Conditions: Covid19
Keywords: COVID19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1971
Healthy volunteers: no

Brief summary:
ACTIV-1 IM is a master protocol designed to evaluate multiple investigational agents for the treatment of moderately or severely ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The research objectives are to evaluate each agent with respect to speed of recovery, mortality, illness severity, and hospital resource utilization. Each agent will be evaluated as add-on therapy to the standard of care (SoC) in use at the local clinics, including remdesivir (provided). The SoC may change during the course of the study based on other research findings. Comparisons of the agents among themselves is not a research objective.

The study population corresponds to moderately and severely ill patients infected with the coronavirus disease 2019 (COVID-19) virus. Recruitment will target patients already hospitalized for treatment of COVID-19 infection as well as patients being treated for COVID-19 infection in Emergency Departments while waiting to be admitted to the hospital. Patients both in and out of the ICU are included in the study population.

Detailed description:
ACTIV-1 IM is a master protocol designed to evaluate immune modulators for the treatment of moderately or severely ill hospitalized patients infected with COVID-19. Trial participants will be assessed daily while hospitalized. If the participants are discharged from the hospital prior to Day 29, they will have follow-up study visits at Days 8, 11, 15, 22, and 29. For discharged participants, it is preferred that the Day 8, 11, 15, and 29 visits are in person to obtain safety laboratory tests and blood (serum/plasma) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the participant to return to the clinic. In this case, these visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone. The Day 60 assessment will be conducted by phone.

The effectiveness of each therapeutic agent as add-on therapy to SoC plus remdesivir (provided) will be evaluated based on the primary endpoint of time to recovery by Day 29. The sample size requirements are based on the ability to detect a moderate improvement in time to recovery (3-4 fewer days) for each agent. A total of 788 recoveries are required for each comparison to provide approximately 85% power to detect a recovery rate ratio of 1.25. Assuming 73% of participants achieve recovery in 28 days, consistent with the ACTT-1 results, the total sample size to evaluate 1, 2, and 3 agents in ACTIV-1 IM is approximately 1080, 1620, and 2160, respectively. Because each agent is being compared to SoC with no between-agent comparisons, no multiplicity adjustments for multiple agents are planned.

The CVC arm of the study was closed to enrollment on 3-Sep-2021.

Arms:
arm 1: infliximab (single dose IV 5mg/kg given on day 1) or matching placebo arm 2: abatacept (single dose IV 10 mg/kg up to 1,000 mg given on day 1) or matching placebo arm 3: cenicriviroc \[tablet, Day 1/Loading Dose: 450 mg (300mg morning and 150mg evening) Day 2 - 29/Maintenance Dose: 300 mg (150 mg BID) through Day 29\]. or matching placebo

Interventions: intervention 1: Infliximab intervention 2: Abatacept intervention 3: Remdesivir intervention 4: cenicriviroc (closed to enrollment as of 3-Sep-2021)
Intervention descriptions: intervention 1: study drug or matching placebo intervention 2: study drug or matching placebo intervention 3: Standard of Care intervention 4: study drug or matching placebo

Protocol document:
ICF_000.pdf: 
 
Informed Consent Template Document 
Study Title: Randomized Master Protocol for Immune Modulators for Treating COVID-19 
NCT Number: Pro00106301 
Document Version Date:12-02-2020, WCG approved 12-31-2020 
 


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RESEARCH PARTICIPANT INFORMED CONSENT 
AND PRIVACY AUTHORIZATION FORM 
 
TITLE: 
Randomized Master Protocol for Immune Modulators for 
Treating COVID-19 
 
PROTOCOL NO.: 
ACTIV-1 IM 
 
WIRB® Protocol #20202874 
 
SPONSOR: 
Daniel K. Benjamin, MD, MPH, PhD 
 
INVESTIGATOR: 
Name 
 
Address 
 
City, State  Zip 
 
Country 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Phone Number 
 
Phone Number (24 hours) 
 
[24 hour number is required] 
 
 
Key Information 
 
This form is for use in a research study that may involve participants who may or may 
not have the capacity to consent to take part in the study. When the participant cannot 
legally consent to take part, pronouns “you” and “your” should be read as referring to 
the participant rather than the person (legally authorized representative) who is signing 
and dating this form for the participant. In cases where the participant’s representative 
gives consent, the participant should be informed about the study to the extent possible 
given his/her understanding. During the course of the study, if the participant regains 
the capacity to consent, informed consent will be obtained from the participant and the 
participant offered the ability to leave the study if desired.  
 
Summary 
 
PURPOSE 
This is a research study and your participation in this study is 
voluntary. The purpose of this study is to evaluate the ability of 
various experimental drugs to improve health outcomes for people 
hospitalized with COVID-19. We also want to see if these study drugs 
are safe to use, and if these study drugs can stop the disease 
process and prevent you getting sicker. This study is designed to 
quickly identify safe and effective drugs that may treat COVID-19. 
 


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STUDY DRUG 
Remdesivir (Veklury) is an anti-viral drug that is approved by the U.S. 
Food and Drug Administration (FDA) for use in treating adults and 
children 12 years of age and older weighing greater than 40 
kilograms who have COVID-19 that is severe enough to require 
hospitalization.  Use of remdesivir in the US is considered part of 
usual care for patients like you.  Use of remdesivir in this study is 
investigational because this study includes the additional 
administration of a second study drug known as an immune-
modulator drug. 
 
All study participants, except those with poor renal (kidney) function, 
may receive remdesivir as part of their usual care.  Your providers 
may also include other medications to fight COVID-19 as part of 
usual care. 
 
In addition to the usual care, you will receive one of three immune 
modulators referred to as “study drugs” or its matching placebo.  The 
three study drugs target inflammation, they include infliximab 
(Remicade), abatacept (Orencia), and cenicriviroc (CVC).  A placebo 
looks like a “real” drug, but it does not have any active drug.  You will 
be randomly assigned to receive either usual care (which may 
include remdesivir), plus one of the three study drugs, or usual care 
(which may include remdesivir), plus a matching placebo for one of 
the three study drugs.  
 
Approximately 75% of participants, or 3 out of 4, will receive active 
immune-modulator study drug and 25% of participants, or 1 out or 4, 
will receive matching placebo. You will know which of the three 
immune modulator study drugs to which you are randomly assigned, 
but you will not know whether you receive the active drug or the 
matching placebo.  
 
This study will test whether adding one of the three immune-
modulator study drugs listed above to standard of care treatment 
including remdesivir is safe and effective for the treatment of COVID-
19. The study drug you receive will be either an active drug or a 
placebo. 
NUMBER OF 
PARTICIPANTS 
2160 
 


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LENGTH OF 
STUDY 
Your participation in the study will last for about 60 days (2 months). 
You will be seen several times during the first 29 days and contacted 
again 60 days after you enroll in the trial.  During those 60 days you 
will not be allowed to enter any other clinical trial that studies 
treatments of COVID-19, with the exception of the ACTIV-4 trial. If 
your treating physician considers it appropriate, you will receive 
remdesivir for up to 10 days total. Depending on which immune-
modulator study drug you are assigned to at random, the study drug 
or placebo will be administered up to a maximum of 28 days.  
 
REQUIRED 
ACTIVITIES 
If you are in this study, the following study procedures are required:  
• you will receive study drugs, 
• you will provide blood samples, 
• after you are discharged from the hospital, you may be asked to 
return to the clinic a few times for in-person visits for blood 
draws and assess your health. If you cannot return to clinic in 
person, a member of the study staff will call you for a telephone 
interview. 
 
RISKS 
There are some risks that are specific to the study drugs that you 
might receive.  
• Side effects of remdesivir are rare.  The most common are 
allergic reactions (which may result in increase or decrease in 
blood pressure, increase or decrease in heart rate, rash or 
difficulty breathing), and effects on liver activity. 
• Participants receiving infliximab (Remicade) have a higher risk 
of getting infections including pneumonia and other infections 
caused by viruses, bacteria, or fungi. 
• The most common side effects with abatacept (Orencia) include 
headache, upper respiratory tract (airway) infection, 
nasopharyngitis (pain and inflammation in the nose and throat), 
and nausea. 
• The most common side effects with cenicriviroc (CVC) are 
gastrointestinal problems, joint pain, rash, vomiting, fever, joint 
swelling, abnormal physical weakness or lack of energy, contact 
dermatitis and increases in levels of liver enzymes. 
We will tell you more details about the risks in the second part of this 
consent form. 
 
BENEFITS 
If you take part in this study, there may be a direct benefit to you, but 
no guarantee can be made. It is also possible that you will receive no 
benefit from being in this study. Information learned from this study 
will help others who have COVID-19. 
 


