statistics ............................................................................ 170 
 
Planned Interim and Early Analyses ................................................................... 170 
 
Interim Safety Analyses .................................................................................. 170 
 
Interim Efficacy Review ................................................................................. 170 
 
Subgroup Analyses ............................................................................................. 170 
 
Exploratory Analyses .......................................................................................... 171 
 
Multiplicity Adjustment ...................................................................................... 171 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS – ALL 
STAGES ..................................................................................................................................... 172 
 
 
 


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LIST OF TABLES 
Table 1. National Early Warning Score (NEWS) ......................................................................... 25 
Table 1. Schedule of Assessments (SOA) .................................................................................... 57 
Table 2. National Early Warning Score (NEWS) ......................................................................... 91 
Table 3. Blood Volume for Subjects Consenting for Genetic Testing Involving PAXgene and 
PBMC Collection .......................................................................................................................... 95 
Table 4a. Venipuncture Volumes for Subjects NOT Consenting for Genetic Testing Involving 
Transcriptomics and Complete Immunophenotyping Analysis 1 ................................................. 96 
Table 5b. Venipuncture Volumes for Subjects Consenting for Genetic Testing At Sites that Do 
NOT Collect PBMCs 1 .................................................................................................................. 96 
Table 6c. Venipuncture Volumes for Subjects Consenting for Genetic Testing At Sites that 
Collect PBMCs 1 ........................................................................................................................... 97 
Table 7. Hypothesis tests of interest for ACTT-3 ....................................................................... 103 
Table 8. Number of recoveries needed for 85% power assuming a type I error rate of 5% for 
various recovery ratios. ............................................................................................................... 104 
Table 9: Possible scenarios for the distribution of ordinal outcomes for the control arm at Day 
15................................................................................................................................................. 106 
Table 10: 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. .................................. 106 
Table 11. Treatment ordinal outcome proportions under an odds ratio of 1.75 for five scenarios 
in Table 5 at Day 15. ................................................................................................................... 107 
Table 1. Schedule of Assessments (SOA) .................................................................................. 116 
Table 2. Mortality from ACTT-2 and RECOVERY trials. ........................................................ 120 
Table 3. Summary of Adverse Reaction Rates in Subjects with Mild, Moderate, or Severe 
COVID-19 in ACTT-1 ................................................................................................................ 121 
Table 4. Serious Adverse Events Occurring in 5 or More Subjects in Any Preferred Term by 
Treatment Group ......................................................................................................................... 123 
Table 5. National Early Warning Score (NEWS) ....................................................................... 155 
Table 6. Blood Volume for Subjects Consenting for Genetic Testing Involving PAXgene 
Collection .................................................................................................................................... 158 
Table 7. Venipuncture Volumes for Subjects NOT Consenting for Genetic Testing Involving 
Transcriptomics Analysis 1 ......................................................................................................... 159 
Table 8. Venipuncture Volumes for Subjects Consenting for Genetic Testing Involving 
Transcriptomics Analysis 1 ......................................................................................................... 159 
Table 9: Sample size estimates and study power. ....................................................................... 167 
 
 
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 Schedule of Assessment in each appendix 
for details. All subjects will undergo a series of efficacy, safety, and laboratory assessments. See 
stage specific schedule of assessment for details.  
 
The primary, key secondary, and other outcomes will be modified for each trial stage.  However, 
common endpiints (allowing comparability across the studies) include: 
 
Study Objectives  
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
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: 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
• Hospitalized, not requiring supplemental 
oxygen - no longer requires ongoing 
medical care; 
• Not hospitalized, but new or increased 
limitation on activities and/or requiring 
new or increased home oxygen; 
• Not hospitalized, no limitations on 
activities. 
Recovery is evaluated up until Day 29. 
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, but new or increased 
limitation on activities and/or requiring 
new or increased 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  
• WBC with differential, hemoglobin, 
platelets, creatinine, glucose, total 


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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). 
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 will 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  
ACTT-2: Baricitinib/Remdesivir vs. Remdesivir  
ACTT-3: Interferon beta-1a/Remdesivir vs. Remdesivir  
ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
 
1.3 
Study Schema 
 
 
 
 
2. 
INTRODUCTION 


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Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 18 of 172 
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 are currently few vaccines approved worldwide and a 
number of them in the pipeline 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 
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 


Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 19 of 172 
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.  
 
The primary, key secondary, and other outcomes will be modified for each trial stage.  However, 
common endpoints (allowing comparability across the studies) include: 
 
Study Objectives  
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
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, but new or increased 
limitation on activities and/or requiring 
new or increased home oxygen; 
• Not hospitalized, no limitations on 
activities. 
Recovery is evaluated up until Day 29. 
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, but new or increased 
limitation on activities and/or requiring 
new or increased 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 
 
 
 


Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 20 of 172 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
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 (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 


Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 21 of 172 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
 
• 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 
reported as INR) 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/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). 
  
4. 
STUDY DESIGN 


Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 22 of 172 
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 sample size will be described in each stage specific appendix.  
 
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 
Specific Populations 


Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
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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. 
5.2 
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 
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.  


Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
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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 
Each stage will detail the exact assessments to be completed.  Common elements will be used 
across stages to ensure comparability of the data across the stages and interventions.  These 
common elements include: 
 
Severity and Efficacy Scales  
 
The following scales are used throughout the different stages/appendices for both baseline 
assessment of severity and as efficacy endpoints: 
 
 
Ordinal Scale 
The ordinal scale used in this study is as follows (from worst to best): 


Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 25 of 172 
• 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, but new or increased limitation on activities and/or requiring new or 
increased 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 1). 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 1. 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 
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.  
 
8.2 
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) 


Protocol 20-0006 
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An AE or suspected adverse reaction is considered serious (i.e., is an SAE) if, in the view of 
either the investigator or the Sponsor, it results in any of the following outcomes: 
• Death; 
• A life-threatening AE; 
• Inpatient hospitalization or prolongation of existing hospitalization; 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; or 
• A congenital anomaly/birth defect. 
 
Important medical events that may not meet the above criteria may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias, convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
“Life-threatening” refers to an AE that at occurrence represents an immediate risk of death to a 
subject. An event that may cause death if it occurs in a more severe form is not considered life-
threatening. Similarly, a hospital admission for an elective procedure is not considered a SAE. 
 
All SAEs, as with any AE, will be assessed for severity and relationship to study intervention. 
 
All SAEs will be recorded on the SAE CRF. 
 
All SAEs will be followed through resolution or stabilization by a licensed study physician (for 
IND studies, a physician listed on the Form FDA 1572 as the site PI or Sub-Investigator). 
 
All SAEs will be reviewed and evaluated by DMID and will be sent to the DSMB (for periodic 
review), and the IRB/IEC. 
 
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 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).  
 


Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 28 of 172 
For AEs not included in the Table, the following guidelines will be used to describe severity. In 
addition, all deaths related to an AE are to be classified as grade 5 according to the DAIDS Table.  
 
 
• Moderate (Grade 2): Events that are usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living and 
causes discomfort but poses no significant or permanent risk of harm to the research 
subject. 
 
• Severe (Grade 3): Events that interrupt usual activities of daily living, or significantly 
affect clinical status, or may require intensive therapeutic intervention. Severe events are 
usually incapacitating. 
 
• Severe (Grade 4): Events that are potentially life threatening. 
 
• Deaths (Grade 5): All deaths related to an AE are to be classified as grade 5. (per DAIDS 
Table). 
 
 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 


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Investigators Reporting of SAEs 
Any AE that meets a protocol-defined criterion as a SAE must be submitted within 24 hours of 
site awareness on an SAE form to the DMID Pharmacovigilance Group, at the following 
address:  
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
 
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible. The DMID Medical Monitor will review and 
assess the SAE for regulatory reporting and potential impact on study subject safety and protocol 
conduct. 
 
At any time after completion of the study, if the site PI or appropriate sub-investigator becomes 
aware of an SAE that occurred during the subject’s participation in the study, the site PI or 
appropriate sub-investigator will report the event to the DMID Pharmacovigilance Group. 
 
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.  
8.3 
Unanticipated Problems 


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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: 
 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, 


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and enrollment of subjects. The IRB review shall be in accordance with 45 CFR 46 and 21 CFR 
50, 21 CFR 56 (IRBs), and other federal, state, and local regulations and policies, as applicable. 
 
Site IRBs may have additional national and local regulations. 
 
Any amendments to the protocol or consent materials will be approved by the IRB before they 
are implemented. IRB review and approval will occur at least annually throughout the duration 
of the study. The investigator will notify the IRB of deviations from the protocol and SAEs, as 
applicable to the IRB policy. 
 
DMID must receive the documentation that verifies IRB-approval for this protocol, informed 
consent documents, and associated documents prior to the recruitment, screening, and enrollment 
of subjects, and any IRB-approvals for continuing review or amendments as required by the 
DMID. 
 
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. 
 


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


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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. 
 
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. 


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Data Sharing for Secondary Research 
Data from this study may be used for secondary research. All of the individual subject data 
collected during the trial will be made available after de-identification. The SAP and Analytic 
Code will also be made available. This data will be available immediately following publication, 
with no end date.  
 
The investigator may request removal of data on individual study subjects from NIH data 
repositories in the event that a research subject withdraws or changes his or her consent. 
However, some data that have been distributed for approved research use cannot be retrieved. 
 
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 


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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. 
 
 
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. 
 


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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. 
 
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. 
 


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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. 
 
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. 


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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 
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. 
 
 
Public Readiness and Emergency Preparedness Act 
The drugs remdesivir, baricitinib, interferon beta-1a, and all other study products to be evaluated 
using the ACTT clinical trial platform during this pandemic 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 


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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. 
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 


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Abbreviation 
Definition 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
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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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.  
7.0 
15Jul2020 
 
 
 
General 
The Public Readiness and Emergency Preparedness Act 
(PREP Act) was moved from Appendix C (for US sites 
only) to the main protocol document as this is available for 
all sites including international sites.  


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Appendix A 
As ACTT-1 as detailed in Appendix A is completed and the 
database is locked, Appendix A was removed from the 
protocol document (to keep the protocol document a 
manageable size).  
 
Appendix C 
As this is an adaptive study, an additional treatment stage 
“ACTT-3” was added. This stage will evaluate remdesivir + 
interferon beta-1a compared to remdesivir alone (+ placebo 
control). All sections within Appendix C are new with this 
version.  
 
8.0 
17Sep2020 
 
 
Appendix C – 
1.1 
General 
Updated to reflect the DSMB recommendation to close 
enrollment in ordinal category 6, and potential reasons for 
this.  
Appendix C – 
1.1 
Inclusion 
Allows Saliva PCR  for SARS-CoV-2 testing. 
Appendix C – 
1.1 
Exclusion 
Excludes those in ordinal category 6 and 7. 
Appendix C – 
1.2 
Schedule of 
Assessment 
Updated to reflect option additional samples for those that 
agree to genetic testing.  
2.2.1 
Known 
potential risks 
Updated to include risks of genetic testing.  
3 
Objectives and 
Endpoints 
Key secondary endpoint revised to include those in ordinal 
4 and 5 only (from ordinal category 4-6). 
3 
Objectives and 
Endpoints 
Added exploratory endpoint for immunophenotyping. 
6.3.1 
Randomization 
Revised to note closing of ordinal category 6, and specific 
DSMB recommendations.  
6.5.1 and 
6.5.2 
Concomitant 
therapy 
Rewritten for clarity.  
8.1.3.2 
 
Added details for the exploratory endpoint of 
immunophenotyping. 
8.2 
Venipuncture 
volume tables 
Revised tables and added tables to describe the anticipated 
venipuncture volumes for those getting genetic testing and 
PBMC collection.  
8.3.1 
Adverse events 
Reworded to give examples of when new and worsening 
COVID-19 related AEs  should be reported.  
9.3 
Sample Size 
Revised, still with same treatment effect size (and thus same 
recoveries), but with revised calculations for total sample 
size. 
9.0 
10Nov2020 
 
 
Main 
protocol 
document, 
General 
As this is a platform trial, the main protocol document 
serves as a general overview.  These edits remove specific 
details that may be confused or contradict the currently 


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sections 1, 
1.3, 3, 5, 8  
active study stage.  All of the details that are removed can 
still be found in the study specific appendix.   
Appendix B 
General 
As ACTT-2 as detailed in Appendix B is completed and the 
database is locked, Appendix B was removed from the 
protocol document (to keep the protocol document a 
manageable size). 
Appendix D 
General 
As this is an adaptive study, an additional treatment stage 
ACTT-4 was added to Appendix D. This stage will evaluate  
Baricitinib/Remdesivir vs Dexamethasone/Remdesivir.  
All sections within Appendix D are new with this version.  
10.0 15 Jan 
2021 
 
 
Appendix D– 
2  
Introduction 
Added information about EUA Baricitinib.  
 
Appendix D – 
3 
Objectives 
Added secondary objective: to evaluate the clinical efficacy 
of treatment arms among subjects with a baseline ordinal 
scale of 5 as assessed by the proportion that do not progress 
to ordinal scale 6, 7 or 8 at any time by Day 29. 
Added Exploratory Objective of a Alternative Desirability of 
Outcome Ranking (DOOR) at Day 15 and 29  
 
Appendix D– 
5.2 
 
Exclusion 
Criteria 
 
Revised criterion  #1 to add clarification about those who 
have been early terminated.  
Revised #5, to change the eGFR lower limit from 20 to 15 
per FDA comment, and a clarified that  HD and HF patients 
are also excluded.  
Revised #12: clarified prior Baricitinib use, and pre-study 
use of monoclonal antibody for SARS-CoV-2 
Revised #14: clarified language about dexamethasone 
dosage 
Revised #15: clarified steroid should be po or IV 
Revised#18: clarified COVID 19 vaccine is allowed: 
ADDED #19: to exclude those who have had VTE during 
the current COVID-19 illness. 
Appendix D – 
5.6. 
Strategies 
for 
Recruitment 
and Retention 
 
5.6.1. 
Revised: clarified language on pre-screening and screening 
activities 
 
Appendix D – 
6.1. 
Study 
Product(s) and 
Administration  
 
6.1.2. 
Added language clarifying dosing and administration of 
Remdsivir, and also the anti-inflammatory IP, particularly 
the options to consider if dexamethasone received as per 
SOC prior to enrollment but on day of enrollment.  
 


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Appendix D – 
6.1 
Study 
Product(s) and 
Administration  
 
6.1.4. Dosing Modifications 
-Remdesivir: changed the cutoff to stop Remdesivir infusion, 
from 20 mL/min  to 15  mL/min as per FDA recommendation 
-Clarified language for holding oral IP and potential need for 
anti-inflammatory coverage and  allowance of off-study anti-
inflammatory after oral IP held for more than 2 days : 
 
Appendix D – 
6.3. 
Measures 
to 
minimize bias 
6.3.2.1.: Unblinding at end of study 
Clarified timepoints when the data will be locked: 
 
6.3.2.3. Unblinding for adverse event.  Clarified language on 
unblinding for SAE as per FDA recommendation.  
Appendix D– 
6.5 
Concomitant 
Medications  
6.5.2.  
Added language on potential clinical need for anti-
inflammatory coverage if oral is held for more than 2 days.  
 
6.5.3: 
Added language about recording steroids use after discharge 
through Day 29 (+6 day window) visit 
 
6.5.4: Clarified procedures for subjects progressing to OS 7  
Added language specifying exceptions to steroid prohibition 
(low dose immunosuppression in solid organ transplant 
patients or mineralocotricoids in shock). 
Appendix D– 
7.1 
Halting Criteria 
and 
Discontinuation 
of 
Study 
Intervention 
 
7.1.1. Revised and restructured language on halting any IP 
due to hypersensitivity, which is clinically significant.  
 
7.1.1.2 Combined the halting rules for oral and IV study 
products as per FDA recommendations 
 
Appendix D – 
8.1 
Screening and 
Efficacy 
Assessments 
8.1.1. Screening procedures  
-Clarified COVID 19 vaccine documentation, also removed 
height and weight from screening procedures, and removed 
hight and weight as screening procedure.  
-Added language clarifying what to do for early 
terminations, before and after receiveing the study drugs. 
-Clarified acceptable timing of pregnancy test during 
current hospitalization (i.e., confinement to hospital)  
 
8.1.2.1 Added language on different oxygen devices, to 
clarify the classification for low versus high flow delivery.  
  
8.1.3. Added details on day 60 visit 
 


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Statistical 
Analysis 
 
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Appendix A - ACTT-1: Remdesivir vs Placebo 
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APPENDIX A - ACTT-1: REMDESIVIR VS PLACEBO 
ACTT- 1 was closed to enrollment on April 29, 2020. 
All follow up visits have been completed. 
ACTT-1 database was locked on June 25, 2020.  
 
 
The details of the ACTT-1 stage of the protocol have been removed from the protocol document. 
Please see protocol version 6.0 dated 25 May 2020 for the final version of the ACTT-1 stage of 
this protocol. 


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Appendix B - ACTT-2: Baricitinib/Remdesivir vs Remdesivir 
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CONFIDENTIAL 
Page 53 of 172 
 
APPENDIX B - ACTT-2: BARICITINIB/REMDESIVIR VS. REMDESIVIR  
ACTT-2 was closed to enrollment on June 30, 2020. 
All follow up visits have been completed. 
ACTT-2 database was locked on September 9, 2020.  
 
 
The details of the ACTT-2 stage of the protocol have been removed from the protocol document. 
Please see protocol version 8.0 dated 28 Sep 2020 for the final version of the ACTT-2 stage of 
this protocol.  


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APPENDIX C - ACTT-3: REMDESIVIR + INTERFERON BETA-1A  
1. 
PROTOCOL SUMMARY 
1.1 
ACTT-3 – Synopsis 
Study overview  
ACTT-3 will evaluate the combination of subcutaneous interferon beta-1a and remdesivir 
compared to placebo and remdesivir. In vitro studies suggest significant suppression of the 
intrinsic interferon response following SARS-CoV-2 infection. (1-6) Recent data from several 
studies indicate that there may be a subset of hospitalized patients with COVID-19 who lack a 
prominent interferon signature despite high viral titers and this phenotype may be associated with 
worse clinical outcomes (2-5). Type 1 interferon can inhibit SARS-CoV, MERS-CoV, and SARS-
CoV-2 in vitro (6-9) and recent data suggests that SARS-CoV-2 may be more sensitive than SARS-
CoV to inhibition by interferon (6, 10). Lastly, two small RCTs and an exploratory, non-
randomized clinical trial in hospitalized adult COVID-19 patients suggest a possible clinical 
benefit from treatment with interferon beta (11-13). In summary, there is emerging data that 
suggests interferon may be a good candidate to improve outcomes of patients with COVID-19. 
 
Enrollment Period 
It is anticipated that enrollment may be completed in 3 to 4 months. 
 
General 
The design of ACTT-3 will follow the design of ACTT-1 and ACTT-2. 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, home visit or remote telehealth procedure as per institutional standards. If 
Day 15 and 29 visits are conducted by phone or remotely by telehealth procedure, only clinical 
data will be obtained (i.e., no specimens). The Day 22 visit does not have laboratory tests or 
collection of samples and is conducted by phone or remote telehealth procedure.  
 
The trial will enroll only those subjects with mild moderate disease (defined as being in ordinal 
category 4 and 5). The trial initially enrolled ordinal category 6 (those on high flow oxygen or non-
invasive mechanical ventilation), but enrollment in this category was closed September 4, 2020 
after the DSMB reviewed interim safety data and noted concern for risk in this category. Emerging 
data from ACTT-1 (remdesivir vs placebo) (14) and the RECOVERY trial (dexamethasone vs 
standard of care) (15) suggests that the hospitalized population may be a continuum where control 
of the virus is most important in mild disease and control of the host inflammatory response is 
most important late in the disease. Interferon, having antiviral as well - and anti-inflammatory 
properties, may have increased the inflammation seen in those enrolled as ordinal category 6. 
Therefore neither ordinal category 6 or 7 (those on mechanical ventilation or ECMO) will be 
enrolled in this trial. The DSMB confirmed that there was no signal or concern for harm in ordinal 
4 or 5 categories, and they recommended the study continue to enroll patients in those groups. 


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The trial will accrue until approximately 831 recoveries. Assuming that 90% of subjects achieve 
recovery in 28 days, the total sample size is approximately 923.  
 
Study Population 
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 (e.g., NAAT and antigen tests) in any respiratory 
specimen or saliva, as documented by either of the following:  
• PCR or other assay positive in sample collected < 72 hours prior to 
randomization; OR 
• 
PCR or other assay positive in sample collected ≥ 72 hours but < 7 days prior to 
randomization AND progressive disease suggestive of ongoing SARS-CoV-2 
infection. 
Note: if written documentation of the positive test result is not available at the time of 
enrollment (e.g., report came from other institution), the subject may be enrolled but the PCR 
should be repeated at the time of enrollment.  
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 
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 (both pharmacologic and other types of 
interventions) for the treatment of COVID-19 through Day 29. 
 
Exclusion Criteria 
1. Anticipated discharge from the hospital or transfer to another hospital which is not a 
study site within 72 hours. 
2. Subject meets criteria for ordinal scale category 6 or 7 at the time of screening.  
3. Subject has a positive test for influenza virus during this current hospital admission 
4. Subjects with an estimated glomerular filtration rate (eGFR) < 30 mL/min are excluded 
unless in the opinion of the PI, the potential benefit of receiving remdesivir outweighs the 
potential risk of study participation. 
5. ALT or AST > 5 times the upper limits of normal. 
6. Total white cell blood cell count (WBC) <1500 cells/µL. 


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7. Platelet count <50,000/µL. 
8. History of chronic liver disease (e.g., jaundice, ascites, hepatic encephalopathy, history of 
bleeding esophageal or gastric varices). No laboratory testing is needed.  
9. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day 
1 to three weeks after the last study product is given are not excluded). 
10. Allergy to any study medication including history of hypersensitivity to natural or 
recombinant interferon beta or human albumin. 
11. Patient has a chronic or acute medical condition or is taking a medication that cannot be 
discontinued at enrollment, that in the judgement of the PI, places them at unacceptable 
risk for a poor clinical outcome if they were to participate in the study.  
12. Received three or more doses of remdesivir, including the loading dose, outside of the 
study for COVID-19.  
13. Received convalescent plasma or intravenous immunoglobulin [IVIg] for the treatment of 
COVID-19. 
14. Received any interferon product within two weeks of screening, either for the treatment 
of COVID-19 or for a chronic medical condition (e.g., multiple sclerosis, HCV 
infection). 
15. Received any of the following in the two weeks prior to screening as treatment of 
COVID-19: 
• small molecule tyrosine kinase inhibitors (e.g., baricitinib, imatinib, gefitinib, 
acalabrutinib, etc.); 
• monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 
[IL-1], anti-IL-6 [tocilizumab or sarilumab], etc.);  
• monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19. 
16. Prior enrollment in ACTT-3 
 
Study Intervention 
Subjects will be randomized into two arms (1:1).  
 
Arm 1 
Arm 2 
Interferon beta-1a SQ injection + 
remdesivir IV 
Placebo SQ injection + 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 during hospitalization up to a maximum of 10 total 
doses (i.e., loading + maintenance doses received during study and pre-study if applicable). The 
duration of dosing may be adjusted by the site similar to what is described in the emergency use 
authorization and based on a subject’s clinical course and ultimate disease severity.  
 
For the subcutaneous interferon beta-1a or placebo component, subjects will receive either active 
product or placebo as follows: 
• Interferon beta-1a will be administered every other day as a 44-microgram subcutaneous 
dose for a total of 4 doses while hospitalized.  


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• A matching placebo will be administered every other day as a subcutaneous injection for 
a total of 4 doses while hospitalized.  
 
Duration of therapy: 
• IV remdesivir – 5 - 10 consecutive days while hospitalized. A full 10-day course in 
patients still in the hospital is not required per protocol. 
• Subcutaneous (interferon beta-1a or placebo) component – Days 1, 3, 5, and 7 while 
hospitalized. 
• Both stop on discharge from hospital. If readmitted after discharge, see Section 7.4. 
 
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 
+ 6 
ELIGIBILITY 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Demographics & Medical Hx 
X 
 
 
 
 
 
Review SARS-CoV-2 results 
X 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Administration of 
investigational agent 
 
• Remdesivir daily infusion for 5-10 
days or until discharge.  
• Interferon beta-1a or placebo SQ 
injection on Days 1, 3, 5, and 7, or 
until 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 
X 
X 
From Day -7 to Day 29 
 
 
 
 
 
 
 
 
 
 
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 FOR ALL SUBJECTS 
 
 
 
Blood for plasma to test by PCR 
for SARS-CoV-2 and cytokines/ 
inflammatory markers 
 
X4 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
 
 
X9 


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Oropharyngeal swab 10 
 
X4 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
X9 
 
X9 
Blood for serum (secondary 
research) 
 
X4 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
X9 
 
X9 
ONLY FOR SUBJECTS CONSENTING FOR GENETIC RESEARCH 
 
 
 
Blood for RNA for transcriptomic 
analysis (in PAXgene tube)  
 
X4 
Day 3, 8 (all ± 1 day) if 
hospitalized 
X9, 11 
 
X9 
Blood for PBMC to T cells/innate 
cells and epigenetics (in CPT) 12 
 
X4,12 
Day 8 (all ± 1 day) if 
hospitalized12 
X9, 11, 12 
 
X9, 12 
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: white blood cell (WBC) count, platelet count, ALT, AST, and 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. Laboratory tests performed in the 48 hours prior to enrollment will be accepted 
for determination of eligibility. See Section 8.1.1. for more information about pregnancy tests in post-partum women. 
4 Baseline assessments should be performed 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 36 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 count, differential, hemoglobin, platelet count, creatinine, 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.  
8 Daily until hospital discharge or end of study, whichever comes first. See Section 8.1.2.1 for more information about doing 
an ordinal scale assessment on the day after hospital discharge and on the day after a subject dies. 
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 call, home visit or remote telehealth procedure as per 
institutional standards. 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 or home visit: collect clinical data, 
vital signs, safety laboratory tests, and research laboratory samples (OP swab and serum only) as able.  
• 
If phone call or remote telehealth visit 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.  
11.Subjects who consented for genetic testing and are discharged prior to Day 8 (or Day 11 for proteomics) should get blood 
drawn at Day 15. That is, if subject is missing either a Day 8 Paxgene or CPT sample, or Day 11 proteomic sample, get 
missing sample (proteomics, PAXgene or PBMC) at the Day 15 visit if site is able to do an in-person visit. 
12. Only collected at selected clinical trial sites that are capable of collecting and processing PBMCs. 
  
 
2. 
INTRODUCTION 
2.1 
Background 
 
ACTT-3 – Interferon beta-1a /Remdesivir vs. Placebo/Remdesivir Trial 


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Data from ACTT-1 showed that hospitalized adults with COVID-19 who were randomized to 
receive remdesivir had a shorter time to clinical recovery than those who received placebo (10 vs. 
15 days, recovery rate ratio 1.29 (95% CI 1.12 to 1.49, p<0.001) (14). The odds of improvement 
were higher in the group that received remdesivir than in the placebo group (odds ratio 1.50; 95% 
CI 1.2 to 1.9, p < 0.001). After the release of these preliminary findings, the U.S. Food and Drug 
Administration (FDA) issued an Emergency Use Authorization (EUA) to permit the use of 
remdesivir for treatment of suspected or laboratory-confirmed COVID-19 in adults and children 
hospitalized with severe disease. Remdesivir has also received, full or conditional approval in 
several other countries. On August 28, 2020, the FDA expanded the scope of the EUA to include 
hospitalized patients with suspected or laboratory-confirmed mild or moderate COVID-19 based 
on final data from ACTT-1 and two other clinical studies. 
 
While remdesivir is emerging as the standard of care for COVID-19, significant morbidity and 
mortality still occur despite its use. In ACTT-3, we will evaluate if we can improve clinical 
outcomes among hospitalized COVID-19 adult patients by administering combination therapy 
with subcutaneous interferon beta-1a. Subcutaneous interferon beta-1a was selected because of its 
in vitro potency against SARS-CoV-2, known safety profile, and worldwide availability as a 
licensed drug.  
 
Interferons are naturally occurring proteins and glycoproteins that are produced in response to 
pathogens, cancers and other biologic inducers and effect both innate and adaptive immune 
responses. There are three major classes of interferons with distinct biologic actions: type I 
interferons (-α,-β,-δ,-ε,-ζ,-κ,-τ, and -ω), type II interferons (-γ) and type III interferons (-λ1, -λ2, -
λ3). Interferon beta is produced by several cell types including fibroblasts and macrophages (16, 
17). Natural interferon beta and interferon beta-1a are glycosylated with a single N-linked complex 
carbohydrate. Glycosylation of proteins can affect their stability, activity, aggregation, 
biodistribution, and serum half-life. Interferon beta-1a is a 166 amino acid glycoprotein with a 
molecular weight of approximately 22,500 Daltons. It is produced by recombinant DNA 
technology using genetically engineered Chinese Hamster Ovary cells into which the human 
interferon beta gene has been introduced. The amino acid sequence of interferon beta-1a is 
identical to that of natural human interferon beta. 
Interferon-β has antiviral and anti-inflammatory properties. In response to infection with a single-
stranded RNA virus, type I interferons including interferon beta are initially expressed after 
recognition of double-stranded RNA, the replicative intermediate of the virus, by cellular pattern-
recognition receptors, such as melanoma differentiation-associated gene 5 (MDA-5; also known 
as Ifih1) and toll-like receptors (TLR), leading to activation of interferon regulatory factor (IRF) 
3 and induction of interferon-β expression. Secreted interferon-β then functions in either an 
autocrine or paracrine manner to activate the Janus kinase–signal transducer and activator of 
transcription (STAT) pathway, inducing a wave of de novo transcription of antiviral genes, as well 
as expression of more type I interferon (18). For these reasons, interferon has been suggested as a 
putative therapeutic for SARS-CoV-2 (19, 20).  
Interferon may be a good candidate for the treatment of COVID-19 because in vitro studies suggest 
weak induction of interferon following SARS-CoV-2 infection (6, 8, 10, 21-23). Preliminary data 
from a cohort of hospitalized patients with COVID-19 indicate that there may be a subset of 
patients who lack a prominent interferon signature despite high viral titers and this phenotype may 


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be associated with worse clinical outcomes [(3, 4, 24) and unpublished data, from NIAID’s 
Immune Phenotyping in a COVID-19 Cohort study (IMPACC)]. Type 1 interferon can inhibit 
SARS-CoV, MERS-CoV, and SARS-CoV-2 in vitro (6-8, 25) and recent data suggests that SARS-
CoV-2 may be more sensitive than SARS-CoV to inhibition by interferon (6, 10).  
Cohort studies evaluating the efficacy of type I interferons for the treatment of SARS-CoV and 
MERS-CoV did not demonstrate clinical benefit (26-28). An uncontrolled cohort study of 
subcutaneous interferon alpha in the SARS-CoV-1 outbreak in Canada in 2003 demonstrated 
interferon plus corticosteroids was associated with reduced disease-associated impaired oxygen 
saturation, more rapid resolution of radiographic lung abnormalities, and lower levels of creatine 
kinase. (29) 
In a cohort study of interferon alpha 2b in Wuhan, Hubei Province, China, nebulized interferon 
therapy decreased time to clearance of virus in upper airway secretions by a mean of seven days 
compared to arbidol (a drug with no known anti-SARS-CoV-2 activity) (13).  
In an open-label, randomized study (NCT04276688) in hospitalized adults with mild COVID-19 
disease evaluated lopinavir/ritonavir (LPV/r) and ribavirin plus subcutaneous interferon beta-1b 
(in those initiating treatment <7 days after onset) compared with a LPV/r control group (12). They 
found that combination treatment was associated with shorter median time from treatment 
initiation to negative RT-PCR result in nasopharyngeal swab (7 vs. 12 days), earlier resolution of 
symptoms (4 vs. 8 days), and shorter hospital stay (9 vs. 14.5 days) compared with control (LPV/r). 
There was no significant difference in time to negative RT-PCR result, time to resolution of 
symptoms, or duration of hospital stay between arms among the subgroup of patients who did not 
receive interferon beta-1b. In this study, interferon beta-1b (8 million units on alternate days) was 
administered for 1, 2, or 3 doses when initiated on day 5-6, 3-4, or 1-2, respectively, following 
symptom onset. Fifty-two of 86 patients randomized to the combination treatment arm received 
all 3 drugs, and 41 patients in control arm received LPV/r.  
An open-label, randomized study in hospitalized adults with severe suspected or RT-PCR-
confirmed COVID-19 in Iran evaluated subcutaneous interferon beta-1a (44 mcg SQ, 3 times per 
week for 2 weeks) plus standard care (7 to 10 days of hydroxychloroquine plus LPV/r or 
atazanavir/ritonavir) compared with standard care alone (42 in combined, 39 in control arm) (11). 
Time to clinical response defined as hospital discharge or 2-score improvement in a 6-category 
ordinal scale did not differ significantly between the arms (9.7 vs. 8.3 days); duration of hospital 
stays, ICU stay, and mechanical ventilation also did not differ between the arms. However, a higher 
proportion (67% vs. 44%) of patients in the treatment arm compared with the control arm were 
discharged by day 14 (OR=2.5; 95%CI: 1.05- 6.37). The 28-day overall mortality was significantly 
lower in the interferon group (19% vs. 44%, p=0.015). There were no significant drug reactions 
within 14 days of treatment. 
In summary, the data suggest that SARS-CoV-2 infection may decrease interferon response, and 
two small RCTs in COVID-19 are suggestive of possible benefit from treatment with interferon 
beta. 
2.2 
Risk/Benefit Assessment 
 
Known Potential Risks 


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Risks of Phlebotomy 
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 2.2.2 and 2.2.3), 
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. Subcutaneous injections may cause pain and discomfort 
and result in erythema and bruising of the skin at the infection site. 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. 
 
Risks of Targeted Genetic Testing (applicable only to subjects consenting for genetic 
research) 
Study analyses will not result in discoveries about identity or paternity. This study will not involve 
genetic tests intended to discover disease-determining genes. However, study analyses could 
potentially result in medically relevant incidental findings. In the future, novel disease-associated 
phenotypes may be discovered that might be identified in samples stored under this study. During 
the informed consent process, potential subjects will be informed about the transcriptomics and 
interferon-stimulating-gene (ISG) analysis that will be conducted as part of an exploratory 
analysis. They will be given the opportunity to ask questions and decide if they would like to 
participate in that part of the study. Genetic findings can have emotional and psychological 
consequences as well as implications for health, employability, and insurability for the subject and 
family members. Samples and the resulting data will be coded and kept private. Additionally, to 
protect confidentiality, results will be entered into a password-protected database restricted to the 
PI or appointed designees.  
 
 
Remdesivir  


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Potential Risks of Remdesivir  
Remdesivir is not currently licensed in all countries where this study is conducted. In some 
countries where this study is conducted it is licensed, in some countries it is available under 
Emergency Use Authorization or conditional approvals, and in some countries, it is still considered 
an investigational therapeutic agent. As such, there are limited clinical data available for 
remdesivir.  
 
Hypersensitivity reactions including infusion-related and anaphylactic reactions have been 
observed during and following administration of remdesivir. Signs and symptoms may include 
hypotension, tachycardia, bradycardia, dyspnea, wheezing, angioedema, rash, nausea, vomiting, 
diaphoresis, and shivering.  
 
Asymptomatic transaminase elevations have been observed in healthy volunteers who received 
200 mg of remdesivir followed by 100 mg doses for up to 10 days. Transaminase elevations have 
also been reported in patients with COVID-19 who received remdesivir in clinical trials. As 
transaminase elevations have been reported as a component of COVID-19, including in patients 
receiving placebo in clinical trials of remdesivir, discerning the contribution of remdesivir to 
transaminase elevations in this patient population is challenging. Preliminary data from a large 
randomized trial (ACTT-1) showed no differences in hepatotoxicity between the remdesivir and 
placebo arm. 
 
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 will be assessed by the PI and they will be eligible 
only if the benefit of participation outweighs the risk. 
 
See Package Insert for full discussion of clinical experience and risks.  
 
Coadministration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not 
recommended based on in vitro data demonstrating an antagonistic effect of chloroquine on the 
intracellular metabolic activation and antiviral activity of remdesivir. In a study using human 
epithelium derived from HeLa-T (Hep2) cells, there was a 2-fold increase in ED50 with an increase 
of chloroquine from 0 to160 nM. Another study that evaluated the co-incubation of 1 uM 
remdesivir with either 1 uM chloroquine or 10 uM chloroquine found that there is a dose dependent 
inhibition of the formation of the active nucleoside triphosphate metabolite of remdesivir.  
 
Currently, SARS-CoV-2 is susceptible to remdesivir. There is potential for SARS-CoV-2 
developing resistance to remdesivir during treatment, which could result in decreased efficacy. 
The clinical impact of the development of resistance is not clear at this time.  


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In vitro induction studies have demonstrated that a clinically relevant interaction with 
contraceptive steroids is considered to be of limited clinical significance. However, for this study, 
the use of hormonal contraception with remdesivir is not recommended as the sole method for 
preventing pregnancy. 
 
 
Potential Benefits of Remdesivir 
ACTT-1 demonstrated that subjects that received remdesivir had a 29% faster time to recovery 
(medians of 10 vs 15 days, recovery rate ratio 1.29 (1.12, 1.49), p<0.001), and a decrease in 
mortality (11.4% vs 15.2% by 28 days, p = 0.07). As a result, all subjects in ACTT-3 will be given 
remdesivir.  
 
This drug may be available outside of clinical trials, though given varying states of licensure (as 
described above) and limited availability, one potential benefit of participating may be receiving 
remdesivir as part of the study.  
 
 
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 
those with elevated liver transaminases and decreased kidney function, and appropriate monitoring 
during the study, we can minimize the risk to subjects. While remdesivir is currently the only 
therapeutic antiviral agent known to be 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.  
 
 
Subcutaneous Interferon beta-1a 
 
Potential Risks of Subcutaneous Interferon beta-1a  
Interferon beta-1a was first approved for licensure by the FDA in 1996 for intramuscular injection 
(AVONEX®); a subcutaneous injection was approved in 2002 (Rebif®). Interferon beta-1a is 
indicated for the treatment of patients with relapsing forms of multiple sclerosis and has been 
extensively studied in clinical trials (30, 31).  
In a randomized, double-blind placebo-controlled trial, the most common adverse reactions among 
patients with relapsing multiple sclerosis who received 44 micrograms of subcutaneous interferon 
beta-1a three times per week for two years were depression, headache, influenza-like symptoms 
(e.g., fatigue, fever, rigors, chest pain, back pain, myalgia, arthralgia), abdominal pain, 
lymphadenopathy, leukopenia, transaminitis, and injection site reactogenicity. The most 
frequently reported adverse reactions resulting in clinical intervention (e.g., discontinuation of 
Rebif®, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction) 
were injection site reactions, influenza-like symptoms, depression, and elevation of liver enzymes. 
The influenza-like symptoms typically last for about one day after injection, and the occurrence of 


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these symptoms lessen or go away with time. Additional risks have been described with chronic 
treatment with interferon beta. It is unknown to what degree these risks apply to short term 
treatments, though it should be assumed similar risks exist.  
Interferon beta-1a has been associated with worsening depression and exacerbating psychotic 
disorders. A study by Patten et al., that reviewed data from 23 clinical trials of subcutaneous 
interferon beta-1a involving 3995 multiple sclerosis patients found an association between 
depression and interferon use during the first 6 months of therapy (10% of IFN-treated subjects 
versus 8% of placebo recipients) (32). No association was found between interferon treatment and 
suicide attempts. The most consistent risk factor was a prior history of depression. Depressive 
symptoms are common in the early stages of treatment, but typically peak between 4 and 16 weeks 
(33). Prophylactic treatment with antidepressants reduces the risk of IFN-related depression; 
antidepressants also effectively treat the condition (34). In this inpatient study, it is not feasible to 
assess worsening depression and determine relatedness to study product as critical COVID-19 
illness and long-term confinement in quarantine are likely to worsen symptoms of major 
depression. We will inform potential subjects of the risk at the time of informed consent so they 
can determine whether the benefit of participation outweighs the risk of developing depression or 
having pre-existing symptoms of depression worsen. During the study, subjects with pre-existing 
depression or other psychiatric conditions will continue to receive treatment for these conditions 
as clinically indicated.  
Asymptomatic elevation of liver transaminases can occur among those taking interferon beta-1a. 
These effects are generally transient and transaminase levels normalize upon temporary 
discontinuation of Rebif. Severe hepatic injury including hepatic failure has been reported rarely 
in patients taking interferon beta-1a. In ACTT-3, we will mitigate risk of liver injury by excluding 
patients with elevated AST and/or ALT from participating in the study. For those enrolled, we will 
monitor liver transaminase levels and hold subcutaneous injections when ALT and/or AST >5 
times upper limits of normal. Lastly, we will discontinue subcutaneous injections if subject 
develops symptomatic drug-induced liver injury and/or ALT and/or AST >8 times the upper limits 
of normal.  
Decreased peripheral blood counts have been described among those treated with interferon beta-
1a including leukopenia, thrombocytopenia, neutropenia, lymphocytopenia, and anemia. We will 
mitigate the risk to the subject by limiting participation based on platelet count and WBC count at 
time of screening and actively monitoring the WBC count, differential, and hemoglobin. 
Subcutaneous injections will be held if the subject develops severe leukopenia and/or 
thrombocytopenia. 
Cases of thrombotic microangiopathy (TMA) including thrombotic thrombocytopenic purpura 
(TTP) and hemolytic uremic syndrome have been reported with interferon beta products, including 
Rebif® (35). Some of these cases have been fatal. Cases have been reported several weeks to years 
after starting interferon beta. These adverse reactions have been identified during post-approval 
use of Rebif®. Because these events are passively reported from a population of uncertain size, it 
is not possible to reliably estimate their frequency or relationship to the drug. While the diagnosis 
of TMA may be difficult in hospitalized COVID-19 patients, safety laboratory monitoring will 
enable detection of the characteristic clinical features of TMA including thrombocytopenia, 
microangiopathic hemolytic anemia, and acute kidney injury. The principal treatment of drug-
induced TMA is withdrawal of the suspected drug so subcutaneous injections will be discontinued 


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if clinical signs and symptoms and laboratory findings consistent with TMA are detected. Cases 
will be managed as clinically indicated.  
New or worsening autoimmune disorders have been described including systemic lupus 
erythematosus and autoimmune hepatitis. These adverse reactions have been identified during 
post-approval use of Rebif®. Because these events are passively reported from a population of 
uncertain size, it is not possible to reliably estimate their frequency or relationship to the drug. As 
the risk of COVID-19 is likely larger than these risks, subjects with autoimmune disorders are 
permitted to participate in the study. All potential subjects will be informed of the risk for 
autoimmune diseases worsening or the development of a new autoimmune disorder at the time of 
informed consent. 
Seizures have been temporally associated with interferon beta in clinical trials and post-marketing 
surveillance. It is not known if the events were related to multiple sclerosis, the active drug, or a 
combination of both. According to the package insert, a relationship between occurrence of 
seizures and the use of Rebif® has not been established. The subcutaneous injections (interferon 
beta-1a/placebo) will be discontinued if subject has a seizure that is not attributable to COVID-19, 
a medical complication associated with COVID-19, or other medical condition. 
In clinical trials, the majority of subjects who received Rebif® had inflammation at the injection 
site. Other less common adverse reactions associated with subcutaneous interferon beta-1a 
included necrosis, atrophy, edema and hemorrhage at the injection site. During the study, we will 
alternate the injections site and monitor for signs of local reaction.  
Rebif® contains albumin derived from human blood. Because of this, patients who have a history 
of hypersensitivity to human albumin will not be allowed to participate in the study. In addition, 
patients with a history of hypersensitivity to natural or recombinant interferon or any other 
component of the formulation will not be allowed to participate. Anaphylaxis is a rare complication 
and allergic reactions including skin rash and urticaria can also occur. If a subject develops 
anaphylaxis that is temporally related to subcutaneous injection, the injections will be 
discontinued. 
Data from a large population-based cohort study, as well as other published studies over several 
decades, have not identified a drug-associated risk of major birth defects with the use of interferon 
beta during early pregnancy. Findings regarding a potential risk for low birth weight or miscarriage 
with the use of interferon beta in pregnancy have been inconsistent. However, interferon beta may 
cause harm to the fetus based on animal reproduction studies. While no teratogenic effect on fetal 
development were observed in pregnant non-human primates (NHP) given interferon beta-1a at 
100 times the recommended weekly human dose based on a body surface area comparison, 
abortifacient effects were observed in NHPs after three to five doses were administered at this 
level. There are no adequate and well-controlled studies with interferons in pregnant women to 
determine if interferon can cause miscarriage in humans. Because of this, pregnant women will 
not be allowed to participate in the study. 
 
It is not known whether interferon beta-1a is excreted in human milk. Because of the potential of 
serious adverse reactions in nursing infants, lactating women will need to agree to discard breast 
milk from Day 1 to three weeks after the last study product is given.  


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See package insert for Rebif® for full discussion of clinical experience and risks.  
 
 
Potential Benefits of Subcutaneous Interferon beta-1a 
Subcutaneous interferon beta-1a 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 Subcutaneous Interferon beta-1a  
In the context of the cumulative knowledge for subcutaneous interferon beta-1a regarding the 
safety profile, the potential to inhibit SARS-CoV-2 replication and favorable distribution in tissues 
including the lungs, the benefit/risk balance for this study is assessed to be favorable. Given what 
we learned from our staged enrollment approach including frequent DSMB safety reviews, as of 
September 4, 2020, patients with an ordinal scale score of 6 at enrollment are not eligible for 
enrollment, and those with an ordinal scale score of 4 or 5 at enrollment who progress to a 6 or 7, 
will have injectable study product discontinued. In this way, we maximize the potential benefit for 
subjects enrolled in ACTT-3 while preventing harm.  
 
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 of RDV+ 
interferon beta-1a compared to RDV + 
placebo, as assessed by time to recovery for 
patients with baseline ordinal score 4, 5 and 6. 
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, but new or increased 
limitation on activities and/or new or 
increased requirement for home oxygen; 
• Not hospitalized, no limitations on 
activities. 
Recovery is evaluated up until Day 29 (+ 6 
days). 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
Key Secondary  
 
To evaluate the clinical efficacy of RDV+ 
interferon beta-1a compared to RDV + 
placebo, as assessed by clinical status (8-point 
ordinal scale) at Day 15 for patients with 
baseline ordinal score 4 and 5. 
 
 
 
• 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, but new or increased 
limitation on activities and/or new or 
increased requirement for home oxygen; 
• Not hospitalized, no limitations on 
activities. 
To evaluate the clinical efficacy of RDV+ 
interferon beta-1a compared to RDV + 
placebo, as assessed by time to recovery for 
patients  with a baseline ordinal score of 4 and 
5. 
 
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, but not requiring 
supplemental oxygen and– no longer 
requires ongoing medical care; 
• Not hospitalized, but new or increased 
limitations on activities and/or new or 
increased requirement for home oxygen; 
• Not hospitalized, no limitations on 
activities. 
 
Recovery is evaluated up until Day 29 (+ 6 
days). 
Additional Secondary- by baseline severity 
moderate (4 or 5) and severe (6) 
 
To evaluate the clinical efficacy of RDV+ 
interferon beta-1a compared to RDV + 
placebo 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 
 
 
• Laboratory efficacy: 
o d-dimer, and C-reactive protein (CRP) 
over time 
 
 
• 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). 
 
2. To evaluate the safety of RDV+ interferon 
beta-1a compared to RDV + placebo as 
assessed overall, and by baseline ordinal scale 
category (categories 4 and 5 versus category 
6) 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, total bilirubin, 
alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), and 
INR over time (analysis of lab values in 
addition to AEs noted above). 
 
 
 
 
• SAEs 
• Grade 3 and 4 AEs  
• WBC count with differential, 
hemoglobin, platelets, creatinine, total 
bilirubin, ALT, AST, and 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 RDV+ 
interferon beta-1a compared to RDV + 
placebo 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. 
 
 
 
 
 
 
• Qualitative and quantitative polymerase 
chain reaction (RT-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). 
 
• Deep sequencing of the SARS-CoV-2 
virus for those subjects with sustained 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
• 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. 
 
viral shedding (to be defined after 
qualitative PCR results are available)_ 
 
• Qualitative and quantitative PCR for 
SARS-CoV-2 in blood on Day 1; Days 3, 
5, 8, and 11 (while hospitalized). 
 
To define immunophenotype of subjects most 
likely to benefit from interferon beta-1a by 
analyzing markers of inflammation, 
transcriptomics, epigenetics and cell 
populations. 
• Proteomic analysis of cytokines, markers 
of inflammation, and other circulating 
proteins Day 1; Days 3, 5, 8, and 11 
(while hospitalized) and Day 29 
• Additionally, in a subset of subjects: 
o Transcriptomic analysis of RNA in 
whole blood and individual immune 
cells on Days 1, 3, 8 and 29 
o Analysis of interferon-stimulated-
gene (ISG) expression levels on 
Days 1, 3, 8 and 29 
o Assessment of T-cell and innate 
immune cells subpopulations in 
PBMCs on Days 1, 3, 8 and 29 
o Epigenetic modifications based on 
analysis of DNA extracted from 
PBMCs on Days 1 and 29 
 
 
 
4. 
STUDY DESIGN 
4.1 
Overall Design 
ACTT-3 will evaluate the combination of subcutaneous interferon beta-1a and remdesivir 
compared to remdesivir plus placebo. 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 call, home visit 
or remote telehealth procedure as per institutional standards. If the Day 15 and 29 visits are 
conducted by phone or remotely, only clinical data will be obtained (i.e., no specimens collected). 
The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone 


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or remote telehealth procedure unless the subject is still hospitalized at Day 22 and then the visit 
is conducted in person.  
 
The primary outcome is time to recovery by Day 29. Recovery is defined by discharge from the 
hospital (i.e., ordinal scale categories 1 or 2) or subject is still hospitalized, but not requiring 
supplemental oxygen and no longer requires ongoing medical care (category 3). See table above 
in Section 3 for more details.  
4.2 
Scientific Rationale for Study Design 
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. 
 
The ACTT-3 design will specifically evaluate the contribution of interferon beta-1a antiviral and 
immunomodulatory effect in combination with remdesivir while the control arm will receive the 
monotherapy with remdesivir plus placebo.  
 
4.3 
Justification for Dose 
 
Justification for Dose of Remdesivir 
The dose of remdesivir used in this study will be the same dose used in ACTT-1 and ACTT-2 and 
that is available under the EUA, with updates on duration of therapy and dosing for patients with 
low eGFR to reflect the wording in the EUA. The duration of dosing may be adjusted by the site 
similar to what is described in the EUA. The maximum number of doses to be given during 
hospitalization is ten doses. This includes the loading dose and all maintenance doses given during 
the study and pre-study if applicable. 
 
 
Justification for Dose of Subcutaneous Interferon beta-1a  
We will be administering a subcutaneous 44 mcg dose of Rebif® (interferon beta-1a) every other 
day for 4 doses while a subject is hospitalized. This is the dose that has been used in other COVID-
19 clinical trials including the World Health Organization’s Solidarity Trial.  
 
Interferon beta has a bioavailability of about 30% after subcutaneous or intramuscular 
administration, demonstrating peak serum concentrations within several hours of a dose (36). 
Serum levels of interferon beta-1a typically peak 3 to 15 hours after intramuscular administration. 
After injection, it is absorbed mainly in the lymphatics. Interferon beta is distributed throughout 
the body, and likely does not cross the blood-brain barrier. It is unclear whether interferon beta 
crosses the placenta. Interferon beta is excreted by hepatic and renal pathways. In healthy 
volunteers, a single subcutaneous injection of 60 mcg of Rebif® resulted in a peak serum 
concentration (Cmax) of 5.1 ± 1.7 IU/mL (mean ± SD), with a median time of peak serum 
concentration (Tmax) of 16 hours. The serum elimination half-life (t1/2) was 69 ± 37 hours. 


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Following every other day subcutaneous injections, an increase in AUC of approximately 240% 
was observed, suggesting that accumulation of interferon beta-1a occurs after repeat 
administration. Total clearance is approximately 33-55 L/hours.  
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 
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 (e.g., NAAT and antigen tests) in any respiratory 
specimen or saliva, as documented by either of the following:  
• PCR or other assay positive in sample collected < 72 hours prior to 
randomization; OR 
• 
PCR or other assay positive in sample collected ≥ 72 hours but < 7 days prior to 
randomization AND progressive disease suggestive of ongoing SARS-CoV-2 
infection. 
Note: if written documentation of the positive test result is not available at enrollment (e.g. 
report from other institution), the subject may be enrolled but the PCR should be repeated at 
the time of enrollment.  
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 
 
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 (both pharmacologic and other types of 
interventions) for the treatment of COVID-19 through Day 29. 
 