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OTHER 
CHOICES 
Instead of being in this study, you have the option of receiving:  
• treatment with prescription drugs available to you through your 
health care provider 
• treatment with other investigational drugs if you qualify  
• no treatment 
 
 
This document may contain words and information that you do not understand.  Please 
ask your study doctor or study staff to explain anything that is not clear to you. Please 
take time to read all the information carefully and talk about it with friends and relatives 
if you wish. 
 
What is the purpose of this study?  
 
SARS-CoV-2 is a new virus that has caused a widespread outbreak of an illness called 
COVID-19. In some people, it causes mild to moderate symptoms, like a “cold.” In 
others, this virus can cause pneumonia (an inflammation of the lungs), which can be 
serious and life threatening.  
 
The Food and Drug Administration (FDA) has approved the use of remdesivir to treat 
adults and children 12 years of age or older weighing greater than 40 kilograms who 
have COVID-19 that is severe enough to require hospitalization. Remdesivir acts to 
block the growth of the virus, SARS-CoV-2 which causes COVID-19. Some people still 
get sicker even though they receive remdesivir. We think this may be due to an 
overactive immune response to the virus.  
 
The study is designed to rapidly evaluate new therapies to treat the overactive immune 
response that has been observed in some COVID-19 patients. We are studying three 
different study drugs called infliximab (Remicade), abatacept (Orencia), and cenicriviroc 
(CVC).  All three drugs target inflammation (overactive immune response) and have 
been studied in animals and people; however, none are approved by the FDA to treat 
COVID-19 and are considered investigational in this study. Two of the drugs, infliximab 
and abatacept, are approved by the FDA to treat other inflammatory medical conditions 
such as arthritis, bowel disease and severe skin disease. Cenicriviroc (CVC) is not 
approved by the FDA as a treatment for anything.  
 
This study will compare the effects and safety of remdesivir when used with and without 
each of the three study drugs. Remdesivir may be provided to all study participants 
except those with poor kidney function. Remdesivir may also be available to you outside 
of this study. Your doctor may also prescribe other medications to treat your COVID-19 
infection. This study will also provide you with one of these three study drugs or its 
matching placebo. The combination of remdesivir (including other medications used to 
treat COVID-19) with the study drugs is investigational because it has not been studied 
before. 
 


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What does the study involve? 
 
If you decide to join the study, you will be asked 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, there will be no 
penalties, and you will not lose any benefits you are otherwise entitled to or regular 
health care services you already are getting.  
 
Each study participant, with the exception of those with poor kidney function, may 
receive remdesivir. In addition to remdesivir, participants in this study will be put into 
one of four groups (assigned by chance, like pulling a name out of a hat or rolling dice). 
One group (about one out of four, or 25% of participants in the study) will be given a 
placebo (IV infusion or a pill with no drugs in it). The other three groups (about three out 
of four or 75% of participants in the study) will get one of three study drugs. The study 
team will use a computer to randomly decide which group you will be in. The study team 
will not tell you if you are receiving a study drug or placebo. Only the pharmacist who is 
preparing the medication will know if you are getting the study drug or placebo. 
 
If you would like to be in this study, after you have read, signed, and dated this consent 
form, the following activities will occur over the course of the study.  
 
Screening (Day 
-1 to Day 1) 
The study team will: 
• Confirm you have a positive COVID-19 test result recorded 
• Ask about your medical history and the medications you are 
taking and confirm with your records 
• Collect information from your medical records including test 
results, treatments, and vaccines that you have received  
• Perform a physical exam  
• Record your vital signs (temperature, blood pressure, 
breathing rate, heart rate, oxygen levels) 
• Check if you are pregnant (if applicable) 
• Do blood tests to check your health, 10ml (about 2 
teaspoons) 
• Ask you not to: 
o get pregnant, impregnate your partner, or breastfeed 
through Day 60  
o take part in another treatment study through Day 60 
(with the exception of the ACTIV-4 study). 


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Day 1  
Before you receive remdesivir and study drug/placebo, the study 
team will: 
• Check and record how you are feeling and any problems 
you may be having 
• Review and record your medical condition and the 
medications you are taking and update any changes 
• Record your vital signs (temperature, blood pressure, 
breathing rate, heart rate, oxygen levels) 
• Do blood tests to check your health and record results, 10ml 
(about 2 teaspoons) 
• Take extra blood samples for future research, 18ml (about 4 
teaspoons), if you agreed to provide them [remove if your 
site will not be collecting this sample] 
• Take an extra blood sample for future genetic testing, 8ml 
(about 2 teaspoons), if you agreed to provide it [remove if 
your site will not be collecting this sample] 
• Depending on which study drug you will receive, you may 
require additional tests for other infections.  If you test 
positive, you may need additional treatment.  You will still 
receive the study drug regardless. 
• Place a small tube called an intravenous (IV) catheter into 
your vein to allow for medications to be given (if you do not 
already have one).  
 
You will then receive study drugs: 
• You may receive remdesivir which will be given by an 
infusion into a vein.  
• NOTE: Remdesivir will be given for a maximum of 10 days; 
this includes days you received remdesivir before you joined 
the trial. 
• You will also receive the study drug or matched placebo that 
has been randomly assigned to you. Depending on which 
study drug you have been assigned to, you may be given an 
intravenous infusion or pills by mouth.  
o If you are randomized to receive infliximab or 
abatacept or their matched placebo as study drug, 
you will receive a single dose.  It will be given into a 
vein over 30-120 minutes and will not be given at the 
same time as the remdesivir dose. 
 
o If you are randomized to receive oral study drug 
cenicriviroc (CVC) or the corresponding placebo pills, 
you will take your first dose.  It should be taken with 
food and will not be given at the same time as the 


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remdesivir dose. NOTE: You will continue to take the 
pills twice daily for 28 days. 
 
After you receive remdesivir and study drug/placebo: 
• A blood sample will be drawn to check  levels of study drug 
in your body, 4ml (about 1 teaspoon) 
Daily while in 
hospital 
through Day 14 
Every day while you are in hospital the study team will: 
• Check on and record your medical condition, changes in 
medications, and problems you may be having  
• Measure and record your vital signs (temperature, blood 
pressure, breathing rate, heart rate, oxygen levels) 
 
On Day 3 (+/- 1 day) you will have: 
• blood tests to check your health, 10ml (about 2 
teaspoons) 
• blood samples for future research, 18ml (about 4 
teaspoons), if you agreed to provide them [remove if 
your site will not be collecting this sample] 
 
On Day 5 (+/- 1 day) you will have: 
• blood tests to check your health, 10ml (about 2 
teaspoons) 
 
On Day 8 (+/- 1 day) or on the day of discharge from hospital: 
• blood tests to check your health, 10ml (about 2 
teaspoons) 
• blood samples for future research, 18ml (about 4 
teaspoons), if you agreed to provide them [remove if 
your site will not be collecting this sample] 
• blood samples to check the levels of drug in your body, 
4ml (about 1 teaspoon) 
 
On Day 11 (+/- 1 day) or on the day of discharge from hospital: 
• blood tests to check your health, 10ml (about 2 
teaspoons) 
 
While you remain in hospital:  
• You may continue to receive remdesivir every day 
through the vein for up to a total of 10 days. 
• If you were assigned to receive cenicriviroc (CVC) or the 
corresponding placebo pills study pills, you will continue 
to take these twice daily with food for 28 days. 
 
 


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If you are discharged from the hospital before Day 10, remdesivir 
will be discontinued.  
 
If you are readmitted to the hospital prior to Day 14 of the study: 
• you may be given the remainder of the remdesivir course 
(up to 10 days in total) 
• If you were receiving cenicriviroc (CVC) or the 
corresponding placebo study pills, you will continue to 
take pills twice a day (28 days in total) 
 
If you are discharged from the hospital prior to Day 8, the study 
team will schedule in-person visits (preferably) for Day 8 and Day 
11, or over the phone visits (telehealth) if in-person visits are not 
possible. At these visits, the study team will (where possible): 
• Check on and record your medical condition, changes in 
medications, and problems you may be having  
• Measure and record your vital signs (temperature, blood 
pressure, breathing rate, heart rate, oxygen levels)  
• Take blood samples as specified for Day 8 and Day 11 
above. 
 