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5.2 
Exclusion Criteria 
1. Anticipated discharge from the hospital or transfer to another hospital which is not a 
study site within 72 hours. 
2. Subject meets criteria for ordinal scale category 6 or 7 at the time of screening.  
3. Subject has a positive test for influenza virus during this current hospital admission. 
4. Subjects with an estimated glomerular filtration rate (eGFR) < 30 mL/min are excluded 
unless in the opinion of the PI, the potential benefit of receiving remdesivir outweighs the 
potential risk of study participation. 
5. ALT or AST > 5 times the upper limits of normal. 
6. Total white cell blood cell count (WBC) <1500 cells/µL. 
7. Platelet count <50,000/µL. 
8. History of chronic liver disease (e.g., jaundice, ascites, hepatic encephalopathy, history of 
bleeding esophageal or gastric varices). No laboratory testing is needed.  
9. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day 
1 until three weeks after the last study product is given are not excluded). 
10. Allergy to any study medication including history of hypersensitivity to natural or 
recombinant interferon beta or human albumin. 
11. Patient has a chronic or acute medical condition or is taking a medication that cannot be 
discontinued at enrollment, that in the judgement of the PI, places them at unacceptable 
risk for a poor clinical outcome if they were to participate in the study.  
12. Received three or more doses of remdesivir, including the loading dose, outside of the 
study for COVID-19.  
13. Received convalescent plasma or intravenous immunoglobulin [IVIg]) for the treatment 
of COVID-19. 
14. Received any interferon product within two weeks of screening, either for the treatment 
of COVID-19 or for a chronic medical condition (e.g., multiple sclerosis, HCV infection) 
15. Received any of the following in the two weeks prior to screening as treatment of 
COVID-19: 
• small molecule tyrosine kinase inhibitors (e.g. baricitinib, imatinib, gefitinib, 
acalabrutinib, etc.); 
• monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 
[IL-1], anti-IL-6 [tocilizumab or sarilumab], etc.);  
• monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19 
16. Prior enrollment in ACTT-3 
 
 
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. Interferon beta-1a has not been studied in pediatric patients, 
and no formal trials of Rebif® have been conducted in children or adolescents. 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, this 
research is not known to have the prospect of direct benefit to individual child subjects, and the 
risk/benefits do not warrant inclusion of this population into this trial at this time.  
 


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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. Toxicology studies 
in all tested animal species (rats, mice and monkeys) showed that subcutaneous interferon beta-1a 
was well tolerated both in single-dose and repeat-dose studies. Interferon beta-1a showed no 
evidence of mutagenicity or teratogenicity, however it may have abortifacient potential. Because 
the effects of the study products 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. Similar animal studies 
have not been conducted for Rebif® and it is not known whether subcutaneous interferon beta-1a 
is excreted in human milk. Because the effects of remdesivir and subcutaneous interferon beta-1a 
on the breastfeeding infant is not known, women who are breast feeding will not be eligible for 
the trial unless they agree to discard breast milk produced from Day 1 to three weeks after the last 
study product is given.  
 
5.3 
Inclusion of Vulnerable Subjects 
Certain 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 this clinical trial, we will not enroll 
prisoners or detainees as subjects.  
 
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 or 
studies of SARS-CoV-2 diagnostics are permitted; however, participation in both ACTT 


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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.  
 
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 for hospitalization to participating 
clinical trial sites, 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 (e.g., pregnant, < 18 years of age, chronic liver disease, 
etc.). Information about the study will be presented to potential subjects or LAR and questions will 
be asked to determine potential eligibility. Screening procedures can begin only after informed 
consent is obtained. 
 
 
Retention 
Retention of subjects is critical to the success of the trial since the primary endpoint is measured 
through Day 29 (+ 6-day window) and every effort should be made to retain subjects in the study. 
As such, after hospital discharge, subjects will be reminded of subsequent study visits and every 
effort will be made accommodate the subject’s schedule to facilitate follow-up within the specified 
visit window. However, there are many circumstances impact a site’s ability to obtain outcome 
information after discharge. For example, given the clinical course of COVID-19, a subject may 
be readmitted to another hospital after discharge and therefore be unavailable at Day 15 or Day 
22. Even if a study visit is missed or study product is discontinued, every effort should be made to 
keep subjects in the study to monitor for safety, mortality and ordinal scale at Day 29. Subjects 
should not be withdrawn from the study because a site is unable to contact them for a follow-up 
visit.  
 
Another common lost-to-follow-up scenario during ACTT-1, involved subjects (or their LARs) 
asking that the study products and blood draws be discontinued due to terminal illness. These 
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determination by chart review or phone call. To facilitate retention, follow-up visits may be 
conducted by phone, home visit or remote telehealth procedure as per institutional standards if in-
person visits at the clinical site on Days 15 and 29 are not feasible. Day 22 visit is by phone call 
or remote telehealth procedure. 
 
 
Compensation Plan for Subjects  
Compensation, if any, will be determined locally and in accordance with local IRB requirements 
and 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  
 
Subjects will be randomized into one of two arms (1:1). 
 
 
Arm 1 
Arm 2 
Interferon beta-1a SQ injection + remdesivir IV 
Placebo SQ injection + remdesivir IV 
 
 
Study Product Description  
Remdesivir component: 
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 and solution formulations of remdesivir contain the following inactive ingredients: 
water for injection, SBECD, and hydrochloric acid and/or sodium hydroxide. 
 
Interferon beta-1a /Subcutaneous Placebo component: 
Rebif®, an interferon beta-1a, is a purified 166 amino acid glycoprotein produced by recombinant 
DNA technology using genetically engineered Chinese Hamster Ovary cells into which the human 
interferon beta gene has been introduced. The amino acid sequence of Rebif® is identical to natural 
fibroblast derived human interferon beta.  
 
Rebif® (interferon beta-1a) is formulated as a sterile solution in a prefilled syringe intended for 
subcutaneous injection. Each prefilled syringe contains 0.5 mL of Rebif®. Each 0.5 mL of Rebif® 
will contain 44 mcg of interferon beta-1a, 4 mg human albumin, USP; 27.3 mg mannitol, USP; 
0.4 mg sodium acetate; and water for injection, USP.  


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Placebo subcutaneous injection will be either: 
 Matching empty syringes that will be filled with 0.5 mL 0.9% normal saline at each site 
pharmacy; OR 
 Matching syringes prefilled with 0.5 mL 0.9% normal saline or 0.5 mL sterile water for 
injection.  
 
 
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 up to a 10-day total course while hospitalized. 
Enrollment may proceed for subjects who received one or two doses of remdesivir under EUA or 
similar mechanism prior to randomization. If subjects already received the loading dose, then start 
at 100 mg/day on Day 1. Any doses of remdesivir under an EUA (or similar mechanism) within 1 
week of enrollment will be counted, so the maximum number of remdesivir doses given to a 
subject is 10 (i.e. EUA doses + doses on this trial). 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 subcutaneous interferon beta-1a / placebo component, subjects will receive either active 
product or placebo as follows: 
• Interferon beta-1a will be administered every other day as a 44-microgram subcutaneous 
dose for a total of 4 doses while hospitalized  
• A saline placebo will be administered every other day as a subcutaneous injection for a 
total of 4 doses while hospitalized 
 
Study teams will instruct the administering nurse to use a different site for each subcutaneous 
injection. If there is an injection site reaction including skin that is irritated, edematous, reddened, 
bruised, or necrotic, the study product should not be administered into the affected area. If possible, 
select a unique site for each subsequent injection. 
 
Dosing of the two medications does not need to occur at the same time. 
 
Duration of therapy: 
• IV remdesivir – up to 10 consecutive days while hospitalized (i.e., maximum of 10 total 
infusions pre-enrollment and during study). 
• Subcutaneous (Interferon beta-1a or placebo) component – Days 1, 3, 5, and 7, while 
hospitalized.  
• Both stop on discharge from hospital. If readmitted after discharge, see Section 7.4. 
 
 
Dose Escalation 
Not Applicable 
 
 
Dose Modifications 


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The protocol-required safety laboratories (per the SOA) are anticipated to be sufficient for 
evaluating for dose modifications, but if other laboratory data obtained as part of standard care are 
available, these should also be used in the evaluation.  
 
Remdesivir component: 
The infusion should be held and not given if the subject is found to have any of the following 
laboratory values: 
 
• eGFR decreases to < 20 mL/min 
o Remdesivir infusion will be held until the eGFR increases to a point that the potential 
benefit of giving remdesivir outweighs the potential risk. Note: this is consistent with 
the FDA Fact Sheet instructions for Health Care Providers, US EUA of Veklury® 
(remdesivir): “Veklury is not recommended in adult patients with eGFR less than 30 
mL/min…unless the potential benefit outweighs the potential risk”. 
• ALT and/or AST increases to > 5 times upper limits of normal (ULN) 
o Remdesivir infusion will be held and not be restarted until the ALT and AST ≤ 5 
times ULN. 
 
Interferon beta-1a /Subcutaneous Placebo component: 
The subcutaneous injection should be held and not given if the subject is found to have any of 
the following laboratory values: 
 
• ALT and/or AST increases to > 5 times ULN 
o Subcutaneous injection will be held and resume when ALT and AST ≤ 5 times ULN.  
• Total white cell blood cell count (WBC) <1000 cells/µL 
o Subcutaneous injection will be held and resume when WBC ≥1000 cells/ µL 
• Platelet count <25,000/µL 
o Subcutaneous injection will be held and resume when platelet count ≥ 25,000/µL. 
 
Any dose that is held as described above, may be given later that day if the laboratory parameters 
improve. Any dose that is missed during the study due to any reason is not made up. The treatment 
course continues as described above even if the subject becomes PCR negative while hospitalized.  
 
For laboratory values that meet permanent discontinuation thresholds (see Section 7.1), 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 
Overdose is not anticipated in the context of a clinical trial. Subjects will be given the 
subcutaneous injection every other day and daily infusions of remdesivir. No study product will 
be given after hospital discharge. 
 
6.2 
Preparation/Handling/Storage/Accountability 


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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. 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 
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 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 
Remdesivir may be supplied in two formulations: 
• 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. 


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• The concentrated solution is supplied as a single dose vial containing 100 mg/20 mL (5 
mg/mL) of remdesivir per vial for dilution into 0.9% sodium chloride infusion bag. It is a 
sterile, preservative-free, clear, colorless to yellow, aqueous-based concentrated solution 
that is to be diluted into 0.9% sodium chloride infusion bag prior to administration by 
intravenous infusion. Remdesivir injection, 100 mg/20 mL (5 mg/mL), is supplied in a 
single-dose clear glass vial. For more information, refer to the MOP and EUA Fact Sheet. 
 
Remdesivir will be labeled according to manufacturer specifications. 
 
Subcutaneous Interferon beta-1a component 
 
Rebif® (interferon beta-1a) is formulated as a sterile solution. It is supplied as a prefilled syringe 
intended for subcutaneous injection. Each prefilled syringe contains 0.5 mL of Rebif®. Each 0.5 
mL of Rebif® will contain 44 mcg of interferon beta-1a, 4 mg human albumin, USP; 27.3 mg 
mannitol, USP; 0.4 mg sodium acetate; and water for injection, USP.  
Subcutaneous placebo component 
Placebo will match the active product in appearance. Placebo subcutaneous injection is 0.9% 
normal saline. The placebo will be supplied as either: 
 Matching empty syringes that will be filled with approximately 0.5 mL 0.9% normal 
saline at each site pharmacy; OR 
 Matching syringes prefilled with 0.5 mL 0.9% normal saline or 0.5 mL sterile water for 
injection.  
 
Study products will be supplied by the sponsor or its designee in accordance with current Good 
Manufacturing Practice (cGMP). 
 
 
Product Storage and Stability 
The MOP provides instructions for the preparation, handling, and storage of remdesivir. The 
MOP describes site responsibility and accountability for the administered products. Interferon 
beta-1a drug product will be described in the package insert. See most recent version of package 
insert posted on the Emmes website. 
 
 
Preparation 
Refer to the protocol-specific MOP for details about preparation.  
 
Remdesivir is not considered a hazardous drug as defined by NIOSH 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 
Package Insert.  
 


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For Rebif® (interferon beta-1a) it is supplied as a close system and therefore no specific handling 
is required. See MOP for preparing Placebo for Rebif. 
 
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 Hospitalized, requiring supplemental oxygen, or 
o Hospitalized, not requiring supplemental oxygen. 
 
Note: Category 7 (hospitalized, on invasive mechanical ventilation/ECMO) and Category 6 
(hospitalized, on non-invasive ventilation or high flow oxygen devices) are not eligible for 
enrollment. See description of recommendations made by the DSMB on September 4, 2020 
below. 
 
The randomization procedure will be described in the MOP.  
 
There was the hypothetical concern that interferon may worsen the pro-inflammatory state seen in 
COVID-19 late in the clinical course of the disease. For this reason, enrollment was staged based 
on severity of disease.  
 
• For the first 2 weeks of the study, enrollment was limited to non-intubated, hospitalized 
COVID-19 patients who meet all eligibility criteria (i.e., patients with baseline ordinal 
scale score of 4, 5 or 6).  
• On September 4, 2020, the DSMB met for an interim safety review of the ACTT-3 data. 
After their review, they notified NIAID that their recommendation was to close further 
enrollment to patients with a baseline ordinal score of 6. The DSMB noted there was no 
increase in mortality in this group, but that the risk/benefit in this group did not warrant 
further enrollment. Specifically, it was recommended by the DSMB:  
o No further enrollment of subjects with ordinal score of 6 at time of randomization. 
o Do not enroll subjects with ordinal score of 7 at time of randomization 
o Continue to enroll patients with a baseline ordinal score of 4 and 5.  
• Furthermore, the DSMB recommended: 
o Subjects currently enrolled who have an ordinal score of 6, should not be given any 
more study injections (interferon/placebo) for the remainder of the study.  
o Subjects enrolled as a baseline ordinal 4 or 5 and remain as ordinal 4 or 5, should 
continue to receive study injections (interferon/placebo) and remdesivir per 
protocol.  
o If a subject is enrolled as a baseline ordinal 4 or 5 and progresses to ordinal 6 or 7, 
the study injections (interferon/placebo) should be discontinued for the remainder 
of the study. In this case, the remdesivir infusions would continue per protocol. 


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Importantly, all subjects should remain in the study and followed through day 29 
in accordance with the protocol. 
 
 
Blinding and Masking Procedures 
As both arms are receiving remdesivir, the remdesivir product is not blinded and study infusions 
can be labeled accordingly.  
 
The subcutaneous interferon beta-1a/matching placebo component is blinded. Interferon beta-1a 
and placebo will be 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.  
Treatment group-level unblinded analyses of subjects randomized in ordinal score category 6 
may be conducted and published prior to the end of the trial to communicate the safety signal 
observed in this group by the DSMB during a safety review. If this analysis is conducted, only 
members of the unblinded analysis team will have access to subject-level treatment data while 
the study is ongoing; all other members of the study group will remain blinded to individual 
subject treatments as originally planned.  
 
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. 
 
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 at 
screening to determine eligibility as described in the exclusion criteria. Exclusionary medications 
include the receipt of convalescent plasma or intravenous immunoglobulin [IVIg]) for the 
treatment of COVID-19. It also includes small molecule tyrosine kinase inhibitors (e.g., baricitinib, 
imatinib, gefitinib, acalabrutinib) or monoclonal antibodies targeting cytokines (e.g., TNF 
inhibitors, anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab]), or T-cells or B-cells, 
taken in the two weeks prior to screening for the treatment of COVID-19. Lastly, those who 
received interferon within 2 weeks of screening either for the treatment of COVID-19 or for a 
chronic medical condition (e.g., multiple sclerosis, HCV infection) will not be eligible for the 
study. 
 


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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.  
 
Medications used for other non-COVID-19 diseases that also are claimed to be treatments for 
COVID-19, do not need to be discontinued at the time of enrollment. Examples would include 
lopinavir/ritonavir for HIV, hydroxychloroquine for lupus, etc. The disease being treated is 
important: if used as an off-label medication for COVID-19 treatment, they are prohibited; if used 
for non-COVID-19 diseases, they are allowable.  
 
 
Prohibited Concomitant Therapy 
A subject cannot participate in another clinical trial for the treatment of COVID-19 until after Day 
29 (see exclusion criteria).  
 
Once enrolled, concomitant medications for the treatment of COVID-19 as described in written 
policy or guideline (i.e., not just an individual clinician decision) are permitted. In the absence of 
a local written standard of care, the National Institutes of Health (NIH) COVID-19 Treatment 
Guidelines may be used (https://www.covid19treatmentguidelines.nih.gov/). This includes anti-
inflammatory medications such as dexamethasone and convalescent plasma. 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, and not specified in the local or NIH COVID-
19 Treatment Guidelines are prohibited. Specifically, use of any biologic therapy not specified on 
the written policy or guideline are prohibited including: 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) (e.g., baricitinib, imatinib, gefitinib, 
acalabrutinib); and any type of interferon, convalescent plasma, or immunoglobulin (IgG) 
therapies for COVID-19. Similarly, the concomitant use of hydroxychloroquine to treat COVID-
19 is prohibited unless it is included in the local institutional treatment guidelines.  
 
On August 23, 2020, the FDA issued an EUA for COVID-19 convalescent plasma for the treatment 
of hospitalized patients with COVID-19.  The NIH COVID-19 Treatment Guidelines were updated 
on September 1, 2020 and concludes that “there are insufficient data to recommend either for or 
against the use of convalescent plasma for the treatment of COVID-19”.  According to the NIH 
Guidelines and the EUA Fact Sheet for Health Care Providers, convalescent plasma should not be 
considered the standard of care for the treatment of patients with COVID-19.  However, if a site 
has adopted convalescent plasma as part of their institutional standard of care for the treatment of 
COVID-19 patients, it is allowed as described above. 
 
Concomitant medications will be assessed from 7 days prior to enrollment to Day 29 or upon 
discharge, whichever comes first. All prescription medications should be recorded during this 


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time period with the exceptions listed in the bullets below. All medications, except biologics and 
corticosteroids, can be recorded once regardless of the number of times it was given during the 
time period. For example, vasopressors should be recorded when first dose given (as the start 
date) and the last dose given (as the end date) during the period of assessment.  
 
Sites do not need to record any of the following categories of medications in the eClinical system 
during the period from Day -7 through Day 29: 
o All topical medications: ointments, creams, and lotions; 
o All intranasal medications: nasal decongestants, nasal allergy medications, nasal steroids, 
and nasal saline drops/sprays;  
o All ophthalmic medications: ophthalmic allergy medication, ophthalmic medications for 
infection, and ophthalmic medications for eye dryness (e.g., saline eye drops); 
o Antiseptic mouth wash, lozenges; 
o Cough medication: mucolytics, cough suppressants, and expectorates; 
o GI medications: H2 blockers, proton pump inhibitors, GI stimulants, prokinetics, laxatives, 
stool softeners, antacids, anti-diarrheal and anti-nausea medications; 
o Insulin and medications for diabetic control; 
o Symptomatic care medications: antipyretics, antihistamines, decongestants, and NSAIDs;  
o Vitamins, minerals or herbal supplements, dietary supplements, iron/ferrous sulfate, 
magnesium, calcium, electrolyte replacement; 
o Albumin infusions; 
o Melatonin; 
o Nicotine patch, lozenge, gum, or nasal spray, or other product to treat tobacco dependence; 
o Dyes: iodine – based dye, barium sulfate, and diatrizoate sodium. 
 
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 
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. 


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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 through Day 29. 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 and followed through Day 29. The reason for subject discontinuation of study drug(s) should 
be documented in the case report form. 
 
 
Remdesivir Halting 
See Section 6.1.4. for information about dosing modifications due to laboratory abnormalities. 
For an individual subject, remdesivir infusions must be stopped if they have a suspected drug-
related event of hypersensitivity (Grade 2 or higher) during or shortly after receiving 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 the infusion stopped for a Grade 2 or higher allergic reaction that 
is temporally associated with the infusion and the PI believes it to be related to study product will 
not receive any more remdesivir. 
 
 
Subcutaneous Interferon beta-1a and Placebo Injections Halting 
See Section 6.1.4. for information about dosing modifications due to laboratory abnormalities. 
The subject should not receive any additional subcutaneous injections for the remainder of the 
study if a subject develops any of the following conditions during the study:  
 
• Disease progresses to the point that the subject requires high-flow oxygen or other non-
invasive ventilatory support (i.e., a category 6 on ordinal scale) or mechanical ventilation 
or ECMO (category 7). Note: even if they improve to a category 4 or 5 before study Day 
7, no additional subcutaneous injections will be given. 
• Anaphylaxis temporally associated with subcutaneous injection 
• Seizures not attributable to COVID-19, a medical complication of COVID-19 or another 
medical condition 
• Thrombotic microangiopathy including thrombotic thrombocytopenic purpura and 
hemolytic uremic syndrome thought to be due to interferon beta-1a  
• ALT or AST >8 times ULN 
• Suspected drug-induced liver injury with symptomatic disease (i.e., jaundice, right upper 
quadrant pain or tenderness, fatigue, nausea, vomiting, etc.) 
 
 
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.  


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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 or safety assessment. 
  
The investigator may also withdraw a subject from the study. However, the investigator will be 
encouraged to allow subjects to remain in the study to be followed for safety and final outcome 
assessment at Day 29 (i.e., the ordinal scale and mortality) even if they decide to discontinue 
study products and research laboratory draws. Withdrawing a subject from the study due to an 
inability to contact them for the Day 15 and/or Day 22 follow-up visit is discouraged given the 
possibility of readmission and chaotic social circumstances resulting from the pandemic. 
 
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 the site is unable to contact him or her by phone 
or other means such as text, email, fax or letter (as approved by the IRB) for all follow-up 
assessments at Day 15, 22 and 29. 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 11, they may be given 
the remainder of the remdesivir infusions and if prior to Day 8, they may be given the remainder 
of the subcutaneous injections. If the subject did not withdraw 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.  
 
The natural history of COVID-19 and its impact on pre-existing medical conditions is not 
completely understood. Because of this, all readmissions, regardless of reason, should be 
documented and the subject should get daily clinical status assessments (i.e., ordinal scale and 
NEWS) and other procedures done as per the SOA upon readmission. 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. No 


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subcutaneous injection should be given past Day 7. For all data collection procedures required for 
those readmitted, please see the MOP.  
 
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 
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 chronic medical conditions, including chronic liver disease and chronic 
oxygen requirement. This includes use of continuous positive airway pressure 
(CPAP) ventilatory support at night and oxygen by nasal cannula at home or nursing 
home prior to onset of COVID-19. See conditions included on the Medical History 
(CMX) data collection form. 
• History of medication allergies including history of hypersensitivity to natural or 
recombinant interferon, human albumin, or any other component of the interferon 
beta-1a formulation. 
• 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: 
 ALT and AST 
• Assess if ALT or AST > 5 times ULN 
 WBC  
• Assess if WBC <1500 cells/µL 
 Platelet count 
• Assess if platelet count <50,000/µL  
 Creatinine (and calculate eGFR).  
• Any automated calculation by the clinical laboratory or published formula for the 
calculation of eGFR 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). See instructions below 
for women who are less than 6 weeks postpartum: 
 Do not do a pregnancy test if the patient is post-partum and has not left the hospital 
since delivery. The pregnancy test will likely give a false-positive result as serum 
human chorionic gonadotropin (hCG) is usually detected for up to 4 to 6 weeks after 
delivery. 
 For women who are less than 6 weeks postpartum and have left the hospital, any 
positive pregnancy test should be repeated to determine if the HCG is declining as 
predicted after delivery and therefore the result is a false-positive. Of note, women who 
are less than 6 weeks postpartum and have had heterosexual intercourse since delivery 
and hospital discharge are unlikely to be pregnant because the average time to first 
ovulation varies from 45 to 94 days postpartum, with the earliest reported ovulations at 
25 and 27 days postpartum.  
 
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. A screening lab (i.e., from the 
hematology and chemistry laboratory panels) may be repeated once if, in the opinion of the 
investigator, the laboratory abnormality is due to an intercurrent transient condition or it is an 
aberrant laboratory value.  
 
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 


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administration including the collection of OP swab and blood and completing or recording a 
baseline physical examination that was done. Clinical laboratory tests collected as part of routine 
care of the patients in the 36 hours prior to first dose qualify for baseline safety tests on Day1. 
 
 
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, which is largely measured by the ordinal scale and NEWS, will be 
captured on each study day while hospitalized through Day 29 (+ 6-day window) or day after death 
whichever comes first. The ordinal scale will also be captured on the day after discharge from the 
hospital. This will be done so that discharge and death are accurately recorded and captured in the 
eClinical system. For subjects who received oxygen by nasal cannula or CPAP ventilatory support 
at night at home prior to having COVID-19, sites should assign a recovery ordinal scale score of 
1 or 2 when discharged to home after recovery. The assignment of category 1 versus category 2 
will depend on whether they have new or increased physical limitations post-COVID-19 and/or if 
they have new or increased home oxygen requirement compared with the pre-COVID-19 time 
period.  
 
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, an ordinal scale 
assessment should be completed for the day after death because the ordinal scale captures the worst 
clinical assessment for the previous day. If a subject dies within the window of the final study visit 
(i.e., Day 29 + 6-day window), complete an ordinal scale assessment on the day after death.  
 
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, home visit or remote telehealth procedure as per 
institutional standards if an in-person visit at the clinical trial site is not possible. Clinical status 
will also be captured on Day 22 during a phone call or remote telehealth visit. Unlike the NEWS, 
the ordinal scale can also be evaluated over the phone or by a remote telehealth procedure if the 
discharged subject is unable to return to the clinical trial site for visits on Day 15 and 29 as well 
as on Day 22.  
 
Except for 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. 


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• ECMO requirement. 
• Ongoing medical care preventing hospital discharge (COVID-19 related or other medical 
conditions). 
• Limitations of physical activity (self-assessed and reported as new or increased 
limitations as compared to status prior to the onset of COVID-19). 
• 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), and categories 1, 2 and 3 represent recovery for a subject: 
 
Category 8: Death; 
Category 7: Hospitalized, on invasive mechanical ventilation or ECMO; 
Category 6: Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
Category 5: Hospitalized, requiring supplemental oxygen; 
Category 4: Hospitalized, not requiring supplemental oxygen – requiring ongoing 
medical care (COVID-19 related or otherwise); 
 
Category 3: Hospitalized, not requiring supplemental oxygen – no longer requires 
ongoing medical care; This would include those kept in hospital for quarantine/infection 
control, awaiting bed in rehabilitation facility or homecare, etc. 
 