Day 15 +/- 2 
follow-up visit  
If you are hospitalized, this visit will take place on Day 15 (+/- 1 
day) in the hospital. If you are already at home, the study team will 
schedule an in-person visit (preferably) or an over the phone visit if 
an in-person visit is not possible. At this visit, the study team will 
(where possible): 
• Check on and record your medical condition, changes in 
medications, and problems you may be having  
• Measure and record your vital signs (temperature, blood 
pressure, breathing rate, heart rate, oxygen levels)  
• Do blood tests to check your health and record results, 10ml 
(about 2 teaspoons)  
• Take blood samples for future research, 18ml (about 4 
teaspoons) [remove if your site will not be collecting this 
sample] 
 
Day 22 +/- 3 
follow-up visit  
If you are hospitalized, this visit will take place in the hospital. If you 
are at home, the study team will carry out the visit over the phone. 
The study team will: 
• Check on and record your medical condition, changes in 
medications, and problems you may be having  
 


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Day 29 + 3 
follow up visit  
If you are hospitalized, this visit will take place in the hospital. If you 
are at home, the study team will schedule an in-person visit. At this 
visit, the study team will (where possible):  
• Check on and record your medical condition, changes in 
medications, and problems you may be having  
• Measure and record your vital signs (temperature, blood 
pressure, breathing rate, heart rate, oxygen levels) 
• Do blood tests to check your health and record results, 10ml 
(about 2 teaspoons) 
• Take blood samples for future research, 18ml (about 4 
teaspoons), if you agreed to provide them [remove if your 
site will not be collecting this sample] 
• Take blood sample to check the levels of drug in your body, 
4ml (about 1 teaspoon) 
 
Day 60 +/- 5 
If you are hospitalized, this visit will take place in the hospital. If you 
are at home, the study team will carry out the visit over the phone. 
The study team will: 
• Check on and record your medical condition, changes in 
medications, and problems you may be having  
• Check on and record whether you have been re-admitted to 
the hospital 
 
 
Will I receive the results of any tests? 
 
Blood will be regularly collected from you to check your general health; these results 
may be shared with you if appropriate, and they will also be entered into the study 
database. Other blood samples are intended to check the levels of drug in your blood; 
these samples will be stored for testing at a later date and the results will not be shared 
with you.  
• You may also be offered the option to provide five or six additional blood samples at 
different time points. These samples will be used for future exploratory research, and 
the results will not be shared with you. These tests will be described in greater detail 
at the end of this document, where you will be asked if you would like to provide 
these samples. You will still be allowed to participate in the study even if you decide 
not to provide these additional samples.  
 
You will be told of any new information learned during the course of the study that might 
cause you to change your mind about staying in the study. At the end of the study, you 
will be told when study results may be available and how to learn about them. As with 
all studies, if we find out important information that may affect your care, you will be 
provided with those results. 
 


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What side effects could remdesivir cause? 
 
Remdesivir is currently approved in the United States for the treatment of hospitalized 
patients with COVID-19 and is considered to be part of standard of care. 
 
The most common side effects include (greater than 5%): 
• Nausea 
• Changes in how your liver works, increase in your liver enzymes (shown in blood 
tests) 
 
Rare side effects include: 
Infusion-related reactions.  Symptoms associated with infusion-related reactions may 
include increase or decrease in blood pressure, increase or decrease in heart rate, 
fever, difficulty breathing, rash, or chills.  A slow infusion rate will be used as that may 
prevent these symptoms.  Inform the study team immediately if you have any of these 
reactions. 
 
Remdesivir contains a compound that is eliminated by the kidneys, for this reason, 
participants with poor kidney function will not receive remdesivir. We will monitor your 
kidney function; if you have abnormal test results, we may suspend or stop giving you 
remdesivir. We will share these results with you. 
 
Remdesivir may also affect how your liver works. We will monitor how your liver is 
working, and if you have any abnormal test results we may stop giving you remdesivir.   
We will share these results with you. 
 
What side effects could the study drugs cause? 
 
The possible side effects are different depending on which study drug you receive.  The 
potential side effects of each are detailed below.   
 
Infliximab (Remicade) 
 
Most patients in the clinical studies where these side effects were observed received 
multiple doses of infliximab for chronic conditions. If you are randomized to receive 
infliximab while in this study you will receive one dose.   
 
Most common side effects (greater than 10%): 
• Headache  
• Abdominal pain 
• Nausea 
• Infections (including viral, bacterial and fungal) 
• Reaction to the infusion 
• Pain 
 


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Less common side effects (1% to 10%): 
• Flushing, increased sweating  
• High blood pressure, low blood pressure  
• Tiredness, problems sleeping 
• Indigestion, diarrhea, constipation  
• Low white cell count, low red cell count, or both  
• Changes in how your liver works, increase in your liver enzymes (shown in blood 
tests) 
• Difficult or painful breathing, chest pain 
• Nettle-type rash (hives), itchy rash 
• Balance problems or feeling dizzy 
• Fever, chills 
• Bruising 
• Swollen lymph nodes 
• Eye problems, including red eyes and infections 
• Pain in the joints or muscles 
• Psoriasis, skin problems such as eczema, hair loss and dry skin 
 
Infliximab can cause serious side effects including: 
 
• 
Serious infections: Subjects receiving infliximab have a higher risk of getting 
infections including pneumonia and other infections caused by viruses, bacteria, 
or fungi. There have been uncommon (greater than 1/1,000 to less than 1/100) 
reported cases of serious infections leading to death associated with infliximab. 
o Tuberculosis: Tuberculosis (TB), including reactivation in patients who 
were unaware that they had dormant TB, has been reported uncommonly 
(greater than or equal to 1/1,000 to less than 1/100) in patients treated 
with infliximab after multiple doses.  Patients with TB have frequently 
presented with widespread or atypical disease. You will be tested for TB at 
the beginning of the study.  As the results can take several days, we will 
not wait for the result before giving you the study drug. If your TB tests are 
positive, you may need additional treatments. 
o Hepatitis B: Rarely (greater than 1/10,000 to less than 1/1,000), treatment 
with TNF-blocking agents such as infliximab may result in a reactivation of 
the hepatitis B virus in people who have been known to carry this virus. 
Patients with untreated hepatitis B have experienced worsening liver 
function and liver failure.  You will be tested for hepatitis B at the 
beginning of the study. As the results can take several days, we will not 
wait for the result before giving you the study drug. If your Hepatitis B tests 
are positive, you may need additional treatments.   
o State law requires positive test results for certain communicable diseases, 
including HIV, hepatitis, sexually transmitted infections, and tuberculosis, 
to be reported to a local health agency.  This study involves some of these 
tests. The study doctor can discuss this with you. 


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• 
Congestive Heart Failure (CHF):  Uncommonly, patients with CHF had worsening 
of their disease and some died. 
• 
Allergic reactions: Allergic reactions can happen after receiving infliximab, 
including, uncommonly, a serious condition known as anaphylaxis. Tell your 
physician if you have ever received infliximab in the past, as this could increase 
the risk of an allergic response.  Uncommon cases of reactions up to 2 weeks 
after treatment have occurred in patients treated with infliximab in the past.  Also, 
if you receive infliximab in this study, you will need to tell your healthcare care 
provider in case infliximab is ever considered for you again in the future. 
• 
Cancer: Certain kinds of cancer have been reported in subjects receiving multiple 
doses of infliximab.  The risk is felt to be very low with a single infusion.   
• 
Central nervous system: Rarely, patients, who have a disease of their nervous 
system, have reported that this disease got worse. Seizures and multiple 
sclerosis are examples of nervous system diseases. 
 
Abatacept (Orencia)  
Most patients in the clinical studies where these side effects were observed received 
multiple doses of abatacept for chronic conditions, if you are randomized to receive 
abatacept while in this study you will receive one dose.   
 
Most common side effects with abatacept (greater than 10%): 
• Headache  
• Upper respiratory tract (airway) infection  
• Nasopharyngitis (pain and inflammation in the nose and throat)  
• Nausea  
 
Less common side effects (1% to 10%): 
• Diarrhea  
• Dizziness  
• Cough  
• Back pain  
• Bronchitis  
• Urinary tract infection  
• High blood pressure  
• Inflammation of the sinuses  
• Stomach upset  
• Flu  
• Fatigue  
 
Other common symptoms that could be related to abatacept treatment: 
Some subjects in clinical studies with abatacept have had cold sores (oral herpes), 
some have had mouth ulcers, and some have had stomach pain. 
 


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Abatacept can cause serious side effects including: 
 
• Serious infections: Subjects receiving abatacept have a higher risk of getting 
infections including pneumonia and other infections caused by viruses, bacteria, 
or fungi. There have been reported cases of serious infections leading to death 
associated with abatacept. 
• Allergic reactions: Allergic reactions can happen after receiving abatacept.  
• Cancer: Certain kinds of cancer have been reported in subjects receiving 
abatacept. While it is not known if abatacept increases your chance of getting 
certain kinds of cancer, to date, no increased risk of developing cancer has been 
identified in human studies with abatacept. 
• Patients with COPD experienced a higher frequency of COPD-related adverse 
reactions (COPD exacerbation, cough, dyspnea, pneumonia, rhonchi). 
 
Cenicriviroc (CVC) 
Most common side effects with cenicriviroc (CVC): 
• Diarrhea  
• Nausea  
• Joint pain 
• Rash 
• Vomiting 
• Flatulence and Abdominal distention (gas) 
• Fever 
• Joint swelling 
• Abnormal physical weakness or lack of energy 
• Dermatitis contact ‐ skin rash or irritation caused by touching something 
• Increases in levels of liver enzymes  
 
Risks that are not known: 
You may experience unknown risks and problems related with the use of any of the 
study drugs, including allergic reaction to the medicine or a bad effect because the 
study drug is taken at the same time as another medication. Whenever someone takes 
any new medications, there is a risk that an allergic reaction may occur. Such reactions 
can be serious or fatal. If you suffer from allergies to medications, food products, or 
environmental elements, please tell the study doctor.  
 
What are the other risks or discomforts of the study? 
 
Loss of confidentiality  
In any research, there is a possible risk of loss of confidentiality of the personal 
information you have provided. Every effort will be made to keep your information 
confidential; however, this cannot be guaranteed.  See ‘how will my privacy be 
protected’ for more details about how your privacy will be protected.  
 


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Risks of Placing a Catheter 
If you do not already have one, a small tube called an IV catheter may be placed in your 
vein to allow for the medications to be given. You may feel momentary discomfort 
and/or bruising. Infection, excess bleeding, clotting, or fainting are also possible, 
although unlikely. 
 
Risks of Blood Draw 
Having blood drawn may cause some discomfort, bleeding, bruising, and/or swelling 
where the needle enters the body, and in rare cases it may result in fainting. There is a 
small risk of infection. 
 
Risk of infusion reaction 
Intravenous infusion reactions may affect any organ system in the body. Most are mild 
in severity, although severe and even fatal reactions occur. The most common signs 
and symptoms of infusion reactions are: 
• Fever and/or shaking chills 
• Flushing and/or itching 
• Alterations in heart rate and blood pressure 
• Difficulty breathing or chest discomfort 
• Back or abdominal pain 
• Nausea, vomiting, and/or diarrhea 
• Various types of skin rashes 
 
For Women, Risks Related to Pregnancy: 
If you are a woman, you cannot be enrolled in this study if you are: 
• Pregnant 
• Planning to become pregnant during the study 
• Nursing a child 
 
If you are pregnant or nursing a child during the study, there may be risks to you, the 
embryo, fetus, or nursing child.  
 
If you can become pregnant, you must use an acceptable non-hormonal method of birth 
control, from screening until Day 60 of the study.  
 
Highly effective methods of non-hormonal contraception (less than 1% failure rate) 
include, but are not limited to:  
• implanted contraceptives  
• intrauterine device (IUD) 
• abstinence  
 
Effective methods of contraception include, but are not limited to:  
• diaphragms with spermicide  
 


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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 and cannot use one of 
these birth control methods. Some methods of birth control do not work as well when 
you are taking certain drugs (cenicriviroc). 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 team 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 team may share this information with the study sponsor, the pharmaceutical 
collaborator(s), the data and safety monitoring board (DSMB), and with the Institutional 
Review Board (IRB), a group of people who review research studies to protect the rights 
and welfare of research participants. 
 
For Men, Risks Related to Pregnancy: 
If you are male, and your female partner is capable of becoming pregnant, your partner 
must use an acceptable non-hormonal method of birth control, from screening until Day 
60 of the study.  
 
Highly effective methods of non-hormonal contraception (less than 1% failure rate) 
include, but are not limited to:  
• implanted contraceptives  
• intrauterine device (IUD) 
• abstinence  
 
Effective methods of contraception include, but are not limited to:  
• diaphragms with spermicide  
 
Please speak to the study doctor or staff about acceptable methods of birth control. You 
should not participate in this study if your partner can become pregnant and you cannot 
use one of these birth control methods. Some methods of birth control do not work as 
well when you are taking certain drugs (cenicriviroc). Be aware that women can still 
become pregnant even if using an acceptable birth control method.  
 
If your partner becomes pregnant while you are participating in the CVC study, you 
should report this immediately to the study team. 
 
Are there benefits to being in the study? 
 
You may not benefit from being in this study. If the study drugs work and you received 
them in this study, you may benefit by getting better sooner and/or getting less severe 
disease.  
 


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Your participation in this study is important to learn more about the study drugs and if 
they are safe and work in hospitalized patients with COVID-19. The work done in this 
study may also help in the development of treatments for COVID-19.  
 
What will happen to my samples and personal information? 
 
The study team will store samples that are collected to test the level of study drug in 
your blood and those that will be used for future research until we are able to test all 
samples. Your stored samples and data will be marked with a code and not with your 
name.  
 
Your study information will be placed in a secure electronic system. It will not include 
your name. This information cannot be traced back to you.  
 
Your samples will not be sold. As part of this study, the study team will collect extra 
blood samples to store and use for secondary research. Secondary research may help 
us to understand how remdesivir and the other study drugs work, to study other 
infections or diseases, and/or to develop other treatments. This secondary research on 
your samples will be done without obtaining additional permission from you.  These 
samples may be shared outside of the study team conducting the trial: with laboratories, 
investigators, and the pharmaceutical collaborators whose drugs are being tested in the 
study. 
 
You will not be paid for any products that result from this research. The only risk of 
allowing us to store your samples would be an accidental release of your identity. 
 
The data center for this study may share your data and specimens with other people 
who study COVID-19.  The center will remove any information that could possibly be 
used to identify you before sharing.  This is called “anonymizing the data.”  We will not 
ask you for additional consent for this sharing.  The center will only share data and 
specimens for research projects that are approved by the group that is conducting this 
study. 
 
Can I change my mind about my samples being stored or my data 
being used?  
 
You may change your mind 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. 
 


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What do I need to do for follow-up on this study? 
 
If you develop any new side effects or feel sicker at any time during your participation in 
the study, it is important that you quickly tell the study team at the hospital or call the 
study contact number provided to you. If you have been discharged from the hospital, 
we may ask you to return to the clinic for a medical exam.  
 
Will it cost me anything to be in this study? 
 
It will not cost you anything to be in this study. 
 
Who is paying for the study?  
 
This trial is supported with US federal funding from the Biomedical Advanced Research 
and Development Authority (BARDA), Department of Health and Human Services. The 
National Center for Advancing Translational Sciences (NCATS) within the National 
Institutes of Health (NIH) provides oversight of the trial.  Technical Resources 
International implements the study. 
 
Will I be paid if I join this study? 
 
You will be paid up to a total of $[Amount] if you complete this study. You will be paid for 
the visits you complete according to the following schedule: 
• $[Amount] for Visits [Number].  
• $[Amount] for Visits [Number]. 
• $[Amount] for Visits [Number]. 
 
If you do not complete the study, for any reason, you will be paid for each study visit you 
do complete.  
 
You will be paid [select: “after each visit,” “annually,” “bi-weekly,” etc.] 
 
If you have any questions regarding your compensation for participation, please contact 
the study staff.   
[OR] 
You will not receive any monetary compensation for your participation in this study.  
 
Who is watching over this study? 
 
A Data and Safety Monitoring Board (DSMB) will be looking at the study information 
very closely. The DSMB is made up of doctors and other people who are not directly 
involved in the study and who have a good understanding of severe coronavirus 
infections like COVID-19 and research studies. The DSMB may recommend changing 


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the study or stopping the study earlier than planned if they think it is not safe to 
continue, or if one of the study drugs proves to be effective in treating COVID-19. The 
local institutional review board, health authorities, and the U.S. Food and Drug 
Administration will have the authority to stop the study at any time.   
 
How will my privacy be protected? 
 
We will keep your study information private. All files with information that could identify 
you will be kept in locked cabinets behind a locked door or on secure password 
protected computers.  
 
People responsible for making sure that the research is done properly may look at your 
study records. This includes people who are conducting the study and their designees, 
including staff from this hospital.  External groups including the National Institutes of 
Health (NIH) and their designees and the U.S. Food and Drug Administration (FDA), 
and international regulatory entities as part of their duties. Your records may also be 
viewed by the Institutional Review Board (IRB), responsible for approving the study, 
staff with Technical Resources International and their authorized representatives.  In 
addition, pharmaceutical collaborators that make the drugs, and their designees, may 
view your records. The pharmaceutical collaborators are Gilead Sciences, Inc. 
(remdesivir), Bristol-Myers Squibb (abatacept), Janssen Biotech (infliximab), and 
AbbVie (cenicriviroc). All of these people will also keep your identity private.  
 
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, this study is covered by 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 by a legal exception, such as U.S. 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 U.S. 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  


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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. 
 
Will the study require any of my other health care providers to share 
my health information with the researchers of this study? 
 
As a part of this study, the researchers may ask to see your health care records from 
your other health care providers. You will be asked to give us a list of other health care 
providers that you use. 
 
To do this research, we will need to collect, use, and share your private health 
information. Your private information may include things learned from the procedures 
described in this consent form, as well as information from your medical record. You 
may be asked to sign and date a separate document to authorize the collection, use, 
and disclosure of your personal health information. 
 
The permission you give us to access your medical record will last until the end of the 
study.  Your permission for the researchers to use your research information will not 
expire unless you revoke it.  
 