Category 2: Not hospitalized, but new or increased limitation on activities and/or 
requiring new or increased home oxygen; 
 
Category 1: 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 
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 


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of the final study visit (i.e., Day 29 + 6-day window), 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) 
The NEWS has demonstrated an ability to discriminate subjects at risk of poor outcomes. (Smith, 
2016). The NEWS is being used as an efficacy measure in this study (Table 2). The score is based 
on seven clinical parameters including temperature, systolic blood pressure, heart rate, respiratory 
rate, oxygen saturation, and level of consciousness. The NEWS should be evaluated daily while 
hospitalized and on Days 15 and 29, and can be performed concurrently with the ordinal scale.  
The NEWS and ordinal scale should be evaluated at approximately the same time each study day 
for an individual subject and just prior to the expected infusion time. The seven parameters can be 
obtained from vital signs collected as part of the standard of care and documented in the hospital 
chart or electronic medical record. The last measurement prior to the time of assessment (including 
parameters collected prior to the time of consent) should be recorded. 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. 
 
For details about collection of NEWS, refer to the MOP. 
 
 Table 2. National Early Warning Score (NEWS) 
 
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. 


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Exploratory Assessments and Secondary Research Samples 
The schedule of assessments (SOA, Section 1.2) lists the collection timepoints for specimens for 
both exploratory endpoints and for secondary research.  Sites may opt out of specimen collection 
for secondary research; only serum is collected for secondary research.  Subjects will be consented 
for genetic testing for the second exploratory endpoint. Sites will draw blood (via PAXgene tube) 
for subjects who consent to genetic testing, and at selected sites, blood will be drawn for peripheral 
blood mononuclear cells (PBMC) collection for these consenting subjects.  Proteomic (cytokines 
and other protein) analysis will be done for all subjects using plasma drawn per the schedule 
outlined in the SOA. In some cases, serum may be substituted for plasma for cytokine analyses 
(upon approval by the Sponsor). Data from exploratory assessments may not be submitted as part 
of the primary Clinical Study Report (CSR) for this trial. The data may be submitted separately as 
one or more addenda to the primary CSR. 
 
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 plasma   
• 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 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.  
 
Whole blood for transcriptomics analysis and interferon-stimulating-gene (ISG) analysis 
• Subjects who consent to genetic testing will have a whole blood sample (~2.5 mL in 
PAXgene tube) 
• These samples will be tested in a central laboratory, not locally. 
 


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Blood for PBMCs 
• Some subjects who consent to genetic testing will have blood for PBMCs collected. This 
will occur only at select clinical trial sites. 
• PBMCs  will be tested in a central laboratory, not locally 
 
Blood for serum (for secondary research) 
• If the samples can be processed 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.  
 
 
SARS-CoV-2 Virology Exploratory Assessment 
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 Day 29; and only OP swabs and serum 
on Day 15 (if attends an in-person visit or still hospitalized). Samples are stored as outlined in the 
MOP. Virologic assessments may include PCR or other nucleic acid tests for duration of viral 
RNA, viral load determination and/or the emergence of antiviral resistance.  
 
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.  
 
 
Immunophenotyping Exploratory Assessment  
As outlined in the SOA, blood will be collected for a plasma proteomic analysis of cytokines, 
chemokines, markers of inflammation, and other circulating proteins; whole blood (PAXgene 
tubes) for a transcriptomic analysis of RNA and interferon stimulated gene (ISG) analysis; and 
whole blood PBMCs for an epigenetic analysis and a T cell and innate immune cell phenotyping 
assessment. Samples will be collected, processed and stored as described in the MOP. Only select 
sites will collect and process PBMCs. All sites should collect PAXgene tube for subjects 
consenting to have their samples used for the targeted genetic analysis. If a BSL-3 environment is 
needed for processing of these samples, or if samples cannot be shipped to a central laboratory, 
these samples may be omitted and the omission documented each time omitted.  
 
Blood for plasma for proteomic analysis 
• An aliquot of the collected plasma will be analyzed for cytokines, chemokines, markers of 
inflammation and other circulating proteins on Days 1, 3, 5, 8 and 11 and Day 29 (see SOA 
for details). This blood volume is not an additional 0.5 mL but considered as part of the 8 
mL plasma taken on these days.  
• A subset will have the sample processed using a high-throughput proteomic assay. The 
remainder of subjects will have their samples processed using an antibody-based assay for 


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cytokines.  
 
Whole blood for transcriptomics analysis and ISG analysis 
• Subjects who consent to genetic testing will have a whole blood sample (~2.5 mL in 
PAXgene tube) analyzed using an RNA sequencing assay (RNA-Seq, Illumina). 
Transcriptomics and ISG analysis will be done on Days 1, 3 and 8, and Day 29 (if attends 
in-person visit or still hospitalized) (See SOA for details). 
• Subjects who consent to genetic testing and are discharged prior to Day 8 and therefore 
miss the PAXgene tube collection at Day 8, this sample will be drawn at Day 15. If the 
subject is discharged prior to Day 11 and they miss the Day 11 blood collection, they will 
have blood for plasma proteomic assessment drawn at Day 15.  
• Analysis may include, but not limited to the following assessments depending on the 
sample quality and quantity: 
• Cellular transcriptional activity in immune cell subsets as analyzed by RNA-seq 
or microarrays;  
• Whole blood transcriptome as analyzed by RNA-seq; 
• Single-cell transcriptome as analyzed by RNA-seq or CITE-seq. 
• Description of blood collection in PAXgene tubes for RNA are provided in the MOP. 
 
Blood of PBMCs 
• Some subjects who consent to genetic testing will have blood for PBMCs collected. This 
will occur only at select clinical trial sites. PBMCs will be used to do T-cell and innate 
immune cell phenotyping using samples from Days 1, 3 and 8, and Day 29 and epigenetics 
using Day 1 and Day 29 samples.  
• If a subject is discharged prior to Day 8, this sample will be drawn at Day 15.  
• Description of blood collection in CPTs and processing of blood for PBMCs are provided 
in the MOP. 
• Analysis of PBMCs may include, but not limited to the following assessments depending 
on the sample quality and quantity: 
• PBMC transcriptome as analyzed by RNA-seq; 
• Frequency of leukocytes (to include lymphocyte subsets) in peripheral blood as 
analyzed by complete blood count (CBC) with differential and clinical and 
research flow cytometry; 
• Cellular chromatin accessibility in immune cell subsets as analyzed by the assay 
for transposase-accessible chromatin using sequencing (ATAC-seq); 
• Serum antibody titers; and  
• Additional “omics” assays for assessing immune receptor repertoires, profiling 
molecular states in cells or for quantifying the relative abundance of circulating 
molecules to assess the state of the immune system, or characterizing the 
microbiome in healthy volunteers. 
 
Proposed Timing of Samples for Immunophenotyping Exploratory Objective  
The estimated peak of pathological inflammation is 21 days post-symptom onset. In ACTT-3, 
patients are not enrolled until 7 to 10 days post-symptom onset. For this reason, we propose 


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samples be taken Days 1, 3 and 8 (or if discharged prior to Day 8 then blood is drawn at Day 
15) and then at Day 29.See Table 2 for projected blood volumes for PAXgene and PBMC 
sample collection.  
 
 
Table 3. Blood Volume for Subjects Consenting for Genetic Testing Involving PAXgene 
and PBMC Collection 
Study 
Day 
Transcriptomics and ISG analysis 
Cell Phenotyping and Epigenomics* 
1 
2.5 mL blood, PAXgene blood RNA 
tube 
 
25.5 mL blood in 3 Cell Preparation Tube 
(CPT) 
3 
2.5 mL blood, PAXgene tube 
None 
5 
None 
None 
8 
2.5 mL blood, PAXgene tube 
25.5 mL blood in 3 CPT 
11 
None 
None 
15 
None (unless missed Day 8) 
None (unless missed Day 8) 
29 
2.5 mL blood, PAXgene tube 
25.5 mL to 42.5 mL blood in 5 CPTs 
*Epigenetic analysis done using PBMC sample and only done using the Day 1 and Day 29 samples. 
 
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. 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 count, differential, hemoglobin, 
platelet count, creatinine, total bilirubin, AST, ALT, and INR. C-reactive protein 
and d-dimer are not safety laboratory tests but will be collected at the same time 
as the safety labs.  
• 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. See SOA for details. 


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• Clinical laboratory testing will be performed at each clinical trial site in real time.  
 
Table 4a. Venipuncture Volumes for Subjects NOT Consenting for Genetic Testing 
Involving Transcriptomics and Complete Immunophenotyping Analysis 1 
 
Screen 
Baseline 
 
 
 
 
 
 
Day +/- Window 
−1 to 1 
1 ± 1 
3 ± 1 
5 ±1 
8 ± 1 
11 ± 1 
15 ± 2 
29 + 6 
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 and 
proteomics) 
 
X 
8mL 
X 
8mL 
X 
8mL 
X 
8mL 
X 
8mL 
 
X 
8 mL 
Total volume 
10mL 
42mL 
42mL 
42mL 
42mL 
42mL 
34mL 
42mL 
Total all study days 
 
 
 
 
 
 
 
~296 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. 
 
Table 5b. Venipuncture Volumes for Subjects Consenting for Genetic Testing At Sites that 
Do NOT Collect PBMCs 1  
 
Screen 
Baseline 
 
 
 
 
 
 
Day +/- Window 
−1 to 1 
1 ± 1 
3 ± 1 
5 ±1 
8 ± 1 
11 ± 1 
15 ± 2 
29 + 6 
Safety hematology, 
chemistry, liver tests 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
 X3 
10mL2 
X3 
10mL2 
Blood for Serum 
 
X 
16 mL 
X 
16mL 
X 
16mL 
X 
16mL 
X 
16mL 
X 
16mL 
X 
16mL 
Plasma (PCR and 
proteomics) 
 
X 
8 mL 
X 
8 mL 
X 
8 mL 
X 
8 mL 
X 
8 mL 
(X)4--- 
X  
8 mL 
Blood in PAXgene 
tube 
 
X 
2.5 mL 
X 
2.5 mL 
--- 
X 
2.5 mL 
--- 
(X)4--- 
X 
2.5 mL 
Total volume if 
involved in 
exploratory analysis 
10mL 
36.5 mL 
36.5m
L 
34 mL 
36.5 mL 
34 mL 
26mL 
36.5 mL 
Total all study days 
 
 
 
 
 
 
 
250 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. 
4. If subject discharged prior to Day 8 (i.e., PAXGene tube not collected) or Day 11 (i.e., proteomics not collect), 
site will collect Day 8 and/or Day 11 samples at Day 15 follow-up visit 
 
 


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Table 6c. Venipuncture Volumes for Subjects Consenting for Genetic Testing At Sites that 
Collect PBMCs 1  
  
Screen 
Baseline 
 
 
 
 
 
 
Day +/- Window 
−1 to 1 
1 ± 1 
3 ± 1 
5 ±1 
8 ± 1 
11 ± 1 
15 ± 2 
29 + 6 
Safety hematology, 
chemistry, liver tests 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
 X3 
10mL2 
X3 
10mL2 
Blood for Serum 
 
X 
8 mL 
X 
8 mL 
X 
8 mL 
X 
8 mL 
X 
8 mL 
X 
8 mL 
X 
8 mL 
Plasma (PCR and 
proteomics) 
 
GET THIS FROM 
CPT TUBE 
 
X4 
8 mL 
X4 
8 mL 
X4 
8 mL 
X4 
8 mL 
X4 
8 mL 
(X) 4,5--- 
X  
8 mL 
Blood in PAXgene 
tube 
 
X 
2.5 mL 
X 
2.5 mL 
--- 
X 
2.5 mL 
--- 
(X)5--- 
X 
2.5 mL 
Blood for PBMCs in 
Cell Preparation 
Tube (CPT) 
 
X 
25.5 mL 
--- 
--- 
X 
25.5 mL 
--- 
(X) 4,5--- 
X 
25.5 to 
42.5 mL 
Total volume if 
involved in 
exploratory analysis 
10mL 
46 mL 
20.5 mL 
18 mL 
46 mL 
18 mL 
18 mL 
54 -71 
mL 
Total all study days 
 
 
 
 
 
 
 
230.5 to 
247.5 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. 
4. Plasma will be collected from CPT tube for the proteomics analysis (0.5 mL plasma needed) 
5. If subject discharged prior to Day 8 (i.e., PAXGene tube not collected) or Day 11 (i.e., proteomics not collect), 
site will collect Day 8 and/or Day 11 samples at Day 15 follow-up visit 
 
 
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 
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) 


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AE means any untoward medical occurrence associated with the use of an intervention in humans, 
whether or not considered intervention related. If multiple abnormalities are part of the same 
clinical syndrome, they can be reported together as one AE under a unifying clinical diagnosis. 
 
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. Only Grade 3 and 4 AEs will be captured in this trial and Grade 2 or higher suspected 
drug-related hypersensitivity reactions associated with study product administration. For example, 
worsening respiratory status from Grade 2 (respiratory distress) at Day 1 to Grade 4 (respiratory 
failure) at Day 5 is a condition temporarily associated with use of an intervention and by definition 
is an AE and should be reported even if the investigator believes that this is part of the natural 
history of the disease.  
 
All study required solicited safety laboratory test results will be recorded into the eCRF including 
all Grade 1 and 2 abnormalities.  As the Grade 1 and 2 abnormalities are tracked and available 
within the data system, the Grade 1 and 2 laboratory abnormalities are not expected to be reported 
as adverse events and will not be reviewed by the clinical Monitor. 
 
Given the severity of the underlying illness, subjects will have many symptoms and abnormalities 
in vital signs and laboratory values. As COVID-19 is an emerging, systemic disease involving not 
only the upper and lower respiratory tract, but also the gastrointestinal tract, cardiovascular system, 
endothelial cells, and central nervous system (olfactory neurons), it is important to document 
respiratory AE as well as AEs involving other systems. New symptoms not part of the subject’s 
COVID-19 syndrome at Day 1, should be captured as adverse events. For example, if a subject 
develops new grade 3 gastrointestinal symptoms after Day 1, the gastrointestinal symptoms should 
be reported.  
 
For ACTT-3, the AE reporting window begins with the initial administration of the first study 
product and ends on the last visit (i.e., not from the time the ICF is signed as in ACTT-2). Any 
medical condition that is present at the time that the subject signs the ICF will be considered as 
baseline and not reported as an AE. However, if the severity of any pre-existing (at baseline) 
medical condition increases above baseline to severity grade 3 or 4, it should be recorded as an 
AE. The start date for reporting of an AE/SAE is the date the AE became a Grade 3 AE.  
 
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. 
 
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. 
 


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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 
highest 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.  
 
D-dimer and CRP should not be graded. These are collected on the same schedule as the safety 
laboratory tests (see SOA). However, they will be used in the assessment of study outcomes.  
 
Standardized reporting of AE is essential to interpretation of data between clinical trial sites in 
multi-site clinical trials. The following recommendations are the result of an internal evaluation of 
safety data collected during ACTT-1 and ACTT-2. 
• Medical conditions that rise to the level of an AE  should be reported as an AE and not the 
procedure used to treat that condition. For example, “respiratory failure with ventilator 
support indicated” should be reported as a Grade 4 respiratory failure AE per the DAIDS 
toxicity table versus reporting an intubation (a surgical procedure) as an AE. 
• Clinical syndromes should be reported rather than each symptom, vital sign, or laboratory 
abnormality separately. For example, respiratory failure should be reported as an AE rather 
than separately reporting respiratory acidosis, hypotension, hypoxia; or AKI should be 
reported instead of low eGFR, high creatinine level and CRRT dialysis procedure. 
• Adverse events that worsen from baseline at Day 1 to a Grade 3 or Grade 4 AE or SAE 
during the study should be reported. This includes worsening of respiratory signs and 
symptoms. An AE is any untoward medical occurrence associated with the use of an 
intervention (including investigational products), whether or not considered intervention 
related. This means that the condition may be associated with the underlying disease 
process (COVID-19), but we would still report as an AE.  
• Readmissions that are due to worsening of medical conditions and requiring inpatient 
hospitalization are SAEs by a definition and should be reported. Readmissions for social 
reasons and not for worsening of medical condition (e.g., readmissions of nursing home 
residents or homeless readmitted for monitoring purposes only) is not an SAE. 
 
 
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; 


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• 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) 
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).  
 


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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. 
 
 
Time Period and Frequency for Event Assessment and Follow-Up 
For this study, all Grade 3 and 4 AEs, and all SAEs occurring from the time the first study 
product is initially given on Day 1 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. 
 


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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. 
 
 
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 


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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: 
 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 hypothesis tests whether the time-to-recovery by Day 29 differs between the 
experimental and control arms. 
 
Table 7. Hypothesis tests of interest for ACTT-3 
 
ACTT-3  
 
Primary hypothesis 
RDV + interferon-beta-1a versus RDV + placebo 
  


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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. 
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.  
 
 
 
Table 8. 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 
 


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The study will enroll participants until 831 recoveries. Initially the study was powered for 723 
recoveries in those in ordinal score 4-6 at baseline, with an increase to 831 recoveries due to 
anticipated lower efficacy in ordinal score 7. The same assumption will now be made that ordinal 
score 6 will have a lower efficacy, and therefore the number of  recoveries will remain 
unchanged. However, we anticipate that approximately 90% of subjects recover within 28 days, 
and therefore the total sample size will be approximately 923. The date of study closure will be 
estimated based on enrollment rate and recovery/enrollment percentages. 
 
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; 
• 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, but new or increased limitation on activities and/or requiring new or 
increased home oxygen; 
• Not hospitalized, no limitations on activities. 
 
Note that the data elements contributing to this scale will be captured separately, in order to 
facilitate different orderings or groupings, as might arise if external data provide information 
about the clinical course of disease.  
 


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Table 9: Possible scenarios for the distribution of ordinal outcomes for the control arm at 
Day 15. 
 
Anticipated 
Different scenarios for control arm 
  
Scenario 1 
Scenario 2 
Scenario 3 
Scenario 4 
Scenario 5 
 
 
more mild disease                       more severe disease 
Severity Outcome 
outcome (%) outcome (%) 
outcome (%) outcome (%) outcome (%) 
Death 
2 
1 
1 
2 
3 
Hospitalized, on 
mechanical ventilation or 
ECMO 
1 
1 
1 
1 
3 
Hospitalized, on non-
invasive ventilation or 
high flow oxygen devices 
2 
1 
1 
2 
4 
Hospitalized, requiring 
supplemental oxygen 
7 
2 
5 
5 
9 
Hospitalized, not requiring 
supplemental oxygen – 
requiring ongoing medical 
care (COVID-19 related 
or otherwise) 
8 
5 
7 
17 
23 
Hospitalized, not requiring 
supplemental oxygen – no 
longer requires ongoing 
medical care 
10 
9 
10 
20 
25 
Not hospitalized, 
limitation on activities 
and/or requiring home 
oxygen 
30 
36 
35 
25 
18 
Not hospitalized, no 
limitations on activities 
40 
45 
40 
28 
15 
 
 
Table 10: 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 


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True odds 
ratio 
Total sample size 
 
Scenario 1 
Scenario 2 
Scenario 3 
Scenario 4 
Scenario 5 
2.5 
154 
163 
155 
141 
136 
 
 
Table 11. Treatment ordinal outcome proportions under an odds ratio of 1.75 for five 
scenarios in Table 5 at Day 15. 
  
Scenario 
1 
Scenario 
2 
Scenario 
3 
Scenario 
4 
Scenario 
5 
 
Anticipated more mild disease                more severe disease 
Severity Outcome 
Control % 
Treatment % 
Control % 
Treatment % 
Control % 
Treatment % 
Control % 
Treatment % 
Control % 
Treatment % 
Death 
2 
1.2 
1 
0.6 
1 
0.6 
2 
1.2 
3 
1.7 
Hospitalized, on mechanical 
ventilation or ECMO 
1 
0.6 
1 
0.6 
1 
0.6 
1 
0.6 
3 
1.8 
Hospitalized, on non-invasive 
ventilation or high flow 
oxygen devices 
2 
1.2 
1 
0.6 
1 
0.6 
2 
1.2 
4 
2.5 
Hospitalized, requiring 
supplemental oxygen 
7 
4.3 
2 
1.2 
5 
3.0 
5 
3.1 
9 
5.8 
Hospitalized, not requiring 
supplemental oxygen – 
requiring ongoing medical 
care (COVID-19 related or 
otherwise) 
8 
5.3 
5 
3.1 
7 
4.4 
17 
11.5 
23 
17.4 
Hospitalized, not requiring 
supplemental oxygen – no 
longer requires ongoing 
medical care; 
10 
7.2 
9 
5.9 
10 
6.8 
20 
16.2 
25 
24.4 
Not hospitalized, limitation 
on activities and/or requiring 
home oxygen 
30 
26.5 
36 
29.3 
35 
30.2 
25 
25.9 
18 
22.7 
Not hospitalized, no 
limitations on activities 
40 
53.8 
45 
58.9 
40 
53.8 
28 
40.5 
15 
23.6 
Note that columns may not sum to exactly 100 due to rounding errors. 
 
Other key secondaries for testing combination therapy compared to control will be detailed in an 
addendum SAP 
 


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9.3 
Populations for Analyses 
 
An adjudication or review committee consisting of the DMID MO, her designees and the blinded 
statistical team may review endpoints, medications, deviations, and other special cases where 
expert opinion is requested for handling complicated cases.  
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 as defined by ordinal scale. Deaths will be considered as never recovering 
and censored at Day 29. In ACTT-3, the analyses conducted will depend on the results from 
ACTT-1 according to Table 4. 
 
 
Analysis of the Secondary Endpoint(s) 
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.  
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. 
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). 
 


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Duration of event (e.g., duration of mechanical ventilation) will be summarized according to 
median days with quartiles. 
 
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. 
 
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. 
 
 
 
Analysis of Exploratory Objectives and Endpoints 
Exploratory objectives and endpoints for immunophenotyping including transcriptomics, 
interferon-simulating gene analysis, proteomics, epigenetics, and T cell and innate immune cell 
phenotyping will be handled in a separate analysis plan. Samples for the exploratory objectives 
are outlined in this protocol and details of sample collection, processing, storage and shipping is 
described in detail the MOP, however, the analysis will not take place in real-time, during study 
enrollment. Depending on the timing of the completion of these assays, exploratory results will 
be submitted as one or more addenda to the primary CSR. 
 
 
Safety Analyses 
Safety endpoints include death through Day 29 (+ 6 days), 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, 
median, minimum, maximum 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.  


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On September 4, 2020, the DSMB met for an interim safety review of ACTT-3 data, and they 
recommended that DMID close further enrollment to patients with a baseline ordinal score of 6. 
Given that there are multiple clinical trials evaluating interferon beta for the treatment of COVID-
19 worldwide, a public announcement describing the change in enrollment was made to inform 
the scientific community. If necessary, there may be an early evaluation of safety outcomes for the 
category 6 subjects enrolled in ACTT-3. Specifically, after study Day 29, for all subjects enrolled 
at an ordinal score of 6, those subjects only may be unblinded and an interim analysis may occur. 
This could be done if needed in order to determine the risk in this group of patients and convey 
this risk to other sponsors who can then use this information to make modifications if needed to 
their ongoing studies. This would be followed by a full analysis after the final data cleaning. The 
SAP has been modified to describe this interim analysis as well as a revised analysis for the ordinal 
6 category.  
 
 
Interim Safety Analyses 
Safety analyses will evaluate Grade 3 and 4 AE and SAEs by treatment arm. Safety monitoring 
will be ongoing with the DSMB reviewing safety data approximately every two weeks during the 
study. 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 at approximately 50% 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.  
 
 
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 
(ordinal scale), age, race, ethnicity, 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 


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An exploratory analysis will compare treatment efficacy estimates according to the various scales 
outlined in section 8.1.3. Specifically, the probability of falling into category “i” or better will be 
compared between arms for each i.  
 
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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APPENDIX D - ACTT-4: BARICITINIB/REMDESIVIR VS. 
DEXAMETHASONE/REMDESIVIR  
 
1. 
PROTOCOL SUMMARY 
1.1 
ACTT-4 – Synopsis 
Study overview 
Severe COVID-19 is marked by a hyperinflammatory state characterized by upregulation of 
multiple cytokines. Multiple therapeutic strategies have been proposed to counter this 
inflammatory phase. To date, only two anti-inflammatory medications have demonstrated 
efficacy in large randomized trials – dexamethasone and baricitinib.  
 
In the Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial, treatment with 
dexamethasone demonstrated a lower mortality rate, 22.9% in the dexamethasone group versus 
25.7% in the usual care group (absolute difference 2.8%; p<0.001).(15) In ACTT-2, treatment 
with baricitinib in addition to remdesivir demonstrated a shorter median time-to-recovery of 7 
days versus 8 days with remdesivir alone [rate ratio for recovery 1.16, P=0.03] and a lower 28-
day mortality of 5.1% and 7.8% in the combination and control arms, respectively (absolute 
difference 2.7%; P>0.05). (Kalil et al, 2020)  
 
These two studies, however, are very different – different study populations, different baseline 
mortality rates, and different data collected. Only ACTT-2 was blinded, and only in ACTT-2 was 
the anti-inflammatory intervention given in addition to an antiviral. Therefore direct comparison 
of these studies to determine which interventions are of value in which populations is difficult. 
ACTT-4 will evaluate adult patients hospitalized with COVID-19 and requiring supplemental 
oxygen by low flow, high flow or non-invasive mechanical ventilation modalities to determine if 
baricitinib or dexamethasone in combination with remdesivir are more effective at preventing 
progression to mechanical ventilation or death (among other outcomes) or if they are similar.  
 
Enrollment Period:  
It is anticipated the enrollment will be completed in 3-4 months. 
 
General 
ACTT-4 will evaluate the combination of baricitinib and remdesivir compared to dexamethasone 
and remdesivir in adult patients hospitalized with COVID-19 and requiring supplemental 
oxygen. 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, OP swabs, 
plasma (Day 29), and serum for secondary research as well as clinical outcome data. However, if 
infection control or other restrictions limit the ability of the subject to return to the clinic, 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. Additionally, in 


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ACTT-4, subjects will be contacted by phone, via a telehealth remote visit or in-person visit at 
approximately 2 months after randomization to assess long term efficacy and safety outcomes. 
 