What other things should I know about this research study? 
 
ClinicalTrials.gov 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. 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. 
 
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 


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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. 
 
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.  
 
For any questions about the study or a research-related injury, or if you have 
complaints, concerns or suggestions about the research, contact [Name] at [Number] 
during regular business hours and at [Number] after hours or on a weekend or holiday. 
 
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 questions, concerns or complaints regarding this 
research study, contact the IRB at 800-562-4789 or Help@wirb.com. 
 
What should I do if I am injured or ill as a result of being in this study? 
 
Immediate necessary medical care is available at [Institution] in the event that you are 
injured because of your participation in this study. However, there is no commitment by 
[Institution], your physicians, Duke University (Duke Clinical Research Institute), or the 
regulatory sponsor to provide monetary compensation or free medical care to you in the 
event of a study-related injury. There is no program for compensation through the NIH 
or through Duke University. The cost for this treatment will be charged to you or your 
insurance company.  
 
A new public health declaration, called the Public Readiness and Emergency 
Preparedness Declaration (PREP), was issued by the Department of Health and Human 
Services on March 10, 2020.   
 
This declaration may limit the legal rights of a subject participating in a COVID-19 
clinical study that uses a drug, device or vaccine designed to treat, diagnose, cure or 
prevent COVID-19. This includes remdesivir (Veklury) and the study drugs abatacept 
(Orencia), infliximab (Remicade), and cenicriviroc (CVC).  Subjects using abatacept 
(Orencia), infliximab (Remicade), or cenicriviroc (CVC) in this study may have limits on 
their right to sue the manufacturers, the study sponsor, healthcare providers and others 
for significant injuries and adverse reactions.   
 


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Under some circumstances, compensation may still be available under the PREP 
Declaration for certain patients who sustain injuries.  To find out more, go to 
https://www.hrsa.gov/cicp/about/index.html or call 1-855-266-2427. 
 
Permission To Store And Use My Blood Sample For Future/Secondary 
Research Including Genetic Testing 
 
Your body, like all living things, is made up of cells. Cells contain deoxyribonucleic acid, 
also known as “DNA”. DNA is like a string of information put together in a certain order. 
Parts of the string make up “genes”. Genes contain instructions on how to make your 
body work and fight disease. Differences or changes in DNA explain some of the 
physical differences among people. These differences partly explain why some people 
get diseases like cancer or diabetes while others do not. Genetic testing looks at the 
differences in people’s DNA. This testing also looks at how differences affect health and 
the body’s response to disease and treatment.  
 
If you agree to allow genetic testing of your cells, a sample of your blood will be 
collected on Day 1. This blood may in the future be used to study whether there are 
genetic differences in how sick people get when they are infected with SARS-CoV-2 or 
how they respond to study drugs. This genetic testing might include whole genome 
sequencing (WGS). “Sequencing” is looking at the order of a person’s genes to see how 
this order is different from the order of most people. 
 
A U.S. federal law, called the Genetic Information Nondiscrimination Act (GINA), 
generally makes it illegal for health insurance companies, group health plans and most 
employers to discriminate against you based on your genetic information. 
 
This law generally will protect you in the following ways: 
• Health insurance companies and group health plans may not request your 
genetic information that the sponsor will get from this research. 
• Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premiums. 
• Employers with 15 or more employees may not use your genetic information that 
the sponsor will get from this research when making a decision to hire, promote, 
or fire you or when setting the terms of your employment. 
 
All health insurance companies and group health plans and all employers with 15 or 
more people must follow this law. 
 
Be aware that this Federal law does not protect you against genetic discrimination by 
companies that sell life insurance, disability insurance or long-term care insurance. 
 


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In addition to this genetic testing, the study team would like to collect additional blood 
samples for future research throughout the study (Days 1, 3, 8, 15, and 29). These 
blood samples will be collected for secondary research related to COVID-19. Secondary 
research is research that is not part of this study, and the research is not planned yet. 
This extra research will occur in the future and it will help us understand how the study 
drugs work and to develop new treatments and lab tests. Some of these tests will be 
done after you are done with the study, and other tests are not yet approved by the FDA 
and are still considered “research” tests. These tests will not involve genetic testing, 
and may include: 
 
• the level of inflammation markers and clotting factors in your blood 
• if your body developed antibodies to SARS-CoV-2 
 
If you do not want to allow your samples to be stored for this future research, you may 
indicate this below. 
 
You do not have to agree to participate in this future research including genetic testing. 
Even if you do not agree, you can still participate in the rest of the study. 
 
Please put your initials below to indicate your choice regarding genetic testing: 
 
________ (initials) I understand, and I agree to the genetic testing of my samples. 
 
OR 
 
________ (initials) I understand, but I do not agree to the genetic testing of my samples. 
 
Also, please put your initials below to indicate your choice regarding future research that 
will not involve genetic testing: 
 
________ (initials) I understand, and I agree to the use of my blood samples for other 
future research that will not involve genetic testing. 
 
OR 
 
________ (initials) I understand, but I do not agree to the use of my blood samples for 
other future research that will not involve genetic testing. 
 


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Consent for Future Contact 
 
The study team may be interested in finding out about long-term health outcomes after 
COVID-19 infection. At some point in the future, after you complete your participation in 
this study, the study team may wish to contact you to assess your health and possibly 
ask your consent for future studies. By providing your initials below, you are only giving 
study staff permission to contact you.    
 
Please put your initials below to indicate your choice: 
 
________ (initials) I understand, and I agree to be contacted in the future by study staff. 
 
OR 
 
________ (initials) I understand, but I do not agree to be contacted in the future by 
study staff.  
 
Statement of Consent to Participate in the Study 
 
Study staff have described this research study to me. I have read this consent form. I 
have been encouraged to ask questions and all of my questions have been answered 
by the study staff to my satisfaction. I voluntarily consent to participate in this research 
study with the understanding that I may withdraw at any time. My consent includes 
allowing storage of samples and/or use of my study information and samples for an 
indefinite period of time. By signing and dating this consent form, I have not given up 
any of my legal rights. I will get a copy of the signed and dated consent form for my 
records. 
 
Information below can only be completed by the participant. If you agree to be in this 
study, please sign and date below. 
 
________________________________________ 
Date: _____/_____/_____ 
Signature of participant 
mm      dd      yyyy 
 
 
________________________________________ 
Printed name of participant 
 
 


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Adult Assent Instructions: 
All subjects unable to consent are required to assent, unless the investigator determines 
that the capability of the subject is so limited that the subject cannot reasonably be 
consulted. A Legally Authorized Representative (LAR) must consent for an adult 
participant who is unable to consent for themselves.  
 
If assent is obtained, have the person obtaining assent document assent on the consent 
form. 
 
Statement of Adult Assent 
• 
By signing below I confirm that I understand the information within this 
form and was given enough time to consider the decision to participate in this 
research study.  
• 
The purpose of this research study, procedures to be followed, risks, and 
benefits have been explained to me.   
• 
I have been encouraged to ask questions, and my questions have been 
answered to my satisfaction.   
• 
I have been told whom to contact if I have questions, to talk about 
problems, concerns, or suggestions related to this study.   
• 
I agree to give my assent to participate in this research study, and for the 
use of associated protected health information, with the understanding that 
participation in this research is voluntary. 
• 
I have been told that I may stop participating in this study at any time 
without any penalty or loss of access to treatment or other benefits to which I am 
otherwise entitled.   
 
I have been told that my legally authorized representative (LAR) will be given a signed 
and dated copy of this form. 
 
________________________________________ 
Date: _____/_____/_____ 
Signature of participant, as able 
mm      dd      yyyy 
 
 
________________________________________ 
Printed name of participant 
 


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 I have explained the study to the extent compatible with the subject’s capability, and 
the subject has agreed to be in the study. 
OR 
 The subject is not able to assent because the capability of the subject is so limited 
that the subject cannot reasonably be consulted. 
 
 
________________________________________ 
Date: _____/_____/_____ 
Signature of investigator/designee 
mm      dd      yyyy 
 
 
________________________________________ 
Printed name of investigator/designee 
 
For adults not capable of giving consent  
 
 
________________________________________ 
Date: _____/_____/_____ 
Signature of Legally Authorized Representative (LAR)  
mm      dd      yyyy 
 
 
________________________________________ 
Printed name of LAR 
 
 
________________________________________ 
Relationship of LAR to Participant 
 
 
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 
mm      dd      yyyy 
 
 
________________________________________ 
Printed name of witness 


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**For Sites in California** 
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR 
RESEARCH PURPOSES  
 
What information may be used and given to others? 
The study doctor will get your personal and medical information.  For 
example:  
• Past and present medical records 
• Research records 
• Records about phone calls made as part of this research 
• Records about your study visits. 
 