We anticipate that this trial will require 1348 subjects. Assuming that 8% of subjects are lost to 
follow-up by Day 29, the total sample size is approximately 1500.  
 
Study Population 
Hospitalized adults (≥18 years old) with COVID-19 requiring supplemental oxygen administered 
by low flow, high flow or non-invasive mechanical ventilation modalities. 
 
Inclusion Criteria 
1. Hospitalized with symptoms suggestive of COVID-19. 
2. Subject (or legally authorized representative) provides informed consent prior to 
initiation of any study procedures and understands and agrees to comply with planned 
study procedures. 
3. Male or non-pregnant female adults ≥ 18 years of age at time of enrollment. 
4. Illness of any duration and has laboratory-confirmed SARS-CoV-2 infection as 
determined by PCR or other commercial or public health assay (e.g. NAAT, antigen test) 
in any respiratory specimen or saliva ≤14 days prior to randomization. 
5. Within the 7 days prior to randomization requiring new use of supplemental oxygen (or 
increased oxygen requirement if on chronic oxygen) and requires at the time of 
randomization low or high flow oxygen devices or use of non-invasive mechanical 
ventilation (ordinal scale category 5 or 6). 
6. 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.  
7. Agrees not to participate in another blinded clinical trial (both pharmacologic and other 
types of interventions) for the treatment of COVID-19 through Day 29 (see Section 5.4 
for more information about concurrent trial participation). 
 
Exclusion Criteria 
1. Prior enrollment in ACTT-3 or ACTT-4. Note: this includes subjects whose participation 
in ACTT was terminated early.  
2. On invasive mechanical ventilation at the time of randomization (ordinal scale category 
7).  
3. Anticipated discharge from the hospital or transfer to another hospital which is not a 
study site within 72 hours of randomization. 
4. Positive test for influenza virus during the current illness (influenza testing is not 
required by protocol). 
5. Subjects with a low glomerular filtration rate (eGFR), specifically: 
a. Subjects with an eGFR 15-30 mL/min are excluded unless in the opinion of the 
PI, the potential benefit of participation outweighs the potential risk of study 
participation. 
b. All subjects with an eGFR <15 mL/min are excluded. 
c. All subjects on hemodialysis and/or hemofiltration at the time of screening, 
irrespective of eGFR, are excluded. 


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6. Neutropenia (absolute neutrophil count <700 cells/μL, 0.7 x 103/μL). 
7. Lymphopenia (absolute lymphocyte count <200 cells/μL, 0.20 x 103/μL). 
8. Received five or more doses of remdesivir including the loading dose, outside of the 
study as treatment for COVID-19.  
9. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day 
1 until two weeks after the last study product is given are not excluded). 
10. Allergy to any study medication. 
11. Received convalescent plasma or intravenous immunoglobulin [IVIg] for COVID-19, the 
current illness for which they are being enrolled. 
12. Received any of the following in the two weeks prior to screening as treatment of 
COVID-19: 
• More than one dose of baricitinib for the treatment of COVID-19; 
• Other small molecule tyrosine kinase inhibitors (e.g. imatinib, gefitinib, acalabrutinib, 
etc.); 
• monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 
[IL-1], anti-IL-6 [tocilizumab or sarilumab], etc.);  
• monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19. 
Note: receipt of anti-SARS-CoV-2 mAb prior to enrollment (e.g. bamlanivimab) for their 
current COVID-19 illness is not exclusionary 
13. Use of probenecid that cannot be discontinued at study enrollment. 
14. Received 6 mg or more of dexamethasone po or IV (or equivalent for other 
glucocorticoids) in one day, on more than one day in the 7 days prior to time of 
randomization. Note: 6 mg dexamethasonedose equivalents include 40 mg prednisone, 32 
mg methylprednisolone and 160 mg hydrocortisone. 
15. Received ≥20 mg/day of prednisone po or IV (or equivalent for other glucocorticoids) for 
≥14 consecutive days in the 4 weeks prior to screening. 
16. Have diagnosis of current active or latent tuberculosis (TB), if known, treated for less 
than 4 weeks with appropriate therapy (by history only, no screening required). 
17. Serious infection (besides COVID-19), immunosuppressive state, or immunosuppressive 
medications that in the opinion of the investigator could constitute a risk when taking 
baricitinib or dexamethasone. 
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 including SARS-CoV-2 vaccine is allowed for all subjects. 
19. Had a known VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) during 
the current COVID-19 illness. 
 
Study Intervention 
Subjects will be randomized into two arms (1:1). 
 
Arm 1 
Arm 2 
Baricitinib tablets +  
Placebo IV + 
Remdesivir IV 
Placebo tablets +  
Dexamethasone IV +  
Remdesivir IV 
 
 


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All subjects will receive standard antiviral treatment with remdesivir as a 200 mg intravenous (IV) 
loading dose on Day 1, followed by a 100 mg once-daily IV maintenance dose during 
hospitalization up to a maximum of 10 total doses (i.e., loading + maintenance doses received 
during study and pre-study if applicable). See Section 6.1.4 for details of dosing and dose 
modification.  
 
For the baricitinib component, subjects will receive either: 
• Baricitinib 4 mg** orally (po) (two 2 mg tablets) or dissolved* per NG tube, daily for the 
duration of the hospitalization up to a 14-day total course.  
• Placebo given as two tablets** orally (po) or dissolved per NG tube, daily for the 
duration of the hospitalization up to a 14-day total course. 
* See MOP for instructions on how to prepare and administer baricitinib to patients 
having difficulty swallowing 
** Dose of oral study product will be decreased or held based on eGFR. Specifically: 
eGFR Value  
Dose of Baricitinib/Oral Placebo 
≥60 mL/min 
Two tablets (4 mg total) once daily  
No dose adjustment 
30 - <60 mL/min 
One tablet (2 mg) once daily 
15 - <30 mL/min 
One tablet (2 mg) QOD – every 
other day 
<15 mL/min or require hemodialysis or 
hemofiltration 
Hold oral study product  
 
For the dexamethasone component, subjects will receive either active product or placebo as 
follows: 
• Dexamethasone will be administered as a 6 mg slow IV push over 3 to 5 minutes (1.5 
mL) daily for the duration of the hospitalization up to a 10-day total course. 
• A normal saline placebo will be given as a slow IV push over 3 to 5 minutes daily for the 
duration of the hospitalization up to a 10-day total course 
• If local standards use other means of administration (such as IV infusion), these may be 
used for both active and placebo. 
• Any pre-study dexamethasone (max 1 dose per inclusion criteria) is not counted towards 
the 10 day course.  
 
Duration of therapy: 
• IV remdesivir – 5 - 10 days while hospitalized. 
o The recommended treatment duration for most subjects is 5 days.  
o If a patient does not demonstrate clinical improvement, or deteriorates to require 
invasive mechanical ventilation and/or extracorporeal membrane oxygenation 
(ECMO), treatment may be extended for up to 5 additional days for a total 
treatment duration of up to 10 days. 
• Oral baricitinib (or oral placebo) – 14 days while hospitalized. 
• IV dexamethasone (or IV placebo) – 10 days while hospitalized. 
• All medications stop on discharge from hospital.  


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o Of note, if a subject is retained in the hospital for non-COVID-19 related issues 
and no longer requires supplemental oxygen and ongoing medical care (i.e., 
ordinal scale category 3), the PI may decide to discontinue all medications.  
 
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 
+ 6 
60 
-7 -  
+14 
ELIGIBILITY 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Demographics & Medical Hx 
X 
 
 
 
 
 
 
Review SARS-CoV-2 results 
X 
 
 
 
 
 
 
 Review influenza results if 
available 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Administration of 
investigational agents 
 
• Remdesivir: IV daily for 5-10 days 
or until discharge.  
• Baricitinib or placebo: po daily until 
day 14 or discharge 
• Dexamethasone or placebo: IV daily 
until day 10 or discharge 
 
 
 
 
 
 
 
 
 
 
 
STUDY PROCEDURES 
 
 
 
 
 
 
 
Targeted physical exam 1 
 
X 
 
 
 
 
 
Vital sign and NEWS score 1 
 
X 
 
 
 
 
 
Clinical data collection 2  
 
X4 
Daily until discharge8 
X9 
X9 
X9 
X 
Adverse event evaluation 
 
 
Daily until discharge8 
X9 
X9 
X9 
 
Concomitant medication review 
X 
X 
From Day -7 to Day 29. 
Stop collection after 
discharge 
 
 
 
 
 
 
 
 
 
 
 
 
CLINICAL LABORATORY 
 
 
 
 
 
 
 
Screening clinical lab tests 
X3 
 
 
 
 
 
 
Pregnancy test for females of 
childbearing potential 
X3 
 
 
 
 
 
 
Safety hematology, chemistry 
and liver tests 
 
X4,5,6,7 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 6,7 
X9 
 
X9 
 
 
 
 
 
 
 
 
 
RESEARCH LABORATORY FOR ALL SUBJECTS 
 
 
 
 
Blood for plasma to test by PCR 
for SARS-CoV-2 and cytokines/ 
inflammatory markers 
 
X4 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
 
 
X9 
 
Oropharyngeal swab 10 
 
X4 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
X9 
 
X9 
 


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Blood for serum (exploratory 
and secondary research) 
 
X4 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
X9 
 
X9 
 
ONLY FOR SUBJECTS CONSENTING FOR GENETIC RESEARCH 
 
 
 
 
Blood for RNA for 
transcriptomic analysis (in 
PAXgene tube)  
 
X4 
Day 3, 8 (all ± 1 day) if 
hospitalized 
X9, 11 
 
X9 
 
Notes: 
 
1Targeted physical exam and NEWS (with vital signs) done at baseline. Exam done by the treating licensed 
healthcare provider may be used. The baseline exam can be one that is conducted from screening to Day 1. 
2 Refer to Section 8.1.2 of the protocol for details of clinical data to be collected for ordinal score, oxygen 
requirement, mechanical ventilator requirement, etc. 
3 Screening clinical laboratory tests include: white blood cell (WBC) count with differential, absolute neutrophil 
count (ANC), absolute lymphocyte count (ALC), and creatinine. Sites calculate an estimated glomerular filtration 
rate (eGFR) using the formula selected by the site that is used consistently throughout the study. Laboratory tests 
performed in the 48 hours prior to enrollment will be accepted for determination of eligibility. A pregnancy test 
should be done at screening for females of childbearing potential. See Section 8.1.1. for more information about 
pregnancy tests in post-partum women. 
4 Baseline (Day 1) assessments should be performed prior to first study product administration. Results of Day 1 
laboratory assessment do not need to be reviewed to determine if initial study product should be given. In ACTT-4, 
vitamin D will be assessed on Day 1 only. It will be used to evaluate outcomes and should not be graded as it is not 
a safety laboratory. 
5 Laboratory tests performed as part of routine clinical care in the 36 hours prior to first dose will be accepted for 
the baseline (Day 1) safety laboratory tests. Baseline may be the same as the screening laboratory tests.  
6 Safety laboratory tests include: WBC count with differential, hemoglobin, platelet count, creatinine, glucose, 
total bilirubin, ALT, AST, and INR. D-dimer and C-reactive protein (CRP) are collected at the same time points as 
the safety labs but should not be graded like the safety labs. D-dimer and CRP may predict severity and support 
assessment of outcomes.  
7 Any laboratory tests performed as part of routine clinical care within the specified visit window can be used for 
safety laboratory testing.  
8 Daily until hospital discharge or Day 29, whichever comes first. See Section 8.1.2.1 for more information about 
doing an ordinal scale assessment on the day after hospital discharge and on the day after a subject dies. 
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 call, home visit or remote 
telehealth procedure as per institutional standards. 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 or home visit: collect 
clinical data, safety laboratory tests, and research laboratory samples as able.  
• 
If phone call or remote telehealth visit only on Days 15 and 29 and all Day 22 visits: assess adverse events, 
ordinal scale, readmission to a hospital, and mortality only. At the Day 60 visit, assess oxygen use, physical 
limitations, readmissions, and clinical outcomes including mortality. See Section 8.1.2.1 for more information. 
10 Oropharyngeal swabs are preferred, but if these are not obtainable, nasopharyngeal or nasal swabs may be 
substituted.  
11.Subjects who consented for genetic testing and are discharged prior to Day 8 and therefore missing the Day 8 
Paxgene tube collection should get blood drawn at Day 15, if feasible. 
 
 
1.3 
Study Schema 
 
 
 
 
 
Stage 4 
ACTT-4 
Baricitinib po + IV Placebo + Remdesivir 
Dexamethasone IV + po Placebo + Remdesivir 


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2. 
INTRODUCTION 
2.1 
Background 
 
ACTT-4 – Baricitinib/Remdesivir vs. Dexamethasone/Remdesivir Trial 
ACTT is a multi-site, global clinical trial platform designed to evaluate the clinical efficacy and 
safety of putative investigational therapeutic agents among hospitalized adults with laboratory-
confirmed Covid-19. There have been three, phase 3, randomized, double-blind, placebo-
controlled trials conducted using the ACTT platform, ACTT-1, ACTT-2 and ACTT-3. Each new 
ACTT study is considered another stage of the trial.  
 
Data from ACTT-1 showed that hospitalized adults with COVID-19 who were randomized to 
receive remdesivir had a shorter time to clinical recovery than those who received placebo (10 
vs. 15 days, recovery rate ratio 1.29 (95% CI 1.12 to 1.49, p<0.001) (14). The odds of 
improvement on an ordinal scale by Day 15 were higher in the group that received remdesivir 
than in the placebo group (odds ratio 1.5; 95% CI 1.2 to 1.9, p < 0.001). After the release of these 
preliminary findings, the U.S. Food and Drug Administration (FDA) issued an Emergency Use 
Authorization (EUA) for remdesivir. On October 22, 2020, the FDA approved remdesivir (trade 
name, Veklury®) for use in adults and children 12 years of age and older for the treatment of 
COVID-19 requiring hospitalization. Veklury is the first treatment for COVID-19 to receive 
FDA approval. Remdesivir has also received, full or conditional approval in approximately 50 
other countries.  
 
While remdesivir is considered the standard antiviral for COVID-19, significant morbidity and 
mortality still occur despite its use. Early in the outbreak, it was observed that COVID-19 
patients who developed severe respiratory disease including acute respiratory distress syndrome 
(ARDS) had increased levels of cytokines consistent with that seen in patients infected with 
other pathogenic coronaviruses (e.g., SARS) (37-39). It is postulated that this dysregulated 
inflammatory immune response contributes to the excessive mortality and targeting this response 
would further improve outcomes. While multiple strategies have been proposed to counter the 
hyper-inflammation, to date only two anti-inflammatory strategies have demonstrated efficacy in 
large randomized trials – dexamethasone and baricitinib.  
 
In ACTT-2, subjects receiving the combination treatment of baricitinib and remdesivir had a 
shorter median time-to-recovery of 7 days (95% confidence interval (CI), 6 to 8 days) when 
compared with patients who received remdesivir and placebo (8 days; 95% CI, 7 to 9 days) with 
control [rate ratio for recovery [RRR] 1.16, 95% CI 1.01 to 1.32; P=0.03)]. Patients who 
received combination treatment were 30% more likely to have clinical improvement by day 15 
than those in the control arm (odds ratio [OR] 1.3; 95%CI 1.0 to 1.6). The patients who benefited 
the most from combination treatment were those requiring high-flow oxygen or non-invasive 
ventilation at enrollment with a median of 10 days to recovery compared with 18 days in control 
group (RRR 1.5, 95% CI 1.1 to 2.1) and the best clinical improvement by day 15 (OR 2.2; 95% 


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CI 1.4 to 3.6). Baricitinib also showed benefit to those on low flow oxygen with a median of 5 
days to recovery compared with 6 days in control group (RRR 1.17, 95% CI 0.98 to 1.39) and 
the clinical improvement by day 15 (OR 1.2; 95% CI 0.9 to 1.6). Patients who received 
combination treatment with baricitinib and remdesivir and those in the control arm had a similar 
incidence of adverse and serious adverse events including infections and venous thromboembolic 
events (VTE). On November 19, 2020, the FDA issued an Emergency Use Authorization (EUA) 
for the use of baricitinib in combination with remdesivir in hospitalized adults and children aged 
≥2 years with COVID-19 who require supplemental oxygen, invasive mechanical ventilation, or 
extracorporeal membrane oxygenation (ECMO).  
 
The Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial is a controlled, open- 
label randomized trial, involving all major hospitals in the UK. The trial compared a range of 
possible treatments in patients who were hospitalized with Covid-19. Included, was a treatment 
arm assigned to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily for up 
to 10 days) or to received usual care alone. Overall, 22.9% in the dexamethasone group and 
25.7% in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 
0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). In the dexamethasone group, the 
incidence of death was lower than that in the usual care group among patients receiving invasive 
mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among 
those receiving supplemental oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; 
rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no supplemental 
oxygen respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 
1.55). Remdesivir was not used routinely in the RECOVERY trial. 
 
The ACTT-2 and RECOVERY trials are very different: 
• ACTT 2 randomized patients to baricitinib, a JAK inhibitor and RDV or RDV alone. 
RECOVERY randomized patients to dexamethasone or standard care. 
• Different study populations – ACTT-2 had more restrictive study criteria due to the use 
of remdesivir and baricitinib. Exclusions for liver or renal dysfunctions or cytopenias 
may have selected for a less ill population compared to RECOVERY. 
• Different baseline mortalities – the ACTT-2 study had a mortality of 5.1-7.8% compared 
to 22.9-25.7% in RECOVERY. Even when directly comparing the study population that 
were not on supplemental oxygen at study entry - the ACTT-2 study had no deaths 
compared to 14.0-17.8% in RECOVERY.  
• Study periods - The trials were conducted at slightly different periods early in the 
pandemic. RECOVERY was conducted March 19 to June 8 and ACTT-2 was conducted 
May 8-June 30. 
• Antivirals - All subjects in ACTT-2 were given remdesivir whereas only 3 (< 1%) in 
RECOVERY were given remdesivir. 
• Blinded - ACTT-2 was a double-blind randomized control trial and RECOVERY was 
open label (i.e., not blinded).  
 
Given the above, direct comparison of these studies is difficult. However, the relative risk ratios 
also suggest these two anti-inflammatory strategies may be optimal in different inpatient 


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populations, with baricitinib having the larger effect in the high flow or low flow oxygen group 
and dexamethasone having the largest effect in those on mechanical ventilation (see Table 2). 
 
Table 2. Mortality from ACTT-2 and RECOVERY trials. 
  
  
Ordinal Score at Baseline 
  
Overall 
4 
Not on oxygen 
5 
Low flow oxygen 
6 
High flow oxygen / 
NIMV 
7 
Mechanical 
ventilation/ECMO 
Mortality– ACTT-2 
  
Bari 
+ RDV 
(n=515) 
Placebo 
+ RDV 
(n=518) 
Bari 
+ RDV 
(n=70) 
Placebo 
+ RDV 
(n=72) 
Bari 
+ RDV 
(n=287) 
Placebo 
+ RDV 
(n=276) 
Bari 
+ RDV 
(n=104) 
Placebo 
+ RDV 
(n=113) 
Bari 
+ RDV 
(n=54) 
Placebo 
+ RDV 
(n=57) 
Hazard ratio (95% 
CI)  
0.65  
(0.39, 1.08) ;p=0.09 
NE 
 
0.4  
(0.14, 1.14) 
0.55  
(0.22, 1.37) 
1.00  
(0.45, 2.22) 
28 Day mortality %  
(95% CI) 
5.1 
(3.5, 7.6) 
7.8  
(5.7, 10.6) 
0  
(NE, NE) 
0 
(NE, NE) 
1.9  
(0.8, 4.4) 
4.7  
(2.7, 8.1) 
7.4  
(3.6, 15.0) 
12.9  
(7.7, 21.3) 
23.1  
(13.8, 37.1) 
22.6 
 (13.5, 36.4) 
Mortality – RECOVERY Trial 
  
Overall 
No oxygen 
Oxygen only 
Mechanical ventilation 
  
Dex 
(n=2104) 
Usual 
Care 
(n=4321) 
Dex 
(n=501) 
Usual 
Care 
(n=1034) 
Dex  
(n=1279) 
Usual Care 
(n=2604) 
Dex  
(n=324) 
Usual Care 
(n=683) 
Hazard ratio for 
mortality 
0.83 
p<0.001 
1.19 
 
0.82 
 
0.64 
 
 28 Day mortality % 
22.9 
25.7 
17.8 
14.0 
23.3 
26.2 
29.3 
41.4 
 
For this reason, direct comparison of these two anti-inflammatory interventions is important. 
ACTT-4 will evaluate patients hospitalized with COVID-19 and requiring oxygen and determine 
if baricitinib or dexamethasone (both in addition to remdesivir) is superior or if they are 
comparable. 
 
2.2 
Risk/Benefit Assessment 
 
Known Potential Risks 
Potential risks of participating in this trial are those associated with the study interventions, 
having blood drawn, the IV catheterization, 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 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 


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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. 
 
 
Remdesivir (Veklury®) 
 Potential Risks of Remdesivir  
Remdesivir is an approved antiviral and may be obtained as part of standard care outside the 
clinical trial. For the purpose of the ACTT trials, remdesivir is still considered a study product 
being used as part of an investigational trial and it will be tracked and monitored accordingly.  
 
Transaminase elevations have been observed in healthy volunteers who received remdesivir; the 
transaminase elevations were mild (Grade 1) to moderate (Grade 2) in severity and resolved 
upon discontinuation of remdesivir. Transaminase elevations have also been reported in patients 
with COVID-19 who received remdesivir.  
 
Coadministration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not 
recommended based on cell culture data demonstrating an antagonistic effect of chloroquine on 
the intracellular metabolic activation and antiviral activity of remdesivir. 
 
In ACTT-1, the collection of adverse event data in this trial was limited to severe (Grade 3) or 
potentially life-threatening (Grade 4) adverse events, serious adverse events, adverse events 
leading to study drug discontinuation, and moderate (Grade 2) severity or higher hypersensitivity 
reactions. Rates of adverse reactions (≥ Grade 3), serious adverse reactions, and adverse 
reactions leading to treatment discontinuation are presented in Table 3. 
 
Table 3. Summary of Adverse Reaction Rates in Subjects with Mild, Moderate, or Severe 
COVID-19 in ACTT-1 
Types of Adverse Reactions 
Remdesivir N=532 n (%) 
Placebo N=516 n (%) 
Adverse reactions, Grades ≥3 
41 (8%) 
46 (9%) 
Serious adverse reactions 
2 (0.4%)a 
3 (0.6%) 
Adverse reactions leading to 
treatment discontinuation 
11 (2%)b 
15 (3%)  
a Seizure (n=1), infusion-related reaction (n=1).  
b. Seizure (n=1), infusion-related reaction (n=1), transaminases increased (n=3), ALT increased and AST 
increased (n=1), GFR decreased (n=2), acute kidney injury (n=3). 
 
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 package insert, and 
additional product related information 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.  


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 Potential Benefits of Remdesivir 
In ACTT-1, remdesivir was found to be efficacious and safe. Specifically, patients who received 
remdesivir had a shorter time to recovery (the primary end point) than those who received placebo 
(median, 10 days vs. 15 days; rate ratio for recovery, 1.29 [95% CI,1.12 to 1.49]) and were more 
likely to have improvement in the ordinal scale score at day 15 (key secondary end point; odds 
ratio, 1.5; 95% CI, 1.2 to 1.9). Other secondary end points supported these findings including 
remdesivir treatment resulting in a shorter time to improvement of one and of two ordinal scale 
categories, a shorter time to discharge or to a sustained National Early Warning Score of 2 or 
lower, and a shorter length of initial hospital stay (median, 12 days vs. 17 days). All-cause 
mortality was 11.4% with remdesivir and 15.2% with placebo (hazard ratio, 0.73; 95% CI, 0.52 
to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir 
(24.6%) and in 163 of the 516 patients who received placebo (31.6%). 
 
 Assessment of Potential Risks and Benefits of Remdesivir 
As a result of ACTT-1 findings, remdesivir is given to most subjects hospitalized with COVID-
19, though this may vary based on availability and approval in a given country. Society at large 
may benefit from their participation in this study resulting from insights gained about the efficacy 
of remdesivir combined with either baricitinib or dexamethasone. Determining the optimal anti-
inflammatory strategy to combined with an antiviral for the treatment of severe COVID-19 may 
benefit society during this global COVID-19 pandemic.  
 
In ACTT-1, Remdesivir was found to have a good safety profile compared to placebo. SAEs 
were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 
patients who received placebo (31.6%). There were 47 serious respiratory failure adverse events 
in the remdesivir group (8.8% of patients), including acute respiratory failure and the need for 
endotracheal intubation, and 80 in the placebo group (15.5% of patients). No deaths were 
considered by the investigators to be related to treatment assignment. Grade 3 or 4 adverse 
events occurred on or before day 29 in 273 patients (51.3%) in the remdesivir group and in 295 
(57.2%) in the placebo group; 41 events were judged by the investigators to be related to 
remdesivir and 47 events to placebo. The most common nonserious adverse events occurring in 
at least 5% of all patients included decreased glomerular filtration rate, decreased hemoglobin 
level, decreased lymphocyte count, respiratory failure, anemia, pyrexia, hyperglycemia, 
increased blood creatinine level, and increased blood glucose level. The incidence of these 
adverse events was generally similar in the remdesivir and placebo groups. The potential risks 
are therefore thought to be acceptable given the potential benefits. 
 
 
Baricitinib 
 Potential Risks of Baricitinib 
Baricitinib is licensed drug with a known safety profile. It is indicated for the treatment of 
moderately to severely active rheumatoid arthritis (RA) in adults 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 


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laboratory assessments (potential changes in lymphocytes, neutrophils, hemoglobin, liver 
enzymes, and lipids), and avoidance with the use of live vaccines.  
 
A recent study of patients with active RA exposed to baricitinib including 3770 patients and 
10,127 patient years for a maximum exposure of 7 years found no significant differences in 
adverse events among patients who received baricitinib 4-mg vs placebo (40). This included 
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).  
 
While it is difficult to extrapolate the potential risks of baricitinib in RA to a hospitalized 
COVID-19 population, the duration of baricitinib treatment will be limited to up to 14 days and 
no major safety signals where seen in ACTT-2. In ACTT-2, Grade 3 or 4 adverse events (AE) 
occurred in 207 patients (41%) in the combination arm and 238 (47%) in the control arm. 
Twenty-five AEs were judged to be related to combination treatment and 28 to control. The most 
common Grade 3 or 4 AEs occurring in at least 5% of all patients were hyperglycemia, anemia, 
decreased lymphocyte count, and acute kidney injury. The incidence of these adverse events was 
similar between treatment arms. Of note, a similar proportion of patients in the combination 
treatment arm and control arm were reported to have a serious or non-serious venous 
thromboembolism (VTE) AE (21 patients (4%) versus 16 patients (3%), respectively (RD 1; 
95% CI -1 to 3). 
 
Serious adverse events (SAE) occurred in 77 patients (15%) in the combination treatment arm 
and six of these events were thought to be related to study product (Table 4). SAE occurred in 
103 patients (20%) in the control arm and five of these events were thought to be related to study 
product. All SAE, all AE, SAE with fatal outcome, and AE leading to discontinuation of study 
drug, were each significantly lower in the combination compared to the control group. Overall, 
serious and non-serious infection AE were lower in the combination (30 patients (6%) versus 
controls (56 patients (11%), respectively (RD -5; (95%CI -5 to -2). Patients who received 
corticosteroids post-randomization (N=223) compared to those who did not (N=793) had a 
higher rate of new infection AE and SAE: 51 patients (23%), 39 patients (4.9%). 
 
Table 4. Serious Adverse Events Occurring in 5 or More Subjects in Any Preferred Term 
by Treatment Group 
MedDRA System Organ Class 
Preferred Term 
Baricitinib + RDV 
(N = 507) 
No.(%) 
Placebo + RDV 
(N = 509) 
No.(%) 
Any System Organ Class 
Any Preferred Term 
77 (15.2) 
103 (20.2) 
Cardiac disorders 
Cardiac arrest 
2 (0.4) 
3 (0.6) 
General disorders and administration site conditions 
Multiple organ dysfunction syndrome 
1 (0.2) 
6 (1.2) 
Infections and infestations 
Septic shock 
4 (0.8) 
8 (1.6) 
 
Pneumonia 
2 (0.4) 
8 (1.6) 


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MedDRA System Organ Class 
Preferred Term 
Baricitinib + RDV 
(N = 507) 
No.(%) 
Placebo + RDV 
(N = 509) 
No.(%) 
 
Sepsis 
1 (0.2) 
4 (0.8) 
Renal and urinary disorders 
Acute kidney injurya 
5 (1.0) 
11 (2.2) 
 
Renal failurea 
0 (-) 
5 (1.0) 
Respiratory, thoracic and mediastinal disorders 
Respiratory failureb 
24 (4.7) 
37 (7.3) 
 
Acute respiratory failureb 
16 (3.2) 
9 (1.8) 
 
Acute respiratory distress syndrome 
4 (0.8) 
9 (1.8) 
 
Respiratory distressc 
4 (0.8) 
6 (1.2) 
 
Pulmonary embolism 
5 (1.0) 
1 (0.2) 
 
Hypoxiac 
3 (0.6) 
3 (0.6) 
 
Dyspnoeac 
1 (0.2) 
4 (0.8) 
 
Pneumothorax 
1 (0.2) 
4 (0.8) 
Vascular disorders 
Hypotension 
5 (1.0) 
5 (1.0) 
 
Shock 
2 (0.4) 
4 (0.8) 
No. = number of subjects reporting at least one event. 
a The combined number of subjects with acute kidney injury or renal failure are 5 for Baricitinib + RDV and 16 for Placebo + RDV. 
b The combined number of subjects with respiratory failure or acute respiratory failure is 40 for Baricitinib + RDV and 46 for Placebo + RDV. 
c The combined number of subjects with dyspnoea, hypoxia or respiratory distress are 8 for Baricitinib + RDV and 13 for Placebo + RDV. 
 
 
In addition, the half-life of Baricitinib 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 could potentially increase viral replication (41) though this has not 
been described in the cases series of baricitinib in COVID-19.  
 
Adverse drug reactions of baricitinib include the potential for VTE (deep vein thrombosis 
/pulmonary embolism). 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. In ACTT-2, a similar proportion of patients in the 
baricitinib + remdesivir arm and remdesivir only (control) arm were reported to have a serious or 
non-serious VTE related AE (21 patients (4%) versus 16 patients (3%), respectively; RD 1; 95% 
CI 1 to 3). 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.  
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 


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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 unlikely.  
  
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).  
 
 Potential Benefits of Baricitinib 
Given the ACTT-2 results, baricitinib likely improves the clinical outcome of hospitalized adult 
patients with COVID-19 requiring supplemental oxygen or non-invasive ventilation compared to 
remdesivir alone. However, this drug is available outside of the clinical trial. It is not known if 
treatment with baricitinib is better than treatment with dexamethasone. While there may not be a 
benefit for an individual subject, there may be benefits to society during this global COVID-19 
pandemic to understand which of these anti-inflammatory strategies are best in which 
populations.  
 
 Assessment of Potential Risks and Benefits of Baricitinib 
While baricitinib have been shown to be effective in COVID-19 hospitalized patients, there may 
not be a significant advantage for an individual subject to participate in this trial. However, there 
is also not a significant risk of participation.  
 
 
Dexamethasone  
 Potential risks of dexamethasone 
Dexamethasone is a licensed drug with a known safety profile. It is indicated in hormone diseases, 
rheumatic collagen disorders, GI and respiratory disorders (sarcoidosis, beryllioses, etc.). 
Common side effects include hyperglycemia, secondary infections, psychiatric effects, and 
avascular necrosis. Dexamethasone can also cause side effects involving the musculoskeletal 
system (muscle weakness, steroid myopathy, osteoporosis); gastrointestinal system (peptic ulcer 
with possible subsequent perforation and hemorrhage, perforation of the small and large bowel, 
pancreatitis, abdominal distention, and ulcerative esophagitis); skin (impaired wound healing, thin 
fragile skin, petechiae and ecchymoses, erythema); nervous system (convulsions); and 
cardiovascular system. Fluid and electrolyte disturbances can occur with dexamethasone use 
including sodium and fluid retention, congestive heart failure in susceptible patients, potassium 
loss, hypokalemic alkalosis, and hypertension. These fluid and electrolyte disturbances are less 


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common with dexamethasone than other corticosteroids since dexamethasone does not have any 
mineralocorticoid activity. Prolonged use of systemic corticosteroids may increase the risk of 
reactivation of latent infections (e.g., hepatitis B virus, herpesvirus infections, strongyloidiasis, 
tuberculosis). The risk of reactivation of latent infections for a 10-day course of dexamethasone (6 
mg once daily) is not well-defined. The RECOVERY trial did not collect routine AEs or SAEs, so 
it is unknown how this side effect profile is altered when dexamethasone is used to treat adult 
hospitalized patients with COVID-19. 
 
 Potential Benefits of Dexamethasone 
Given the RECOVERY results, dexamethasone likely improves the clinical outcome of adult 
patients hospitalized with COVID-19. However, this drug is available outside of the clinical trial. 
It is not known if treatment with dexamethasone is better than treatment with baricitinib. While 
there may not be benefits for an individual subject, there may be benefits to society during this 
global COVID-19 pandemic to understand which of these anti-inflammatory strategies are best 
in which populations.  
 
 Assessment of Potential Risks and Benefits of Dexamethasone 
While dexamethasone has been shown to be effective in COVID-19 hospitalized patients, there 
may not be a significant advantage for an individual subject to participate in this trial. However, 
there is also not a significant risk of participation.  
 
3. 
OBJECTIVES AND ENDPOINTS 
The overall objective of ACTT-4 is to evaluate the clinical efficacy and safety of baricitinib and 
remdesivir (Arm 1) versus dexamethasone and remdesivir (Arm 2) among hospitalized adults 
who have COVID-19. 
 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
Primary Objective and Endpoint 
To evaluate the clinical efficacy of 
baricitinib + remdesivir versus 
dexamethasone + remdesivir as 
assessed by the mechanical 
ventilation free survival by Day 29. 
Proportion of subjects not meeting criteria for one of 
the following two ordinal scale categories at any time 
by Day 29 
• Category 8: Death 
• Category 7: Hospitalized, on invasive mechanical 
ventilation or ECMO 
 
Key Secondary Objective and Endpoint 
To evaluate the clinical efficacy of 
baricitinib + remdesivir versus 
dexamethasone + remdesivir 
according to clinical status (8-point 
ordinal scale) at Day 15. 
 
Proportion of subjects meeting criteria for each of the 
8 ordinal scale categories on Day 15  
• Category 8: Death; 
• Category 7: Hospitalized, on invasive mechanical 
ventilation or ECMO; 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
 
 
• Category 6: Hospitalized, on non-invasive 
ventilation or high flow oxygen devices; 
• Category 5: Hospitalized, requiring supplemental 
oxygen; 
• Category 4: Hospitalized, not requiring 
supplemental oxygen – requiring ongoing medical 
care (COVID-19 related or otherwise); 
• Category 3: Hospitalized, not requiring 
supplemental oxygen – no longer requires ongoing 
medical care; 
• Category 2: Not hospitalized, but has new or 
increased limitation on activities and/or new or 
increased requirement for home oxygen over 
baseline, pre-COVID-19 status; 
• Category 1: Not hospitalized, patient is back to 
their baseline, pre-COVID-19 status, that is, no 
new or increased limitations on activities and no 
new or increased oxygen use. 
 
Additional Secondary Objectives and Endpoints 
To evaluate the clinical efficacy of 
baricitinib + remdesivir versus 
dexamethasone + remdesivir among 
subjects with a baseline ordinal scale 
of 5 as assessed by the proportion 
that do not progress to ordinal scale 
6, 7 or 8 at any time by Day 29. 
Proportion of subjects not meeting criteria for one of 
the following ordinal scale categories at any time by 
Day 29 
• Category 8: Death 
• Category 7: Hospitalized, on invasive mechanical 
ventilation or ECMO 
• Category 6: Hospitalized, on non-invasive 
ventilation or high flow oxygen devices 
 
Mortality 
 14-day mortality 
 28-day mortality 
 
 
• Date of death (if applicable) 
 
Time to recovery by Day 29 
 
Day of recovery is defined as the first day on which 
the subject satisfies one of the following three ordinal 
scale categories: 
• Category 3: Hospitalized, not requiring 
supplemental oxygen – no longer requires ongoing 
medical care; 
• Category 2: Not hospitalized, but has new or 
increased limitation on activities and/or new or 
increased requirement for home oxygen over 
baseline, pre-COVID-19 status; 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
• Category 1: Not hospitalized, patient is back to their 
baseline, pre-COVID-19 status, that is, no new or 
increased limitations on activities and no new or 
increased oxygen use. 
 
Time to an improvement of one 
category and two categories from 
Day 1 (baseline) using ordinal 
scale. 
 
Day of one and two category improvement from 
baseline ordinal score  
 
Subject clinical status using ordinal 
scale at 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. 
 
Desirability of Outcome Ranking 
(DOOR) at Day 15 and Day 29 
 
• DOOR at Day 15 and 29 based on ordinal scale:  
1- Recovered (category 1, 2 or 3 on ordinal scale) 
2- Improved (≥ 1 category improvement of ordinal 
scale compared with baseline) & no SAE 
3- Improved (≥ 1 category improvement of the 
ordinal scale compared with baseline) & SAE 
(related or unrelated) 
4- No change in ordinal scale from baseline & no 
SAE 
5- No change in ordinal scale from baseline & SAE 
(related or unrelated) 
6- Worsening (≥ 1 category worse in ordinal scale 
from baseline)  
7- Death 
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) 
 
• Days of invasive mechanical ventilation/ECMO (if 
applicable) up to Day 29. 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
 Ventilator / ECMO use up to Day 
29. 
 Incidence and duration of new 
mechanical ventilation or ECMO 
use during the study.  
 
 
o Hospitalization 
 Duration of hospitalization (days).  
 
 
• Days of hospitalization up to Day 29 
o Laboratory efficacy 
 d-dimer, and C-reactive protein 
(CRP) over time 
 
• 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). 
 
Safety Objectives and Endpoints 
To evaluate the safety of baricitinib + 
remdesivir versus dexamethasone + 
remdesivir 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)). 
 
 
 
 
 
• SAEs 
• Grade 3 and 4 AEs  
• Incidence and number of discontinuation or 
temporary suspension of study product.  
• WBC with differential, hemoglobin, platelets, 
creatinine, glucose, total bilirubin, ALT, AST, 
and 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 Objectives and Endpoints 
Alternative Desirability of Outcome 
Ranking (DOOR) 
• DOOR at Day 15 and 29 using alternative ordinal 
scales combining efficacy and safety (to be 
detailed in the statistical analysis plan) 
 
Virology 
 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
To evaluate the virologic efficacy of 
Arm 1 as compared to Arm 2 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. 
• 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). 
Serology 
To evaluate the influence of 
baricitinib and dexamethasone on 
SARS-CoV-2 antibody response. 
 
 
• SARS-CoV-2 antibody titers on Day 1, 8, and 29 
Immunophenotype 
To define immunophenotype of 
subjects by analyzing markers of 
inflammation and transcriptomics. 
• Proteomic analysis of cytokines, markers of 
inflammation, and other circulating proteins Day 
1; Days 3, 5, 8, and 11 (while hospitalized) and 
Day 29 
• Additionally, in a subset of all subjects who 
consent to genetic testing: 
o Transcriptomic analysis of RNA in whole 
blood and individual immune cells on Days 
1, 3, 8 and 29 
Chronic Clinical Sequelae 
To describe clinical status of subjects 
2 months after treatment, overall and 
by treatment arm . 
Ordinal scale, incidence of supplemental oxygen use 
and physical disability (more than baseline pre-
COVID-19 status), readmission to hospital; proportion 
of subjects with new diagnoses including deep venous 
thrombosis (DVT), infections, post-traumatic stress 
disorder (PTSD), anxiety and/or depression. 
 
  
4. 
STUDY DESIGN 
4.1 
Overall Design 
ACTT-4 will evaluate the combination of baricitinib and remdesivir compared to dexamethasone 
and remdesivir. Subjects will be assessed daily while hospitalized. After the subjects are 
discharged from the hospital, they will have a study visit at Days 15, 22, and 29  (as applicable). 
For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety 
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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. Additionally, subjects will be contacted by 
phone at 2 months to assess long term efficacy and safety outcomes as an exploratory outcome. 
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. 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 with confirmed 
SARS-CoV-2 infection. 
 
The ACTT-4 design will specifically evaluate the contributions of blocking inflammatory 
pathways with the JAK inhibitor baricitinib compared with less specific, anti-inflammatory 
effects of dexamethasone 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 used in previous ACTT studies, 
and is the US FDA approved doses. The duration of dosing may be adjusted by the site according 
to clinical severity. The maximum number of doses to be given during hospitalization is ten 
doses. This includes the loading dose and all maintenance doses given during the study and pre-
study if applicable. 
 
 
Justification for Dose of Baricitinib 
This study will use the same dose and duration of baricitinib that was evaluated in ACTT-2. This 
4-mg daily dose of baricitinib was originally selected for use in this population of adults 
hospitalized with COVID-19 based on clinical data showing an inhibitory effect on cytokine 
signaling. In patients with RA, 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 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 (42).  
 
Justification for Dose of Dexamethasone 
This study will use the same dose and duration of dexamethasone that was evaluated in the 
RECOVERY trial, the largest and most influential study of dexamethasone in COVID-19.  
 


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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.  
 
Subject Inclusion and Exclusion Criteria must be confirmed by an investigator 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 
1. Hospitalized with symptoms suggestive of COVID-19. 
2. Subject (or legally authorized representative) provides informed consent prior to initiation of 
any study procedures and understands and agrees to comply with planned study procedures. 
3. Male or non-pregnant female adults ≥ 18 years of age at time of enrollment. 
4. Illness of any duration and has laboratory-confirmed SARS-CoV-2 infection as determined 
by PCR or other commercial or public health assay (e.g. NAAT, antigen test) in any 
respiratory specimen or saliva ≤14 days prior to randomization. 
5. Within the 7 days prior to randomization requiring new use of supplemental oxygen (or 
increased oxygen requirement if on chronic oxygen) and requires at the time of 
randomization low or high flow oxygen devices or use of non-invasive mechanical 
ventilation (ordinal scale category 5 or 6). 
6. 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.  
7. Agrees not to participate in another blinded clinical trial (both pharmacologic and other types 
of interventions) for the treatment of COVID-19 through Day 29 (see Section 5.4 for more 
information about concurrent trial participation). 
 
5.2 
Exclusion Criteria 
1. Prior enrollment in ACTT-3 or ACTT-4. Note: this includes subjects whose participation in 
ACTT was terminated early. 
2. On invasive mechanical ventilation at the time of randomization (ordinal scale category 7).  
3. Anticipated discharge from the hospital or transfer to another hospital which is not a study 
site within 72 hours of randomization. 
4. Positive test for influenza virus during the current illness (influenza testing is not required by 
protocol). 
5. Subjects with a low glomerular filtration rate (eGFR), specifically: 
a. Subjects with an eGFR 15-30 mL/min are excluded unless in the opinion of the PI, the 
potential benefit of participation outweighs the potential risk of study participation. 
b. All subjects with an eGFR <15 mL/min  
c.  All subjects on hemodialysis and/or hemofiltration at screening, irrespective of eGFR, 
are excluded. 
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7. Lymphopenia (absolute lymphocyte count <200 cells/μL, 0.20 x 103/μL). 
8. Received five or more doses of remdesivir including the loading dose, outside of the study as 
treatment for COVID-19.  
9. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day 1 
until two weeks after the last study product is given are not excluded). 
10. Allergy to any study medication. 
11. Received convalescent plasma or intravenous immunoglobulin [IVIg] for COVID-19, the 
current illness for which they are being enrolled. 
12. Received any of the following in the two weeks prior to screening as treatment of COVID-
19: 
• More than one dose of baricitinib for the treatment of COVID-19; 
• Other small molecule tyrosine kinase inhibitors (e.g. imatinib, gefitinib, acalabrutinib, 
etc.); 
• monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 
[IL-1], anti-IL-6 [tocilizumab or sarilumab], etc.);  
• monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19. 
Note: receipt of anti-SARS-CoV-2 mAb prior to enrollment (e.g. bamlanivimab) for their 
current COVID-19 illness is not exclusionary 
13. Use of probenecid that cannot be discontinued at study enrollment. 
14. Received 6 mg or more of dexamethasone po or IV (or equivalent for other glucocorticoid) in 
one day, on more than one day, in the 7 days prior to time of randomization. Note: 6 mg 
dexamethasone dose equivalents include 40 mg prednisone, 32 mg methylprednisolone and 
160 mg hydrocortisone. 
15. Received ≥20 mg/day of prednisone po or IV (or equivalent for other glucocorticoids) for 
≥14 consecutive days in the 4 weeks prior to screening. 
16. Have diagnosis of current active or latent tuberculosis (TB), if known, treated for less than 4 
weeks with appropriate therapy (by history only, no screening required). 
17. Serious infection (besides COVID-19), immunosuppressive state, or immunosuppressive 
medications that in the opinion of the investigator could constitute a risk when taking 
baricitinib or dexamethasone. 
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 including SARS-CoV-2 vaccine is allowed for all subjects.  
19. Had a known VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) during the 
current COVID-19 illness. 
 
 
Exclusion of Specific Populations 
Information about the epidemiology of COVID-19 indicates that the largest burden of severe 
disease requiring hospitalization occurs among older adults, especially those with comorbidities. 
The incidence of severe morbidity and mortality among children and adolescents is low, and the 
clinical spectrum and natural history of COVID-19 among children and adolescents is not well 
understood. There is also limited data about the use of anti-inflammatory medications such as 
dexamethasone or baricitinib in children. Due to these gaps in knowledge of the disease in this 
population, a low incidence of severe disease, and an inability to justify a benefit to this population, 
children and adolescents will not be included in this trial.  


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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. 
A short course of dexamethasone is routinely used to decrease neonatal complications of 
prematurity in pregnant women with threatened preterm delivery and is generally is well tolerated 
in pregnant women.(43) Infants born of mothers who have received substantial doses of 
corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. 
Because the effects of remdesivir and baricitinib 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. Baricitinib is present in the milk of lactating rats. There is no information 
available on the presence of baricitinib in human milk or the effects of the drug on the breastfed 
infant. Dexamethasone has been used in lactating women. Corticosteroids appear in breast milk 
and could suppress growth, interfere with endogenous corticosteroid production, or cause other 
unwanted effects. Because the effects of remdesivir and baricitinib on the breastfeeding infant is 
not known, women who are breast feeding will not be eligible for the trial unless they agree to 
discharge breast milk from Day 1 until 2 weeks after the last dose is administered. 
 
5.3 
Inclusion of Vulnerable Subjects 
Certain 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 gives consent,  
if the subject regains the capacity to consent during the course of the study, informed consent must 
be obtained from the subject and the subject offered the ability to leave the study if desired. 
 
For this clinical trial, we will not enroll prisoners or detainees as subjects.  
 
5.4 
Lifestyle Considerations 
During this study, subjects are asked to: 
• Avoid getting pregnant during the study from Day 1 through Day 29. 
• Not participate in the following types of trials for the treatment of COVID-19 or SARS-
CoV-2 infection:  


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o Blinded or unblinded interventional trials that evaluate if a non-approved 
medication or intervention is effective are prohibited.  
o Any other blinded interventional trials for treating COVID-19 are prohibited. 
o If a subject is co-enrolled in a prohibited study noted above, this should be 
reported as a protocol deviation, but the subject should not be withdrawn from 
this trial to participate in the other study. Full follow-up should occur per 
protocol.  
• Participation in both ACTT and these studies can only occur if the recommended blood 
collection volumes are not exceeded. 
o Co-enrollment in non-blinded (open-label) interventional studies that evaluate 
how to apply a standard of care intervention or strategy for patients with COVID-
19 (e.g., comparing dose, duration or schedule of VTE prophylaxis regimens; ICU 
strategies such as proning, etc.) is permitted.  
o Co-enrollment in natural history studies of COVID-19 and/or studies of SARS-
CoV-2 diagnostics is permitted.  
5.5 
Screen Failures 
Following consent, after the screening evaluations have been completed, the investigator or 
designee is to review the inclusion/exclusion criteria and determine the subject’s eligibility for the 
study. If there is any uncertainty, the PI should make the decision on whether a potential subject 
is eligible for study enrollment.  
 
Only basic demographic information and the reason(s) for ineligibility will be collected on screen 
failures. Subjects who are found to be ineligible will be told the reason(s) for ineligibility. 
 
Individuals who do not meet the criteria for participation in this study (screen failure) because of 
an abnormal clinical laboratory finding may be rescreened once.  
5.6 
Strategies for Recruitment and Retention 
 
Recruitment 
It is anticipated that patients with COVID-19 will present for hospitalization to participating 
clinical trial sites, 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. 
 
Recruitment activities will include pre-screening activities and will begin with a brief discussion 
between study staff and the subject/LAR before consent. Some subjects will be excluded based on 
demographic data and medical history alone (e.g., pregnant, < 18 years of age, on hemodialysis, 
etc.). In addition, information about the study will be presented to potential subjects or LAR and 
questions will be asked to determine potential eligibility after which time informed consent is 
obtained and further screening is completed (see Section 8.1.1). 
 


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Retention 
Retention of subjects is critical to the success of the trial since the primary endpoint is measured 
at Day 29 (+ 6-day window) and every effort should be made to retain subjects in the study. As 
such, after hospital discharge, subjects will be reminded of subsequent study visits and every effort 
will be made accommodate the subject’s schedule to facilitate follow-up within the specified visit 
window. To facilitate retention, follow-up visits may be conducted by phone, home visit or remote 
telehealth procedure as per institutional standards if in-person visits at the clinical site on Days 15 
and 29 are not feasible. The Day 22 visits are by phone call or remote telehealth procedure.  
 
However, there are many circumstances that impact a site’s ability to obtain outcome information 
after discharge. For example, given the clinical course of COVID-19, a subject may be readmitted 
to another hospital after discharge and therefore be unavailable at Day 15 or Day 22. Even if a 
study visit is missed, every effort should be made to keep subjects in the study to monitor for 
safety, readmission and mortality. Subjects should not be withdrawn from the study because a site 
is unable to contact them for a follow-up visit.  
 
Subjects should not be withdrawn from this trial due to terminal illness. If a subject or family is 
pursuing hospice or withdrawal of care, the study visits can be curtailed as needed, but these 
subjects (or their LARs) should be encouraged to remain in study for the Day 29 endpoint 
evaluation by chart review or phone call.  
 
In addition, in ACTT-4 we will have a visit two months after randomization to assess long term 
efficacy and safety outcomes. This visit will be conducted by phone or remote telehealth 
procedure. Because of this visit, sites will need to plan for how they will contact subjects at this 
late time point. 
  
 
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  
Subjects will be randomized into one of two arms (1:1). 
 
Arm 1 
Arm 2 
Baricitinib tablets +  
Placebo IV + 
Placebo tablets +  
Dexamethasone IV +  


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Remdesivir IV 
 
Remdesivir IV 
 
 
 
 
Study Product Description  
Remdesivir Component 
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 and solution formulations of remdesivir contain the following inactive ingredients: 
water for injection, betadex sulfobutyl ether sodium, and hydrochloric acid and/or sodium 
hydroxide. 
 
Baricitinib Component 
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.  
 
Oral Placebo Component (Baricitinib) 
Placebo for baricitinib 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. 
 
Dexamethasone Component 
Dexamethasone Sodium Phosphate Injection, USP, is an adrenocortical steroid anti-
inflammatory drug. It is a water-soluble inorganic ester of dexamethasone. Each mL contains 
dexamethasone sodium phosphate equivalent to dexamethasone phosphate 4 mg or 
dexamethasone 3.33 mg; benzyl alcohol 10 mg added as preservative; sodium citrate dihydrate 
11 mg; sodium sulfite 1 mg as an antioxidant; Water for Injection q.s. Citric acid and/or sodium 
hydroxide may have been added for pH adjustment (7.0 to 8.5). Dexamethasone is supplied as a 
5 mL multi-dose vial.  
 