Who may use and give out information about you? 
The study doctor and the study staff.  [They may also share the research 
information with [enter SMO company name], an agent for the study doctor. 
delete if the site does not have an SMO] 
 
Who might get this information? 
The sponsor of this research.  “Sponsor” means any persons or companies 
that are: 
• working for or with the sponsor, or  
• owned by the sponsor. 
 
Your information may be given to:  
• The U.S. Food and Drug Administration (FDA), 
• Department of Health and Human Services (DHHS) agencies, 
• Governmental agencies in other countries,  
• The institution where the research is being done, 
• Governmental agencies to whom certain diseases (reportable 
diseases) must be reported, and 
• Institutional Review Board (IRB)  
 


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Why will this information be used and/or given to others? 
• to do the research,  
• to study the results, and  
• to make sure that the research was done right.   
 
If the results of this study are made public, information that identifies you 
will not be used. 
 
What if I decide not to give permission to use and give out my health 
information? 
Then you will not be able to be in this research study. 
 
May I review or copy my information? 
Yes, but only after the research is over.  
 
May I withdraw or revoke (cancel) my permission? 
This permission will be good until December 31, 2070. 
 
You may withdraw or take away your permission to use and disclose your 
health information at any time.  You do this by sending written notice to the 
study doctor.  If you withdraw your permission, you will not be able to stay 
in this study. 
 
When you withdraw your permission, no new health information identifying 
you will be gathered after that date.  Information that has already been 
gathered may still be used and given to others.   
 
Is my health information protected after it has been given to others? 
There is a risk that your information will be given to others without your 
permission. 
 


ACTIV-1 IM  
Version 2.0, Protocol version date: 02 December 2020 
Page 28 of 32   
IRB Approved Template 
 
MUST BE APPROVED 
 
FOR SITES BEFORE USE 
 
AS MODIFIED 
 
Dec 31, 2020 
 
 
Authorization: 
I have been given the information about the use and disclosure of my health 
information for this research study.  My questions have been answered. 
 
I authorize the use and disclosure of my health information to the parties 
listed in the authorization section of this consent for the purposes described 
above. 
 
AUTHORIZATION SIGNATURE: 
 
 
 
 
 
 
Signature of Subject 
 
Date 
 
 
_________________________________________________________________ 
__________________ 
Signature of Legally Authorized Representative (LAR) 
Date  
 
 
 
________________________________________ 
Printed name of LAR 
 
 
________________________________________ 
Relationship of LAR to Participant 
 


ACTIV-1 IM Addendum 
Version 2.0, Protocol version date: 02 December 2020 
Page 29 of 32   
IRB Approved Template 
 
MUST BE APPROVED 
 
FOR SITES BEFORE USE 
 
AS MODIFIED 
 
Dec 31, 2020 
 
 
RESEARCH PARTICIPANT CONSENT ADDENDUM 
 
TITLE: 
Randomized Master Protocol for Immune Modulators for 
Treating COVID-19 
 
PROTOCOL NO.: 
ACTIV-1 IM 
 
WIRB® Protocol #20202874 
 
SPONSOR: 
Daniel K. Benjamin, MD, MPH, PhD 
 
INVESTIGATOR: 
Name 
 
Address 
 
City, State  Zip 
 
Country 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Phone Number 
 
Phone Number (24 hours) 
 
[24 hour number is required] 
 
What treatments are currently available for this study? 
 
The ACTIV-1 IM study involves multiple different types of potential treatments. You will 
be asked to review information for each study treatment to learn more about its risks 
and benefits. The current list of possible study treatments is below in Table 1, and more 
detailed information about these treatments is included in this consent form. The study 
team has marked (put an X or check mark) next to the treatments that are available for 
you to possibly receive.  
 
Table 1: Available Treatments  
 
Study Treatment 
Study Staff will 
‘X’ or check all 
available 
Treatments 
Remdesivir and Infliximab (Remicade) 
 
Remdesivir and Abatacept (Orencia) 
 
Remdesivir and Cenicriviroc (CVC) 
 
 


ACTIV-1 IM Addendum 
Version 2.0, Protocol version date: 02 December 2020 
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IRB Approved Template 
 
MUST BE APPROVED 
 
FOR SITES BEFORE USE 
 
AS MODIFIED 
 
Dec 31, 2020 
 
 
Please sign below to indicate you understand the available treatment options in the 
study: 
 
 
________________________________________ 
Date: _____/_____/_____ 
Signature of participant 
mm      dd      yyyy 
 
 
________________________________________ 
Printed name of participant 


ACTIV-1 IM Addendum 
Version 2.0, Protocol version date: 02 December 2020 
Page 31 of 32   
IRB Approved Template 
 
MUST BE APPROVED 
 
FOR SITES BEFORE USE 
 
AS MODIFIED 
 
Dec 31, 2020 
 
 
 
Assent Instructions: 
• All subjects unable to consent are required to assent, unless the investigator 
determines that the capability of the subject is so limited that the subject cannot 
reasonably be consulted.  
• If assent is obtained, have the person obtaining assent document assent on the 
consent form. 
 
 
________________________________________ 
Date: _____/_____/_____ 
Signature of participant 
mm      dd      yyyy 
 
 
________________________________________ 
Printed name of participant 
 
 
 I have explained the study to the extent compatible with the subject’s capability, and 
the subject has agreed to be in the study. 
OR 
 The subject is not able to assent because the capability of the subject is so limited 
that the subject cannot reasonably be consulted. 
 
 
________________________________________ 
Date: _____/_____/_____ 
Signature of investigator/designee 
mm      dd      yyyy 
 
 
________________________________________ 
Printed name of investigator/designee 
 
 
For adults not capable of giving consent  
 
 
________________________________________ 
Date: _____/_____/_____ 
Signature of Legally Authorized Representative (LAR)  
mm      dd      yyyy 
 
 
________________________________________ 
Printed name of LAR 
 
 
________________________________________ 
Relationship of LAR to Participant 


ACTIV-1 IM Addendum 
Version 2.0, Protocol version date: 02 December 2020 
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IRB Approved Template 
 
MUST BE APPROVED 
 
FOR SITES BEFORE USE 
 
AS MODIFIED 
 
Dec 31, 2020 
 
 
 
 
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 
mm      dd      yyyy 
 
 
________________________________________ 
Printed name of witness 

SAP_002.pdf: 
 
 
 
 
 
 
 
 
Statistical Analysis Plan (ACTIV-1 IM) 
 
 
1 
CONFIDENTIAL 
Master Protocol for Immune Modulators for Treating COVID-19 
Protocol: ACTIV-1 IM 
 
STATISTICAL ANALYSIS PLAN (SAP) 
Protocol Version 2.0  
 
Protocol Version Date: 02 DEC 2020 
 
SAP Version Number: 5.0 
 
11 APR 2022 
 
Daniel K. Benjamin, MD, MPH, PhD 
Kiser-Arena Distinguished Professor, Duke University Pediatrics 
Duke Clinical Research Institute 
300 W. Morgan Street, Suite 800 
Durham Center 
Durham, NC 27701 
Tel: 919-668-7081 
E-mail: danny.benjamin@duke.edu 
 
 
 


 
 
 
 
 
 
 
 
Statistical Analysis Plan (ACTIV-1 IM) 
 
 
2 
CONFIDENTIAL 
SAP Approval Page 
 
Study Title: Master Protocol for Immune Modulators for Treating COVID-19 
 
Version: 5.0 
 
Date of Issue: 11 APR 2022 
 
Study Sponsor: Daniel K. Benjamin, MD, MPH, PhD 
                             Kiser-Arena Distinguished Professor, Duke University Pediatrics 
                             Duke Clinical Research Institute 
                             300 W. Morgan Street, Suite 800 / Durham Centre / Durham, NC 27701 
 
We, the undersigned, have read and approve of this SAP and agree on its content. 
 