Placebo Component (Dexamethasone) 
The dexamethasone placebo will be 0.9 % sodium chloride injection, USP. The USP grade 0.9% 
Sodium Chloride Injection, or normal saline, is a sterile, nonpyrogenic, isotonic solution; each 
mL contains sodium chloride 9 mg. It contains no bacteriostatic agent, antimicrobial agent, 
preservatives, or added buffer and is supplied only in single-dose containers. The solution may 
contain hydrochloric acid and/or sodium hydroxide for pH adjustment (pH 5.3, range 4.5-7.0). 
This product will be used as the placebo for dexamethasone IV push administration at an equal 
volume at the same schedule.  
 


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Dosing and Administration 
Dosing of the medications does not need to occur at the same time. Study Day 1 is the first day 
any of the 3 study products is administered (i.e., study remdesivir, baricitinib/po placebo, or 
dexamethasone/IV placebo given on study) and is used to determine timing of protocol 
assessments and safety analyses as outlined in SOA. Sites have 24 hours between randomization 
(enrollment) and initial study product administration.   
 
Remdesivir 
• 
Up to four doses of remdesivir are allowed prior to randomization. Remdesivir should be given 
as soon as possible after randomization. If a patient receives remdesivir in the emergency 
department late at night or early in the morning on day of enrollment, the dosing may be 
transitioned to daytime hours if desired by allowing a minimum 12-hour window between the 
pre-study dose and Day 1 dose.    
• 
After Day 1, remdesivir should be given approximately every 24 hours +/- 2 hours. Protocol 
deviations do not need to be submitted if remdesivir given outside of this window. Protocol 
deviations should be submitted if a daily dose is missed completely. 
• 
This dosing should occur as described regardless of the options for anti-inflammatory dosing 
discussed below.  
• 
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 prior to study 
enrollment, then start at 100 mg/day on Day 1. Any doses of remdesivir given prior to 
enrollment will be counted, so the total duration of remdesivir (i.e. pre-enrollment + on this 
trial) is 10 days (i.e., a maximum of 10 total infusions). Any doses of remdesivir were 
administered prior to study enrollment should be documented in Advantage eClinical as a 
concomitant medication given prior to Day 1. The duration of dosing may be adjusted by the 
site similar to what is described in the package insert and based on a subject’s clinical course 
and ultimate disease severity.  
 
ANTI-INFLAMMATORY AGENTS (DEXAMETHASONE/IV PLACEBO + BARICITINIB/ PO PLACEBO)   
• The anti-inflammatory agents should be given as soon as possible after randomization, but 
they also should be given around the same time so one arm is not receiving treatment sooner 
than the other arm.    
For patients, who have received dexamethasone before enrollment as part of their clinical care:  
• If a patient has received dexamethasone the day prior to enrollment, then the baricitinib/po 
placebo and dexamethasone/IV placebo can be administered right after randomization and 
this becomes Day 1.  
• If a patient has received dexamethasone at any time on the day of enrollment but before 
randomization/enrollment, then there are several options as described below.  
o It is preferred to randomize and give remdesivir + dexamethasone/po placebo + 
baricitinib/IV placebo on the same calendar day as randomization. This could result 
in subjects receiving two doses of dexamethasone on Day 1 (a pre-study dose and 
an on-study dose of dexamethasone/IV placebo).   


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o If the site is concerned with this high dose of dexamethasone, sites have 24 hours 
between randomization (enrollment) and initial study product administration (i.e. 
both drugs may be delayed until the calendar day after randomization but within 24 
hours of randomization).  
o Alternatively, if necessary (but not preferred), sites may randomize and give 
remdesivir and baricitinib/po placebo on the same calendar day as randomization 
(this becomes Day 1) and on Day 2, give all other study products and submit a 
protocol deviation for missed dose of IV push study product on Day 1 and this 
missed dose of dexamethasone/IV placebo will not be made-up during the study. 
The subject will receive only 9 doses of  dexamethasone/IV placebo from Day 2 
through Day 10. This option allows the PI to decide the risk /benefit ratio of a 
potential double dose of dexamethasone on Day 1 for their patients.   
 
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 dissolved 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 dissolved 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 baricitinib for renal failure. 
• See MOP for instructions on how to prepare and administer baricitinib to patients having 
difficulty swallowing 
 
For dexamethasone component, subjects will receive either active product or placebo as follows: 
• Dexamethasone will be administered as a 6 mg slow IV push over 3 to 5 minutes daily 
for the duration of the hospitalization up to a 10-day total course. 
• A placebo will be given as an equal volume normal saline, as a slow IV push daily for the 
duration of the hospitalization up to a 10-day total course. 
• If local standards use other means of administration (such as IV infusion), these may be 
used for both active and placebo after approval of the sponsor. Reports of intense perineal 
pain and/or burning are reported immediately after given IV push too quickly. 
• Any pre-study dexamethasone (see exclusion criteria) is not counted towards the 10 day 
course.  
 
 
Duration of therapy: 
• IV remdesivir – up to 10 days while hospitalized (i.e., maximum of 10 total infusions pre-
enrollment and during study). 
• Oral baricitinib (or oral placebo) – 14 days while hospitalized (i.e., maximum of 14 total 
doses). 
• IV dexamethasone (or IV placebo) – 10 days while hospitalized (i.e., maximum of 10 
total doses). 
• All medications stop on discharge from hospital.  
o Of note, if a subject is retained in the hospital for non-COVID-19 related issues 
and no longer requires supplemental oxygen and ongoing medical care (i.e., 
ordinal scale category 3), the PI may decide to discontinue all medications.  


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• If readmitted after discharge, see Section 7.4. 
 
 
Dose Escalation 
Not Applicable 
 
 
Dose Modifications 
The protocol-required safety laboratories (per the SOA) are anticipated to be sufficient for 
evaluating for dose modifications, but if other laboratory data obtained as part of standard care are 
available, these should also be used in the evaluation.  
 
Remdesivir component: 
The infusion should be held and not given if the subject is found to have any of the following 
laboratory values: 
 
• eGFR decreases to < 15 mL/min 
o Remdesivir infusion will resume when the eGFR increases to ≥ 15 mL/min and the 
potential benefit of giving remdesivir outweighs the potential risk.  
o If renal function worsens during the study to the point that they require hemodialysis 
or hemofiltration, remdesivir will be discontinued. 
• ALT and/or AST increases to > 10 times upper limits of normal (ULN); resume remdesivir 
infusions when ALT and AST ≤ 5 times ULN. 
 
Baricitinib/Oral Placebo component: 
Dose of oral study product will be decreased or held based on eGFR. Specifically: 
eGFR Value 
Dose of baricitinib or oral placebo 
≥60 mL/min 
Two tablets (4 mg total) once daily  
No dose adjustment 
30 - <60 mL/min 
One tablet (2 mg) once daily 
15 - <30 mL/min 
One tablet (2 mg) QOD – every other day 
<15 mL/min or require hemodialysis or 
hemofiltration 
Hold oral study product  
 
Oral study product should be temporarily interrupted if the subject develops any of the following 
during the study: 
• eGFR decreases to < 15 mL/min; resume oral study product when eGFR ≥ 15 mL/min 
• Absolute neutrophil count (ANC) <500 cells/μL; resume oral study product when ANC ≥ 
700. 
• Absolute lymphocyte count (ALC) <200 cells/μL; resume oral study product when ALC 
≥ 200.  
• ALT and/or AST increases to > 10 times ULN; resume oral study product when the ALT 
and AST ≤ 5 times ULN. 
• New serious infection identified (i.e., SAE infection); may resume oral study product when 
PI believes that the infection is under control  
 


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Any dose that is held as described above, may be given later that day if the laboratory parameters 
improve. Any daily dose that is missed during the study due to any reason is not made up. The 
treatment course continues as described above even if the subject becomes PCR negative while 
hospitalized. If oral study product is held for more than 2 days, consider that the subject may not 
be receiving any anti-inflammatory. If the clinical condition requires, an open-label (off-study) 
dexamethasone or other anti-inflammatory agent may be added while the oral study product is 
held. No protocol deviation for prohibitory medications (i.e., off-study dexamethasone) would be 
required for these days of anti-inflammatory coverage while the subject has oral study product 
held. 
 
For laboratory values that meet permanent discontinuation thresholds (see Section 7.1), 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 once.  
 
 
Overdosage 
Overdose is not anticipated in the context of a clinical trial. Study product will be administered to 
subjects. There is no known antidote for baricitinib. However, if a site inadvertently gives a subject 
excess baricitinib, the site should contact the Sponsor. The subject should receive supportive 
therapy based on the subject´s signs and symptoms. 
 
Reports of acute toxicity and/or death following overdosage of glucocorticoids are rare. In the 
event of overdosage, no specific antidote is available; treatment is supportive and symptomatic.  
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, unless specified in the protocol-specific 
Manual of Procedures (MOP) or pharmacy manual. 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 
Sponsor’s monitoring staff will verify the participating site’s study product accountability records 


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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 
Remdesivir may be supplied in two formulations: 
• The lyophilized formulation of remdesivir is a preservative-free, white to off-white or 
yellow, lyophilized solid containing 100 mg of remdesivir to be reconstituted with 19 mL 
of sterile water for injection respectively and diluted into IV infusion fluids prior to IV 
infusion.  
• The concentrated liquid solution is supplied as a single-dose glass vial containing 100 
mg/20 mL (5 mg/mL) of remdesivir that is a sterile, preservative-free, clear, colorless to 
yellow, aqueous-based concentrated solution to be diluted into 0.9% sodium chloride 
infusion bag prior to administration by intravenous infusion.  
 
Remdesivir will be labeled according to manufacturer specifications. For complete details of the 
preparation, packaging and administration, please see the package insert and the MOP. 
 
Baricitinib component 
Baricitinib tablets are 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.  
Study interventions (baricitinib and placebo) will be supplied by the sponsor or its designee in 
accordance with current Good Manufacturing Practice (cGMP). 
 
Dexamethasone component 
According to the package insert, dexamethasone is available as 4 mg per mL in a 5 mL multi-
dose vial. It is a sterile solution of dexamethasone sodium phosphate in water for injection for 
intravenous (IV).  
 
Intravenous placebo for dexamethasone component 


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Intravenous normal saline placebo matches the active dexamethasone product in volume and 
appearance. It is supplied in single-use vial. 
A label with the statement “Caution: New drug -Limited by Federal Law to investigational use” 
will be placed on the immediate package. 
 
 
Product Storage and Stability 
The Pharmacy Manual provides instructions for the preparation, handling, and storage of baricitinib 
drug product and placebo, dexamethasone drug product and placebo and remdesivir, and describes 
site responsibility and accountability for the administered products.  
 
See most recent version of package insert and information as posted on the Emmes website. 
 
 
Preparation 
Refer to the protocol-specific MOP for details about preparation of all study products. 
  
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 Hospitalized, on non-invasive ventilation or high flow oxygen devices, OR 
o Hospitalized, 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. 
 
The dexamethasone/placebo IV component is blinded. Dexamethasone and intravenous placebo 
are identical in appearance. 
 
 Unblinding at end of study 
Unblinding of the study will occur after all subjects enrolled have reached the end of study, these 
visits are monitored, and data is cleaned or if the DSMB recommends unblinding. Data through 
Day 29 will be locked prior to the completion and lock of Day 60 data. DMID and the SDCC 
will be unblinded after the Day 29 database lock.  Clinical sites will not be unblinded to subject-
level treatment assignments until after the Day 60 database lock.  
 


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 Unblinding for worsening clinical status 
If a subject’s clinical status worsens to require mechanical ventilation (ordinal 7), the treating 
clinician may request unblinding in order to use the prior treatment assignment to inform future 
treatment. See section 6.5.4 for preferred alternatives prior to unblinding. Any unblinding for this 
purpose will be tracked by the Sponsor, and sites that frequently unblind subjects in this ordinal 
scale category may have enrollment curtailed by the Sponsor.  
 
 Unblinding for adverse event 
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. If unblinded for SAE, the investigator may 
decide to have the blinded study product and/or remdesivir infusions discontinued based on the 
adverse event that led to unblinding and the benefit-risk analysis. The subject should remain on 
study through the Day 60 visit. The procedure for emergency unblinding will be further detailed 
in the Manual of Operations. 
 
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 
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]) 
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 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. 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 is permitted (except for dexamethasone and 


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baricitinib as noted below). There should be plans on how the concomitant drugs are stopped in 
case of additive toxicities. 
 
On August 23, 2020, the FDA issued an EUA for COVID-19 convalescent plasma for the treatment 
of hospitalized patients with COVID-19. The NIH COVID-19 Treatment Guidelines were updated 
on September 1, 2020 and concludes that “there are insufficient data to recommend either for or 
against the use of convalescent plasma for the treatment of COVID-19”. According to the NIH 
Guidelines and the EUA Fact Sheet for Health Care Providers, convalescent plasma should not be 
considered the standard of care for the treatment of patients with COVID-19. However, if a site 
has adopted convalescent plasma as part of their institutional standard of care for the treatment of 
COVID-19 patients, it is allowed as described above. 
 
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 
As the study is comparing baricitinib to dexamethasone, additional baricitinib, dexamethasone and 
other glucocorticoids are prohibited unless the subject worsens and requires invasive mechanical 
ventilation (see Section 6.5.4). In addition, if oral study product is held for more than two days and 
the clinical condition requires, an open-label (off-study) dexamethasone or other anti-
inflammatory agent may be added while the oral study product is held (Section 6.1.4). Exceptions 
to the steroid prohibition include: mineralocorticoids for standard indications are permitted (e.g., 
adrenal insufficiency, shock) and low-dose prednisone as part of immunosuppression regimen for 
solid organ-transplant patients is allowed (e.g., prednisone 5 mg po daily).  
 
Strong inhibitors of organic anion transporter 3 (OAT3) such as probenecid are prohibited during 
the study. 
 
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, and not specified in the 
local or NIH COVID-19 Treatment Guidelines are prohibited. Specifically, use of any biologic 
therapy not specified on the written policy or guideline are prohibited including: 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) (e.g., 
baricitinib, imatinib, gefitinib, acalabrutinib, tofasitinib); and any type of interferon, convalescent 
plasma, or immunoglobulin (IgG) therapies for COVID-19. Similarly, the concomitant use of 
hydroxychloroquine to treat COVID-19 is prohibited unless it is included in the local institutional 
treatment guidelines (and even then, it is discouraged given the interaction with remdesivir).  
 
 
Assessment of Concomitant Therapies 
Concomitant medications will be assessed from 7 days prior to enrollment to Day 29 or upon 
discharge, whichever comes first for all medications except corticosteroids. All corticosteroids 
(except nasal, opthalmic, or topical steroids) including dexamethasone, prednisone, prednisolone, 


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and methylprednisolone should be recorded from Day -7 through Day 29 even after discharge 
from the hospital. Recording corticosteroid use after hospital discharge is important because long 
courses of po corticosteroids given after hospital discharge may impact our study endpoints. All 
prescription medications should be recorded during this time period with the exceptions listed in 
the bullets below. All medications, except biologics and corticosteroids, can be recorded once 
regardless of the number of times it was given during the time period. For example, vasopressors 
should be recorded when first dose given (as the start date) and the last dose given (as the end 
date) during the period of assessment.  
 
Sites do not need to record any of the following categories of medications in the eClinical system 
during the period from Day -7 through Day 29: 
o All topical medications: ointments, creams, and lotions; 
o All intranasal medications: nasal decongestants, nasal allergy medications, nasal steroids, 
and nasal saline drops/sprays;  
o All ophthalmic medications: ophthalmic allergy medication, ophthalmic medications for 
infection, and ophthalmic medications for eye dryness (e.g., saline eye drops); 
o Antiseptic mouth wash, lozenges; 
o Cough medication: mucolytics, cough suppressants, and expectorates; 
o GI medications: H2 blockers, proton pump inhibitors, GI stimulants, prokinetics, laxatives, 
stool softeners, antacids, anti-diarrheal and anti-nausea medications; 
o Symptomatic care medications: antipyretics, antihistamines, decongestants, and NSAIDs;  
o Mineral or herbal supplements, dietary supplements, iron/ferrous sulfate, magnesium, 
calcium, electrolyte replacement; 
o Albumin infusions; 
o Melatonin; 
o Nicotine patch, lozenge, gum, or nasal spray, or other product to treat tobacco dependence; 
o Dyes: contrast media, iodine – based dye, barium sulfate, and diatrizoate sodium. 
 
See the MOP for more information about recording concomitant medications. 
 
 
Progression to Intubation/Invasive Mechanical Ventilation.  
In ACTT-4, non-study product (off-study) baricitinib, dexamethasone and other glucocorticoids 
are prohibited unless the subject worsens to require invasive mechanical ventilation (ordinal score 
7). Mineralocorticoids for standard indications are permitted (e.g., adrenal insufficiency, shock). 
Low-dose prednisone as part of immunosuppression regimen for solid organ-transplant patients is 
allowed as part of standard of care (e.g., prednisone 5 mg po daily).  
 
If additional (off-study) baricitinib, dexamethasone or another glucocorticoid is given when a 
subject is not an ordinal scale category 7, the investigator should file a protocol deviation for use 
of the prohibited medication and decide whether the blinded study products should be 
discontinued.  The subject should remain on study and continue with the SOA as described in the 
protocol though the Day 60 visit. An exception to this is when oral study product is held for more 
than 2 days and the clinical condition requires that an open-label (off-study) dexamethasone or 
other anti-inflammatory agent be added while the oral study product is held (see Section 6.1.4).  
 


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If a subject’s clinical status worsens to require invasive mechanical ventilation (ordinal 7), the 
following should occur: 
• The preference is to continue study medication as originally assigned (i.e. continue 
blinded baricitinib or placebo and continue blinded dexamethasone or placebo) as well as 
the remdesivir infusions. The subject should remain on study though the Day 60 visit.  
• Recognizing the treating clinician may request to stop the randomized blinded study 
medication, the next preferred option is that the baricitinib/placebo po component and the 
dexamethasone/placebo IV component are discontinued without unblinding. This will 
allow the treating clinician to pick any regimen needed for the subject. In this scenario, 
remdesivir infusions should continue and the subject should remain on study though the 
Day 60 visit. 
• If the treating clinician needs to know prior treatment, the site investigator can request 
that the subject treatment assignment be unblinded. This is the least preferred option as it 
unblinds treatment assignment. However, it is available to ensure clinicians have 
information available to give their patients optimal care. In this scenario, remdesivir 
infusions should continue and the subject should remain on study through the Day 60 
visit. 
 
The above treatment choices will be tracked for all subjects that worsen to require 
mechanical ventilation (ordinal 7) and will be tracked by the sponsor. Sites that consistently 
unblind subjects in this category may have enrollment curtailed by the sponsor. The MOP 
Part A Clinical, Section 5 and an informational sheet for staff training located on the Emmes 
website titled, Unblinding for Progression to Mechanical Ventilation, describe the 
unblinding procedure and the documentation that is needed.  It is important that sites know 
the procedure so that site staff, the site PI and other ACTT investigators, and the Sponsor 
remain blinded. The unblinded study pharmacist should only unblind the treating clinician to 
the treatment assigmment if unblinding is deemed necessary.  
 
 
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 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. 
If signs and symptoms of a clinically significant hypersensitivity reaction occurs during or 
shortly after an infusion of Remdsivir or administration of the blinded study products (oral and 
IV push), administration must be stopped and treated as needed. Subjects who have the study 


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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.  See 
Section 7.1.1.2 below for additional  halting criteria for the blinded study products. 
 
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 and IV Study Product Halting 
See Section 6.1.4. for information about dosing modifications for the blinded oral study product 
due to laboratory abnormalities. Otherwise, criteria for discontinuing administration of the 
blinded oral and IV push study products are the same as outlined below. 
 
The subject should not receive any additional blinded oral and IV push study product  if they 
develop any of the following conditions during the study:  
• 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). 
• A systemic fungal infection is confirmed.  
• Clinically significant hypersensitivity, including anaphylaxis or anaphylactoid reaction 
during administration of either blinded oral or IV study product   
 
 
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 


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longer wish to participate in the study and no longer authorize the Investigators to make efforts 
to continue to obtain their outcome data or safety assessment. 
  
The investigator may also withdraw a subject from the study. However, the investigator will be 
encouraged to allow subjects to remain in the study to be followed for safety and final outcome 
assessment at Days 29 and 60 (i.e., the ordinal scale and mortality) even if they decide to 
discontinue study products and research laboratory draws. Withdrawing a subject from the study 
due to an inability to contact them for the Day 15 and/or Day 22 follow-up visit is discouraged 
given the possibility of readmission and chaotic social circumstances resulting from the 
pandemic. 
 
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 the site is unable to contact him or her by phone 
or other means such as text, email, fax or letter (as approved by the IRB) for all follow-up 
assessments at Day 15, 22 and 29. 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 11, they may be given 
the remainder of the remdesivir infusions, baricitinib/po placebo and dexamethasone/IV placebo 
component. If prior to Day 15, they may be given the remainder of the baricitinib/po placebo 
components. If the subject did not withdraw 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.  
 
The natural history of COVID-19 and its impact on pre-existing medical conditions is not 
completely understood. Because of this, all readmissions, regardless of reason, should be 
documented and the subject should get daily clinical status assessments (i.e., ordinal scale) and 
other procedures done as per the SOA upon readmission. 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 remdesivir or dexamethasone/IV placebo component study product 
infusions should be given past Day 10. No baricitinib/po placebo component should be given past 
Day 14. For all data collection procedures required for those readmitted, please see the MOP.  
 
8. 
STUDY ASSESSMENTS AND PROCEDURES 


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8.1 
Screening and Efficacy Assessments 
 
Screening Procedures 
Post consent screening procedures may be done over one to two calendar days (from Day -1 to 
Day 1). See Section 5.6.1 for allowable pre-screening procedures. 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).  
• 
Confirm that patient does not have a positive influenza test during the current illness for 
which they are being screened and possibly enrolled. Influenza testing is not required per 
protocol. 
• 
Take a focused medical history, including the following information:  
• Day of onset of COVID-19 signs and symptoms. 
• Prior enrollment in ACTT-3 or ACTT-4. 
• History of vaccinations within 4 weeks before screening and planned vaccinations.  
• Exclusionary vaccine history includes 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 including the recently EUA approved COVID-19 vaccines. 
Pre-study receipt of SARS-CoV-2 vaccine should be documented in the Medical 
History eCRF.  
• History of chronic medical conditions, including chronic oxygen requirement and/or 
use of CPAP or BiPAP at home, prior to onset of COVID-19. See conditions included 
in exclusion criteria and on the Medical History (CMX) data collection form. 
• History of medication allergies. 
• Medications and therapies for this current COVID-19 illness and history of any 
medication listed in the exclusion criteria. Site should identify if the patient received 
any dexamethasone in the 7 days prior to randomization.  
• Ask if the patient is participating in another clinical trial or plans 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.  


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• 
Blood for screening laboratory evaluations, if not done as part of routine clinical care in the 
preceding 48 hours, should be collected to evaluate the following parameters: 
 White blood cell count (WBC) with differential 
• Assess ANC and ALC as per exclusion criteria 
 
 Serum 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. 
• 
Do urine or serum pregnancy test during screening for women of childbearing potential or 
site may use test done prior to screening during this current hospital admission as long as 
patient has been confined in hospital since test was done. See instructions below for women 
who are less than 6 weeks postpartum: 
 Do not do a pregnancy test if the patient is post-partum and has not left the hospital 
since delivery. The pregnancy test will likely give a false-positive result as serum 
human chorionic gonadotropin (hCG) is usually detected for up to 4 to 6 weeks after 
delivery. 
 For women who are less than 6 weeks postpartum and have left the hospital, any 
positive pregnancy test should be repeated to determine if the HCG is declining as 
predicted after delivery and therefore the result is a false-positive. Of note, women who 
are less than 6 weeks postpartum and had heterosexual intercourse since delivery and 
hospital discharge are unlikely to be pregnant because the average time to first 
ovulation varies from 45 to 94 days postpartum, with the earliest reported ovulations at 
25 and 27 days postpartum.  
Clinical screening laboratory evaluations will be performed locally by the site laboratory. The 
volume of venous blood to be collected is presented in Table 7. A screening lab (i.e., from the 
hematology and chemistry laboratory panels) may be repeated once if, in the opinion of the 
investigator, the laboratory abnormality is due to an intercurrent transient condition or it is an 
aberrant laboratory value.  
 
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 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 the OP swab and blood and completing or recording a baseline physical 
examination that was done, including weight and height (height can be self reported). Clinical 
laboratory tests collected as part of routine care of the patients in the 36 hours prior to first dose 
qualify for baseline safety tests on Day 1. 


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If a subject is found to be ineligible AFTER being randomized and they did not receive any study 
product, the site should file an early study termination and stop all study procedures including 
specimen collection.  
If the subject is found to be ineligible AFTER being randomized and did receive study product, 
they may continue on study if the PI has no safety concerns with their continued participation. The 
site should file a study protocol deviation (i.e., checkbox: met exclusion criteria). However, if the 
PI feels that the risk of participation outweighs the benefit, the site should file an early study 
termination.  
 
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, as measured by the ordinal scale, will be captured at randomization 
and Day 2 through Day 29 (+ 6-day window) while hospitalized or day after death whichever 
comes first. The ordinal scale will also be captured on the day after discharge from the hospital. 
This will be done so that discharge and death are accurately recorded and captured in the eClinical 
system. For subjects who received oxygen by nasal cannula or CPAP ventilatory support at night 
at home prior to having COVID-19, sites should assign a recovery ordinal scale score of 1 or 2 
when discharged to home after recovery. The assignment of category 1 versus category 2 will 
depend on whether they have new or increased physical limitations post-COVID-19 and/or if they 
have new or increased home oxygen requirement compared with the baseline, pre-COVID-19 time 
period.  
 
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, an ordinal scale 
assessment should be completed for the day after death because the ordinal scale captures the worst 
clinical assessment for the previous day. If the site is aware of a subject death after the day 29 visit 
but within the window of the Day 29 study visit (i.e., Day 29 + 6-day window), complete an ordinal 
scale assessment on the day after death. 
 
After a subject is discharged, clinical status as measured by ordinal scale will be collected on 
remaining outpatient visits (Day 15, 22, 29, and 60). The ordinal scale can be assessed at an in-
person clinic visit or by phone, home visit or remote telehealth procedure as per institutional 
standards if an in-person visit at the clinical trial site is not possible.  
 