 
______________________________________________ 
Sponsor Representative – Daniel K. Benjamin, MD, MPH, PhD 
 
_______________________________________________ 
Sponsor Representative – Soju Chang, MD, MPH 
 
_______________________________________________ 
ACTIV-1 Protocol Statistician – Lisa LaVange, PhD 
 
_______________________________________________ 
ACTIV-1 Protocol Chair – William G. Powderly, MD 
 


 
 
 
 
 
 
 
 
Statistical Analysis Plan (ACTIV-1 IM) 
 
 
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CONFIDENTIAL 
TABLE OF CONTENTS 
List of Abbreviations .................................................................................................................................................. 5 
1.0 
Study and Document Overview ......................................................... 7 
2.0 
Study Objectives and Estimands ........................................................ 8 
3.0 
Statistical Hypotheses and Endpoints .............................................. 11 
3.1 
Study Definitions and Derived Variables.......................................... 14 
3.1.1 
Visit Day ........................................................................................... 14 
3.1.2 
8-Point Ordinal Scale ........................................................................ 14 
3.1.3 
Measures of Clinical Support, Limitations, and Infection Control ... 14 
3.1.4 
Extrapulmonary Manifestations ...................................................... 15 
3.1.5 
National Early Warning Score (NEWS) ............................................. 16 
3.2 
Power and Sample Size .................................................................... 18 
3.3 
Randomization Scheme ................................................................... 19 
3.4 
Interim Analyses and Data Monitoring ............................................ 20 
3.4.1 
Interim Safety Analyses ................................................................... 21 
3.4.2 
Interim Analyses for Futility and Efficacy Review ............................ 21 
3.4.3 
Adaptations ...................................................................................... 23 
3.5 
Data Sources .................................................................................... 25 
3.6 
Documentation Convention ............................................................. 26 
3.7 
Verification of Results ...................................................................... 26 
3.8 
Subject Disposition .......................................................................... 26 
3.9 
Populations for Analyses .................................................................. 27 
4.0 
Statistical Analyses ........................................................................... 28 
4.1 
General Approach ............................................................................ 28 
4.2 
Analysis of the Primary and Key Secondary Efficacy Endpoints ....... 31 
4.3 
Analysis of the Other Secondary Efficacy Endpoints ....................... 36 
4.4 
Safety Analyses ................................................................................ 39 
4.4.1 
Laboratory Data ............................................................................... 40 


 
 
 
 
 
 
 
 
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4.4.2 
Vital Signs ......................................................................................... 41 
4.4.3 
Prior and Comcomitant Medications ............................................... 41 
4.4.4 
Treatment Compliance .................................................................... 41 
4.4.5 
Pregnancy Tests ............................................................................... 41 
4.5 
Exploratory Analyses ........................................................................ 41 
4.6 
Baseline Descriptive Statistics .......................................................... 42 
4.7 
Sub-Group Analyses ......................................................................... 42 
4.8 
References ....................................................................................... 44 
4.9 
Appendices....................................................................................... 46 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
Statistical Analysis Plan (ACTIV-1 IM) 
 
 
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LIST OF ABBREVIATIONS 
 
ACTIV 
Accelerating COVID-19 Therapeutic Interventions and Vaccines 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
ATC 
Anatomical Therapeutic Classification 
BMI 
Body Mass Index 
CDISC 
Clinical Data Interchange Standards Consortium  
CI 
Confidence Interval 
COVID-19 
Coronavirus 
CRP 
C-Reactive Protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of AIDS 
DCRI 
Duke Clinical Research Institute 
DSMB 
Data and Safety Monitoring Board 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic Case Report Form 
EOS 
End of Study  
ET 
Early Termination 
FU 
Follow-up 
ITT 
Intent-to-Treat 
LLN 
Lower Limit of Normal 
MedDRA 
Medical Dictionary of Regulatory Activities 
MITT 
Modified Intent-to-Treat 


 
 
 
 
 
 
 
 
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NEWS 
National Early Warning Score 
PT 
Preferred Term 
Q1 
25th Percentile (1st Quartile) 
Q3 
75th Percentile (3rd Quartile) 
RR 
Respiratory Rate 
RRR 
Recovery Rate Ratio 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SoC 
Standard of Care 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
 
 
 
 


 
 
 
 
 
 
 
 
Statistical Analysis Plan (ACTIV-1 IM) 
 
 
7 
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1.0 
STUDY AND DOCUMENT OVERVIEW 
 
ACTIV-1 IM is a master protocol designed to evaluate multiple investigational agents for the treatment 
of moderately or severely ill patients infected with severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2). ACTIV-1 IM is a randomized, controlled, double-blinded trial which will evaluate each 
agent with respect to speed of recovery, mortality, illness severity, and hospital resource utilization. 
Each agent will be evaluated as add-on therapy to the standard of care (SoC) in use at the local clinics. 
The SoC may change during the course of the study based on other research findings. Comparisons of 
the investigational agents among themselves is not a research objective. 
 
This document describes the planned statistical analyses that will be conducted at the completion of the 
ACTIV-1 IM study for each of the investigational agents. Once the initial unblinded data review has 
occurred, only the blinded statistics team members will be allowed to modify the SAP (see Appendix 1 
for the list of blinded and unblinded statisticians).  
 
The study population corresponds to moderately and severely ill adults (≥18 years old) with the 
coronavirus disease 2019 (COVID-19) virus. Recruitment will target patients already hospitalized for 
treatment of COVID-19 infection as well as patients being treated for COVID-19 infection in Emergency 
Departments while waiting to be admitted to the hospital. Patients both in and out of the intensive care 
unit (ICU) will be included in the study population.  Enrollment began in October 2020 with 3 agents 
selected for initial evaluation. Up to 5 agents may be evaluated in ACTIV-1 IM. 
 
The study period is 29 days, with assessments on each day of the hospital stay. If the participants are 
discharged from the hospital, they will have a study visit at Days 8, 11, 15, 22, and 29. For discharged 
participants, it is preferred that the Day 8, 11, 15, and 29 visits are in person to obtain safety laboratory 
tests and blood (serum and plasma) samples for secondary research (Day 29) as well as clinical outcome 
data. Clinical outcome is assessed for the previous day; for example, study visit Days 8, 11, 22, and 29 
represent data for Days 7, 10, 21, and 28. However, infection control or other restrictions may limit the 
ability of the participant 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. There will also be a safety and clinical status assessment at 60 days 
conducted by phone. Treatment periods may vary by agent. 
 
The trial is adaptive in that interim analyses are planned to assess the futility of each agent, with the 
goal of discontinuing those with lower probabilities of success to more effectively utilize trial resources 
for the remaining agents. Additionally, interim analyses are planned for early stopping for efficacy.  


 
 
 
 
 
 
 
 
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Alpha spending functions are used to appropriately control the probability of making an erroneous 
conclusion at the interim and final analyses. Safety monitoring will be performed throughout the trial, 
and formal stopping rules for each agent will be adopted. The Data and Safety Monitoring Board (DSMB) 
established for ACTIV-1 IM will have oversight responsibility for the study.  
 
The effectiveness of each therapeutic agent as add-on therapy to SoC will be evaluated based on the 
primary endpoint of time to recovery through Day 28. The sample size requirements are based on the 
ability to detect a moderate improvement in time to recovery for each agent. A total of 788 recoveries 
are required for each comparison to provide approximately 85% power to detect a recovery rate ratio 
(RRR) of 1.25. Assuming 73% of participants achieve recovery within 28 days, consistent with the ACTT-1 
(Beigel, Tomashek et al. 2020) results, the total sample size to evaluate 1, 2, and 3 agents in ACTIV-1 IM 
is approximately 1080, 1620, and 2160, respectively. Because each agent is being compared to SoC plus 
placebo with no between-agent comparisons, no multiplicity adjustments for multiple agents are 
planned. 
2.0 
STUDY OBJECTIVES AND ESTIMANDS  
 
Primary Objective: 
 
To evaluate the clinical efficacy of different investigational therapeutics relative to the control 
arm in adults hospitalized with COVID-19 with respect to time to recovery through Day 28 from 
randomization. 
 
Key Secondary Objectives: 
 
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) assessed on Day 14 and Day 28  
 
Mortality 
 
Summaries of the questions of interest and descriptions of the estimand attributes are shown in Table 1.  
 
 
 


 
 
 
 
 
 
 
 
Statistical Analysis Plan (ACTIV-1 IM) 
 
 
9 
CONFIDENTIAL 
Table 1. Study Objectives and Estimands. 
Question of 
Interest 
Objective 
Description / 
Study Population 
Endpoint 
Intercurrent 
Events 
Population 
Summary 
Does drug X 
reduce the time-
to-recovery 
compared with 
standard-of-care 
alone for patients 
hospitalized with 
moderate or 
severe COVID-19? 
Primary Objective 
of the Study / All 
Randomized 
Participants  
Time to recovery 
defined as the 
first day with an 
8-point ordinal 
scale score of ≥ 6.  
Death from any 
cause (a semi-
competing event). 
Once an individual 
has experienced 
death, they no 
longer have the 
opportunity to 
‘recover’.  All 
other intercurrent 
events will be 
ignored. 
Recovery rate 
ratio (RRR) and its 
associated 
confidence 
interval from a 
Fine-Gray model. 
Values greater 
than 1.0 indicate 
a benefit for drug 
X.  A value of 2.0 
suggests a larger 
benefit than 1.25. 
Stratification 
factors will 
include region 
and baseline 
severity (2, 3, 4, 
or 5). Other 
covariates in the 
model will include 
age and sex. 
Does drug X 
improve the 
ordinal response 
of the 8-point 
ordinal scale 
compared with 
standard-of-care 
alone? 
Key Secondary 
Objective of the 
Study / All 
Randomized 
Participants* 
The 8-point 
ordinal scale 
score on Day 14. 
A supplemental 
analysis will be 
completed on the 
same scale at Day 
28.  
Deaths are placed 
as the worst 
possible score on 
the ordinal scale.  
All other 
intercurrent 
events will be 
ignored in these 
analyses. 
Odds ratio 
estimate based on 
a proportional 
odds model.  
Values above 1.0 
suggest benefit 
from drug X. The 
model will include 
baseline severity 
(2, 3, 4, or 5), 
region, sex, and 
age (continuous) 
as covariates.  
Does drug X 
reduce the rate of 
death over 28 
days compared 
with standard-of-
care alone? 
Key Secondary 
Objective of the 
Study / All 
Randomized 
Participants* 
Death observed 
between 
randomization 
through Day 28 
All other 
intercurrent 
events will be 
ignored in these 
analyses. 
An odds ratio 
from a logistic 
regression model 
with indicator 
variables for 
treatment group, 