Ordinal scale is an assessment of death or the highest ventilatory support received in the last 24- 
hour period and therefore can be assessed at any time on the subsequent day. The following 
measures are recorded for the ordinal scale. See MOP for more detailed description of ventilatory 
devices in each category: 
 
• Hospitalization. 
• Oxygen requirement. 


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• Non-invasive ventilation requirement (CPAP, BiPAP). 
• 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 and reported as new or increased 
limitations as compared to status prior to the onset of COVID-19). 
• Isolated for infection control purposes. 
 
 Ordinal Scale 
The ordinal scale is used as the primary clinical assessment of subjects during the study.  
 
The scale used in this study is as follows (from worst to best): 
Category 8: Death; 
Category 7: Hospitalized, on invasive mechanical ventilation or ECMO; 
Category 6: Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
Category 5: Hospitalized, requiring supplemental oxygen; 
Category 4: Hospitalized, not requiring supplemental oxygen – requiring ongoing medical 
care (COVID-19 related or otherwise); 
Category 3: Hospitalized, not requiring supplemental oxygen – no longer requires ongoing 
medical care. This would include those kept in hospital for quarantine/infection control, 
awaiting bed in rehabilitation facility or homecare, etc.; 
Category 2: Not hospitalized, but has new or increased limitation on activities and/or new or 
increased requirement for home oxygen over baseline, pre-COVID-19 status; 
Category 1: Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, 
no new or increased limitations on activities and no new or increased oxygen use compared 
with baseline. 
 
As is described in the clinical MOP, specific definitions of ventilatory support for Category 6 and 
5 include:  
Category 6:  
• Non-invasive ventilation includes: CPAP without invasive ventilation (CPAP mask or nasal 
cup devices)  
• BiPAP  
High-flow oxygen device includes:  
• High Flow Nasal Cannula (HFNC): delivers heated and humidified oxygen, with a 
controlled fraction of inspired oxygen (FiO2), at a flow rate of 16 L/min or greater per 
minute via a nasal cannula  
 
Category 5:  
Low-flow oxygen devices provide the delivery of FiO2 at a maximum of 15 liters per minute 
or less and generally less than five liters per minute and include:  
• Non-rebreather mask  


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• HHFS – high humidified face shield  
• Standard nasal cannula  
• Venturi mask  
• High flow nasal cannula (15 L/min or less) 
• Oxymizer  
 
To determine a subject’s clinical status using the ordinal scale:  
• At randomization, the ordinal scale will be assessed and should reflect a subject’s clinical 
status at the time of randomization. As there should be <24 hours between randomization 
and first study product administration, the ordinal scale 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 example, on study Day 3 when completing the form, the 
worst 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). 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 24-hour period (00:00 to 23:59).  
 
Chronic use of home CPAP and BiPAP pre-COVID-19:  
If a patient’s need for CPAP or BiPAP is a new requirement since enrollment and used to treat 
COVID-19 (illness), a subject should be categorized as a Category 6. If CPAP is used for another 
indication prior to COVID-19 (e.g., non-COVID-19 indication like sleep apnea or BiPAP for 
COPD), this should be considered as their baseline, pre-COVID-19 medical status, and use of these 
devices should not be considered when categorizing patients for ACTT. Patients who require low 
flow supplemental oxygen are an ordinal scale category 5 even if they get CPAP at night in the 
hospital for chronic diagnosis of sleep apnea. Patients who require high flow supplemental oxygen 
or have a new requirement for CPAP or new requirement for BiPAP are an ordinal scale category 
6.  
 
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 + 6-day window), complete an ordinal scale assessment on the 
day after death. For more information about the data collected for the ordinal scale, see the MOP. 
 
For more information about the data collected for the ordinal scale, see the MOP. 
 
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 5). In ACTT-4, the NEWS is being 
used as a severity of illness scores and should be evaluated at baseline (Day 1) only. The 7 
parameters can be obtained from the hospital chart or electronic medical record (EMR) using 
measurements taken prior to first study product administration. A numeric score is given for each 
parameter (e.g., a RR of 9 is one point, oxygen saturation of 92 is two points). Typically, ECMO 


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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. However, given that in ACTT-4 the NEWS is done at baseline only, 
no patients should be on ECMO or mechanically ventilated on Day 1. 
 
Table 5. National Early Warning Score (NEWS) 
 
  Level of consciousness = alert (A), and non-alert and arousable only to voice (V) or pain (P), and 
unresponsive (U).  
 
 
 Exploratory assessments 
As part of an exploratory endpoint, all subjects will be called at Day 60 (see SOA). During this 
visit conducted by phone call, remote telemedicine visit, or in-person visit, the site will ask the 
subject for information about their health status including current use of supplemental oxygen 
and physical disabilities to determine ordinal score. The site will also ask the subject whether 
they were readmitted to a hospital since Day 29 (or their last visit). They will also be asked about 
any new diagnoses including deep venous thrombosis (DVT), infections, post-traumatic stress 
disorder (PTSD), anxiety and/or depression. The data collection form will be used as a guide for 
this visit. Sites may review the medical record if there is uncertainty about the subject-reported 
diagnoses at the Day 60 visit especially if these occurred as part of a hospital readmission or 
healthcare visit. Sites may review the medical record to collect information at Day 60 if they are 
unable to contact the subject or if the subject has died. If the subject is admitted at Day 60, the 
Day 60 visit may be conducted in person. 
 
 
Exploratory Assessments and Secondary Research Samples 
The schedule of assessments (SOA, Section 1.2) lists the collection timepoints for specimens for 
both exploratory endpoints and for secondary research. Sites may opt out of specimen collection 
for secondary research; only serum is collected for secondary research. Subjects will be consented 
for genetic testing for the second exploratory endpoint. Sites will draw blood (via PAXgene tube) 


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for subjects who consent to genetic testing. Proteomic (cytokines and other protein) analysis will 
be done for all subjects using plasma or serum drawn per the schedule outlined in the SOA. In 
some cases, serum may be substituted for plasma for cytokine analyses (upon approval by the 
Sponsor). Data from exploratory assessments may not be submitted as part of the primary Clinical 
Study Report (CSR) for this trial. The data may be submitted separately as one or more addenda 
to the primary CSR. 
 
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 plasma  
• 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 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.  
 
Whole blood for transcriptomics analysis  
• Subjects who consent to genetic testing will have a whole blood sample (~2.5 mL in 
PAXgene tube)). 
• These samples will be tested in a central laboratory, not locally. 
 
Blood for serum 
• If the samples can be processed 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.  
 


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SARS-CoV-2 Virology Exploratory Assessment 
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 Day 29; and only OP swabs and serum 
on Day 15 (if attends an in-person visit or still hospitalized). Samples are stored as outlined in the 
MOP. Virologic assessments may include PCR or other nucleic acid tests for duration of viral 
RNA, viral load determination and/or the emergence of antiviral resistance.  
 
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.  
 
 
Immunophenotyping Exploratory Assessment  
As outlined in the SOA, blood will be collected for a plasma proteomic analysis of cytokines, 
chemokines, markers of inflammation, and other circulating proteins in all patients. Whole blood 
(PAXgene tubes) for a transcriptomic analysis of RNA will be collected for those who consent for 
genomic testing. All sites should collect PAXgene tube for subjects consenting to have their 
samples used for the targeted genetic analysis. Samples will be collected, processed and stored as 
described in the MOP. If a BSL-3 environment is needed for processing of these samples, or if 
samples cannot be shipped to a central laboratory, these samples may be omitted, and the omission 
documented each time.  
 
Blood for plasma for proteomic analysis 
An aliquot of the collected plasma will be analyzed for cytokines, chemokines, markers of 
inflammation and other circulating proteins on Days 1, 3, 5, 8 and 11 and Day 29 (see SOA for 
details). This blood volume is not an additional 0.5 mL but considered as part of the mL plasma 
taken on these days. A subset will have the sample processed using a high-throughput proteomic 
assay. The remainder of subjects will have their samples processed using an antibody-based assay 
for cytokines.  
 
Whole blood for transcriptomics analysis 
Subjects who consent to genetic testing will have a whole blood sample (~2.5 mL in PAXgene 
tube) analyzed using an RNA sequencing assay (RNA-Seq, Illumina). Transcriptomics analysis 
will be done on Days 1, 3 and 8, and Day 29 (if attends in-person visit or still hospitalized) (See 
SOA for details). Subjects who consent to genetic testing and are discharged prior to Day 8 and 
therefore miss the PAXgene tube collection at Day 8, this sample will be drawn at Day 15. Analysis 
may include, but not limited to the following assessments depending on the sample quality and 
quantity.  
• Cellular transcriptional activity in immune cell subsets as analyzed by RNA-seq or 


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microarrays;  
• Whole blood transcriptome as analyzed by RNA-seq; 
• Single-cell transcriptome as analyzed by RNA-seq or CITE-seq. 
 
Description of blood collection in PAXgene tubes for RNA are provided in the MOP. 
 
Proposed Timing of Samples for Immunophenotyping Exploratory Objective  
The estimated peak of pathological inflammation is 21 days post-symptom onset. In ACTT-3, 
patients were not enrolled until 7 to 10 days post-symptom onset. For this reason, we propose 
samples be taken Days 1, 3 and 8 (or if discharged prior to Day 8 then blood is drawn at Day 15) 
and then at Day 29. See table below for projected blood volumes for PAXgene sample collection.  
 
 
Table 6. Blood Volume for Subjects Consenting for Genetic Testing Involving PAXgene 
Collection 
Study Day 
Transcriptomics analysis 
1 
2.5 mL blood, PAXgene blood RNA tube 
 
3 
2.5 mL blood, PAXgene tube 
5 
None 
8 
2.5 mL blood, PAXgene tube 
11 
None 
15 
None (unless missed Day 8) 
29 
2.5 mL blood, PAXgene tube 
 
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. No routine physical exam is needed for study visits after Day 1. The physical 
examination DCF will include recording the National Emergency Warning System (NEWS) score 
and whether or not radiographic infiltrates were identified by imaging studies (chest xray, CT 
scan). 
 
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: 


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• 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 INR.  
• D-dimer, and C-reactive protein are drawn on the same days as the safety 
laboratory tests but are not safety labs and should not be graded. See SOA.  
• 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.  
• On Day 1, Vitamin D levels will be assessed. These will be used to evaluate 
outcomes and should not be graded. 
• Clinical laboratory testing will be performed at each clinical trial site in real time.  
 
 
Table 7. Venipuncture Volumes for Subjects NOT Consenting for Genetic Testing 
Involving Transcriptomics Analysis 1 
 
Screen 
Baseline 
 
 
 
 
 
 
Day +/- Window 
−1 to 1 
1 ± 1 
3 ± 1 
5 ±1 
8 ± 1 
11 ± 1 
15 ± 2 
29 + 6 
Screening and 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  
 
 
X 
4mL 
X 
4mL 
X 
4mL 
X 
4mL 
X 
4mL 
 
X 
4 mL 
Total volume 
10mL 
38mL 
38mL 
38mL 
38mL 
38mL 
34mL 
38mL 
Total all study days 
 
 
 
 
 
 
 
~272 
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 tests were done within 48 hours of 
screening that can be used for determining eligibility (screening tests), or within 36 hours prior to first dose that can 
be used for baseline (Day 1) safety laboratory tests. In addition, it assumes there were no routine clinical laboratory 
tests done within the specified window for visits post baseline on Days 1, 3, 5, 8, and 11, and Days 15 and 29.  
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. 
 
Table 8. Venipuncture Volumes for Subjects Consenting for Genetic Testing Involving 
Transcriptomics Analysis 1 
 
Screen 
Baseline 
 
 
 
 
 
 
Day +/- Window 
−1 to 1 
1 ± 1 
3 ± 1 
5 ±1 
8 ± 1 
11 ± 1 15 ± 2 
29 + 6 
Screening and Safety 
hematology, chemistry, 
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  
 
X 
4 mL 
X 
4mL 
X 
4 mL 
X 
4 mL 
X 
4 mL 
 
--- 
X  
4 mL 
Blood in PAXgene tube 
 
X 
2.5 mL 
X 
2.5 mL 
--- 
X 
2.5 mL 
--- 
(X)4 
--- 
X 
2.5 mL 


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Total volume if involved 
in exploratory analysis 
10mL 
40.5mL 
40.5mL 
38mL 
40.5mL 
38mL 
34mL 
40.5mL 
Total all study days 
 
 
 
 
 
 
 
~282mL 
1. See SOA in Section 1.2 for specific tests to be performed. 
2. Total volume calculated assumes there are no routine clinical laboratory tests were done within 48 hours of 
screening that can be used for determining eligibility (screening tests), or within 36 hours prior to first dose that can 
be used for baseline (Day 1) safety laboratory tests. In addition, it assumes there were no routine clinical laboratory 
tests done within the specified window for visits post baseline on Days 1, 3, 5, 8, and 11, and Days 15 and 29.  
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. 
4. If subject discharged prior to Day 8 (i.e., PAXGene tube not collected) site will collect Day 8 samples at Day 15 
follow-up visit. 
 
 
 
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 
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. If multiple abnormalities are part of the same 
clinical syndrome, they can be reported together as one AE under a unifying clinical diagnosis. 
 
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. For example, worsening respiratory status from Grade 2 (respiratory distress) at Day 1 to 
Grade 4 (respiratory failure) at Day 5 is a condition temporarily associated with use of an 
intervention and by definition is an AE and should be reported even if the investigator believes 
that this is part of the natural history of the disease.  
 
All study required solicited safety laboratory test results will be recorded into the eCRF including 
all Grade 1 and 2 abnormalities. As the Grade 1 and 2 abnormalities are tracked and available 
within the data system, the Grade 1 and 2 laboratory abnormalities are not expected to be reported 
as adverse events. 
 


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Given the severity of the underlying illness, subjects will have many symptoms and abnormalities 
in vital signs and laboratory values. As COVID-19 is an emerging, systemic disease involving not 
only the upper and lower respiratory tract, but also the gastrointestinal tract, cardiovascular system, 
endothelial cells, and central nervous system (olfactory neurons), it is important to document 
respiratory AE as well as AEs involving other systems. New symptoms not part of the subject’s 
COVID-19 syndrome at Day 1, should be captured as adverse events. For example, if a subject 
develops new grade 3 gastrointestinal symptoms after Day 1, the gastrointestinal symptoms should 
be reported.  
 
For ACTT-4, the AE reporting window begins with the initial administration of the first study 
product and ends on the Day 29 visit  (i.e., not from the time the ICF is signed as in ACTT-2). Any 
medical condition that is present at the time that the subject signs the ICF will be considered as 
baseline and not reported as an AE. However, if the severity of any pre-existing (at baseline) 
medical condition increases above baseline to severity grade 3 or 4, it should be recorded as an 
AE. The start date for reporting of an AE/SAE is the date the AE became a Grade 3 AE. In addition, 
the following AEs will be reported: 
• Any clinically significant (can be Grade 2 or higher) suspected drug-related 
hypersensitivity reactions associated with study product administration will be reported 
as an AE; 
• Any VTE, defined as PE or DVT, that occur at any time during the study. This does not 
include superficial venous thrombosis. Note: as per the DAIDS toxicity table, thrombosis 
or embolism are Grade 2, 3, 4 and Grade 5 (death) events. 
 
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 
highest 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.  
 
D-dimer, CRP and Vitamin D levels should not be graded. D-dimer and CRP are collected on the 
same schedule as the safety laboratory tests and Vitamin D is collected on Day 1 only (see the 
SOA). However, these parameters will be used in the assessment of study outcomes.  
 
Standardized reporting of AE is essential to interpretation of data between clinical trial sites in 
multi-site clinical trials. The following recommendations are the result of an internal evaluation of 
safety data collected during ACTT-1 and ACTT-2. 


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• Medical conditions that rise to the level of an AE should be reported as an AE and not the 
procedure used to treat that condition. For example, “respiratory failure with ventilator 
support indicated” should be reported as a Grade 4 respiratory failure AE per the DAIDS 
toxicity table versus reporting an intubation (a surgical procedure) as an AE. 
• Clinical syndromes should be reported rather than each symptom, vital sign, or laboratory 
abnormality separately. For example, respiratory failure should be reported as an AE rather 
than separately reporting respiratory acidosis, hypotension, hypoxia; or AKI should be 
reported instead of low eGFR, high creatinine level and CRRT dialysis procedure. 
• Adverse events that worsen from baseline at Day 1 to a Grade 3 or Grade 4 AE or SAE 
during the study should be reported. This includes worsening of respiratory signs and 
symptoms. An AE is any untoward medical occurrence associated with the use of an 
intervention (including investigational products), whether or not considered intervention 
related. This means that the condition may be associated with the underlying disease 
process (COVID-19), but we would still report as an AE.  
• Readmissions that are due to worsening of medical conditions and requiring inpatient 
hospitalization are SAEs by a definition and should be reported. Readmissions for social 
reasons and not for worsening of medical condition (e.g., readmissions of nursing home 
residents or homeless readmitted for monitoring purposes only) is not an SAE. 
 
 
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. 
 


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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) 
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 
each study product using the following guideline: 


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• 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, and all SAEs occurring from the time the first study product 
is initially given on Day 1 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 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 part of the syndrome or diagnosis rather than the individual 
laboratory abnormality. If a clinical site does not have an upper limit of normal (ULN) or a lower 
limit of normal (LLN) for a graded laboratory parameter (e.g., INR), the site will follow the 
reference range as outlined in the MOP.  
 
Each AE will also be described in terms of duration (start and stop date), severity, association with 
each study product (i.e., baricitinib/po placebo versus dexamethasone/IV placebo versus 
remdesivir infusion), the 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 any study 
product must be submitted within 24 hours of site awareness on an SAE form to the DMID 
Pharmacovigilance Group, at the following address:  


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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. 
 
 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 


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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: 
 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 null hypothesis of no difference in the proportion of patients surviving without requiring 
invasive mechanical ventilation between baricitinib/remdesivir and dexamethasone/remdesivir 
will be tested using a superiority test.  
 
A key secondary hypothesis will test whether the distribution of the 8-point ordinal scale at Day 
15 differs between baricitinib/remdesivir and dexamethasone/remdesivir. For this key secondary 
hypothesis, the parameter of interest is the “common odds ratio,” which quantifies the shift in the 
severity distribution resulting from treatment. 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). An odds ratio greater than 1 quantifies an improvement in 
disease severity for the experimental treatment relative to its control. 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 
The primary hypothesis will be a test of the difference in proportions surviving without requiring 
invasive mechanical ventilation between the two treatment arms by Day 29. Estimating the 
expected treatment effect of baricitinib relative to dexamethasone is difficult given the 


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differences between the ACTT-2 and RECOVERY studies as discussed above. In Table 9 , the 
first row of treatment effects is based on estimates from the ACTT-2 and RECOVERY results 
amongst the cohort that most closely resembles the ACTT-4 target population (those in ordinal 5 
and 6). In the second row, the relative findings were changed to assume a gradual improvement 
in standard of care. This corresponds to a sample size of 1382 subjects. Sample size calculations 
were based on an exact unconditional score test of proportions using StatXact v11.1.0. Assuming 
8% lost to follow-up, the sample size is planned to be approximately 1500 subjects.  
 
The remaining lines demonstrate the power of the proposed sample size. There is good power of 
this trial for multiple scenarios unless the proportions surviving without invasive mechanical 
ventilation is much higher than anticipated (thought to be unlikely) or the difference in the 
proportions is smaller than anticipated (possible, but difficult to anticipate given the data 
available).  
 
The formal analyses will be based on Kaplan-Meier estimates of the proportion of patients 
surviving without mechanical ventilation by Day 29 using a large sample normal approximation 
with Greenwood’s variance formula. Accordingly, power for the final analysis is assumed to be 
equal or slightly higher than the power for the exact score as seen below. 
 
Table 9: Sample size estimates and study power. 
Total Sample 
Size 
Proportion 
Dex Arm 
Surviving 
Through Day 
29 Without 
Mechanical 
Ventilation  
Proportion 
Bari Arm 
Surviving 
Through Day 
29 Without 
Mechanical 
Ventilation 
Power 
(unconditional 
exact score) 
Power (KM + 
Greenwood) 
- Baricitinib from ACTT-2 
(OS 5 and 6)  
- Dexamethasone relative 
efficacy (only those on 
oxygen) from RECOVERY 
applied to ACTT-2 placebo 
arm 
1342 
0.814 
0.87 
80.9% 
80.6% 
Estimate of the above 
proportion applied to current 
outcomes given gradual 
improvement in care 
1382 
0.85 
0.9 
80% 
80.5% 
 
Other scenarios showing 
study power for the sample 
size of 1382 
1382 
0.9 
0.95 
94.5% 
94.9% 
1382 
0.9 
0.925 
37.0% 
37.5% 
1382 
0.85 
0.925 
99.4% 
99.4% 
1382 
0.8 
0.875 
96.6% 
96.6% 
1382 
0.8 
0.85 
68.2% 
68.9% 
Note: two-sided type I error rate 5%; Exact unconditional score test of proportions. 
9.3 
Populations for Analyses 


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The primary analysis will be based on an intention-to-treat population, including all subjects 
randomized. 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.  
An Endpoint Review Committee consisting of the DMID MO, her designees and the blinded 
statistical team may review endpoints, medications, deviations, and other special cases where 
expert opinion is requested for handling complicated cases. 
 
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, medians for 
time-to-event data) and 95% confidence intervals.  
 
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 test of superiority of the proportion invasive mechanical 
ventilation free survival between the two treatment arms at Day 29. The test statistic will be a 
large sample test of the difference in Kaplan-Meier based estimates of the 28-day probability of 
mechanical ventilation free survival with a two-sided type I error rate of 0.05. The test of 
difference will assume asymptotic normality and use Greenwood’s variance formula. (44)  
If null hypothesis for the overall population is rejected, the analysis will proceed to test the null 
hypothesis within each baseline ordinal scale subgroup following the strategy described below. 
 
 
Analysis of the Secondary Endpoint(s) 
1) The ordinal scale at Day 15 will be used to estimate a proportional odds model within 
different categories of the ordinal scale at baseline. The hypothesis test will perform a 
strata- adjusted 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. There will be efforts to minimize loss to follow-up. However, small amounts 
of missing data may occur. In such cases, outcomes may be imputed based on rules 
described in the SAP. 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 recovery or time to at least a one 
category improvement in ordinal scale, time to death) by treatment will be summarized 
with Kaplan-Meier curves and 95% confidence bounds, using the Fine-Gray approach for 
competing events when appropriate.  
 
3) Analysis of mortality data will be evaluated using a Cox proportional hazards model.  


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4) Desirability of outcomes response (DOOR). A revised ordinal scale has been constructed 
to incorporate SAEs. SAE may be related or unrelated to study product. Any SAE 
occurring after study product administration through Day 15 (or through Day 29) will be 
counted: 
 
1- Recovered (OS 1,2,3) 
2- Improved by at least 1 OS from baseline & no SAE 
3- Improved by at least 1 OS from baseline & SAE 
4- No change in OS from baseline & no SAE 
5- No change in OS from baseline & SAE 
6- Worsened by at least 1 OS from baseline 
7- Death (OS 8) 
*OS = ordinal scale score based on the 8-point scale 
 
This DOOR scale will be evaluated at Day 15 and Day 29, and between arm differences 
will be tested using a Mann-Whitney U-statistic.  
 
5) Change from baseline 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-, or 3-
point worsening). 
 
6) Duration of event (e.g., duration of mechanical ventilation) will be summarized according 
to median days with quartiles and mean with SD. 
 
7) 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. 
 
8) 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.  
 


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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 AEs, SAEs, and all reportable VTE by treatment 
arm. Safety monitoring will be ongoing (see section 8.3). The unblinded statistical team will 
prepare these reports for review by the DSMB.  
 
 Interim Efficacy Review 
The speed of recruitment impacts the utility of an interim analysis to inform reporting of results. 
If enrollment occurs rapidly, an interim efficacy analysis for a primary outcome that requires 
waiting until Day 29 to assess could be of limited use. A considerable portion of the sample 
could be enrolled during the waiting period to assess outcomes and clean data and the DSMB 
review may occur with only a small percentage of the final sample size remaining to be enrolled.  
 
Therefore, the interim analysis for ACTT-4 will depend on the expected duration of enrollment. 
If full enrollment is expected within four months, no interim efficacy analyses are planned. This 
will be estimated by assessed by enrollment 1.5 months after first enrollment.  
• If the study reaches or exceeds 1/3 of total enrollment within 1.5 months (assumes 
slightly slower enrollment at the beginning), no interim efficacy analysis will be 
performed.  
• If the study does not reach 1/3 of total enrollment within1.5 months, an interim analysis 
will occur after the first third of enrolled subjects have reached Day 29.  The 28-day 
estimate will be based on a Kaplan-Meier estimator, which allows all subjects on-study to 
contribute data according to the amount of observation time contributed. 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 with an overall two-sided type-I 
error rate of 0.05. Accordingly, the planned efficacy stopping boundaries are 3.7307 
(33% information) and 1.9605 (100% information). Note that these values are 
approximate; the actual values will follow the prespecified error spending function and 
the information fractions determined by the analysis times. 
 
 
Subgroup Analyses 


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In addition to the planned subgroup analyses within each baseline ordinal scale, the following 
subgroup analyses for the primary outcomes are planned: geographic region, dexamethasone use 
prior to randomization, other steroid use prior to randomization, duration of symptoms prior to 
enrollment, 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.  
 
Additional exploratory analyses will evaluate different scales for DOOR analyses that were 
described in 9.4.3 item 4. 
 
 
Multiplicity Adjustment 
A fixed sequence testing scheme will control the overall family-wise Type I error rate at a two-
sided  α level of 0.05.  If the primary hypothesis is rejected at two-sided α <0.05, hypothesis 
testing will proceed to four key secondary endpoints. Hypothesis testing will follow the fixed 
ordering below (see figure): 
 
1) Proportion not progressing to ordinal scale 7 or 8; 
2) Day 15 clinical improvement on ordinal scale;  
3) Proportion not progressing to ordinal scale 6, 7 or 8 (amongst baseline ordinal scale 5 
only);  
4) Overall mortality (Day 29); and 
5) Time to recovery (Day 29). 
 
Hypothesis testing will continue at the next endpoint with α = 0.05 only if the previous 
hypothesis is rejected at α=0.05. This method of carrying forward the α -level from the previous 
test is described in the FDA guidance on Multiple Endpoints in Clinical Trials 
[https://www.fda.gov/regulatory-information/search-fda-guidance-documents/multiple-
endpoints-clinical-trials-guidance-industry ].  
 


Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 172 of 172 
 
 
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.