 
 
 
 
 
 
 
 
Statistical Analysis Plan (ACTIV-1 IM) 
 
 
10 
CONFIDENTIAL 
8-point ordinal 
scale (2, 3, 4, or 5) 
at baseline, 
region, sex, and     
age (continuous).   
*For the test agent and pooled control group 
 
 
 
Additional Secondary Objectives: 
 
To evaluate the clinical efficacy of different investigational therapeutics relative to the control 
arm as assessed by clinical severity and hospitalization. 
 
To evaluate clinical status at Day 60. 
 
To evaluate the safety of different investigational therapeutics relative to the control arm.  
 
To evaluate the impact of different investigational therapeutics relative to the control arm of 
extrapulmonary manifestations of COVID-19. 
Exploratory Objectives: 
 
To assess the National Early Warning Score (NEWS). 
 
 


 
 
 
 
 
 
 
 
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11 
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3.0 
STATISTICAL HYPOTHESES AND ENDPOINTS 
 
o The primary null hypothesis being tested is that time-to-recovery does not differ 
between each test agent (plus SoC) and the pooled control group, consisting of 
patients receiving SoC plus placebo. The alternative hypothesis is that the test agent 
and pooled control group differ in time-to-recovery with the hope that the test 
agent group has a shorter time-to-recovery than the pooled control group although 
a two-tailed test will be used. If Drug A, B, and C denote the initial set of agents to 
be tested in ACTIV-1 IM plus SoC, and S denotes patients receiving SoC plus placebo, 
then the primary hypotheses are: 
 
H01: TRA = TRS vs  HA1: TRA ≠ TRS 
H02: TRB = TRS vs  HA2: TRB  ≠ TRS 
H03: TRC = TRS vs  HA3: TRC  ≠ TRS 
 
o Primary Efficacy Endpoint - Time to recovery through Day 28 
 
Day of recovery is defined as the first day on which the participant satisfies 
one of the following three categories from the 8-point ordinal scale (defined 
in Section 3.1.2): 
 
Hospitalized, not requiring supplemental oxygen – no longer 
requires ongoing medical in-patient care; 
 
Not hospitalized, limitation on activities and/or requiring home 
oxygen; 
 
Not hospitalized, no limitations on activities. 
 
o There are two key secondary hypotheses that will be evaluated as supportive 
evidence. 
 
o Key Secondary Endpoint 1 - Clinical status (8-point ordinal scale) on Day 14 
 
The null hypothesis to be tested is that the odds of improvement on the 8-point 
ordinal scale is the same for the placebo and experimental treatment arms (i.e., 
the common odds ratio is 1) on Day 14. For this comparison, the parameter of 
interest is the “common odds ratio,” which quantifies the shift in the severity 
distribution resulting from treatment. The odds ratio will be defined such that a 
value greater than 1 implies better outcomes with active drug compared to 
placebo control.  
 


 
 
 
 
 
 
 
 
Statistical Analysis Plan (ACTIV-1 IM) 
 
 
12 
CONFIDENTIAL 
o Key Secondary Endpoint 2 - Mortality 
 
The null hypothesis to be tested is that there is no difference in mortality rates 
between treatment groups.  Mortality through Day 28 will be analyzed using a 
logistic regression model with an indicator variable for the treatment group, 8-
point ordinal scale (2, 3, 4, or 5) at baseline, region, sex, and age.  
 
o Additional Secondary Endpoints 
o Time to an improvement of one category and two categories from Day 0 
(baseline) using the 8-point ordinal scale. 
o Mean change in the 8-point ordinal scale from baseline to Days 2, 4, 7, 10, 
14, 21, 28, and 60. 
o Differences in total severity score (TSS): 8-point ordinal scale summarized as 
a daily score (for days collected) averaged over time from baseline through 
Day 28. 
o Days alive and free of supplemental oxygen through 28. 
o Incidence and duration of new oxygen use during the study. This includes 
new supplemental oxygen, non-invasive ventilation/high flow oxygen use, 
and invasive mechanical ventilation/extracorporeal membrane oxygenation 
(ECMO). 
o Days alive and free of non-invasive ventilation/high flow oxygen use 
through Day 28. 
o Incidence and duration of new non-invasive ventilation or high flow oxygen 
use during the study. This includes new non-invasive ventilation or high flow 
oxygen use as well as invasive mechanical ventilation/ECMO. 
o Days alive and free of invasive mechanical ventilation/ECMO through Day 
28. 
o Incidence and duration of new mechanical ventilation/ECMO use during the 
study. 
o Days alive and out of hospitalization through Day 28. 
 
o 
Key Safety Endpoints 
o Serious Adverse Events (SAEs) 
o Grade 3 and 4 Adverse Events (AEs) 
o Baseline laboratory tests include CBC with differential (including absolute 
neutrophil count and absolute lymphocyte count), ALT, AST, ALP, total 
bilirubin, creatinine (with calculated eGFR), glucose, Troponin, PT/INR, d-
dimer, and C-reactive protein. On Days 3, 5, 8, 11, 15, and 29, safety 
laboratory tests include WBC with differential, hemoglobin, platelets, ALT, 


 
 
 
 
 
 
 
 
Statistical Analysis Plan (ACTIV-1 IM) 
 
 
13 
CONFIDENTIAL 
AST, ALP, total bilirubin, creatinine (with calculated eGFR), and glucose. On 
Day 8 or on day of discharge (if less than 24 hours prior to Day 8), the 
following additional laboratory assessments are performed: Troponin, 
PT/INR, d-dimer, and C-reactive protein. 
o Incidence of individual and “any” specified extrapulmonary manifestations 
up to Day 29 
 
o Exploratory Endpoints 
o NEWS assessed daily while hospitalized (Day 1 – discharge) and on Days 15 
and 29 
 
 


 
 
 
 
 
 
 
 
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3.1 
STUDY DEFINITIONS AND DERIVED VARIABLES 
 
3.1.1 
VISIT DAY 
 
The baseline visit is the date of randomization. Post-baseline study day visits are documenting the 
clinical information through the completion of the prior day (e.g. Day 2 is collecting the post-
randomization data Day 1 and Day 29 is collecting data that encompasses all of Day 28). However, we 
will present visit day as actual day that is being assessed. 
 
3.1.2 
8-POINT ORDINAL SCALE 
o The 8-point ordinal scale is the basis for the primary and key secondary clinical endpoints in the 
study, namely, time to recovery, improvement in disease severity, and mortality.  
o The scale used in this study is as follows (from worst to best): 
 
1: Death; 
 
2: Hospitalized, on invasive mechanical ventilation or ECMO; 
 
3: Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
 
4: Hospitalized, requiring supplemental oxygen; 
 
5: Hospitalized, not requiring supplemental oxygen – requiring ongoing medical in-patient  
care (COVID-19 related or otherwise); 
 
6: Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical in-
patient care; 
o This would include those kept in hospital for quarantine/infection control/social 
reasons, awaiting bed in rehabilitation facility or homecare, etc. 
 
7: Not hospitalized, limitation on activities and/or requiring home oxygen; 
 
8: Not hospitalized, no limitations on activities 
3.1.3 
MEASURES OF CLINICAL SUPPORT, LIMITATIONS, AND INFECTION CONTROL 
 
The participant’s clinical status will be captured on each study day while hospitalized through Day 29, for 
the previous day. Clinical data status is measured twice on Day 1, once at the time of randomization and 
once at the Day 2 visit for the post-randomization time period. If a participant is discharged prior to Day 
15, clinical status is collected on Day 8, Day 11, Day 15, and Day 29, if the participant returns for an in-
person clinic visit or by phone if an in-person visit is not possible. Clinical status will also be captured on 
Day 22 during a phone visit. Clinical status is largely measured by the 8-point ordinal scale and the 
NEWS. Unlike the NEWS, the ordinal scale can also be evaluated over the phone if the discharged 
participant is unable to return for visits on Day 8, 11, 15, or 29 as well as on Day 22.  


 
 
 
 
 
 
 
 
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Improvement will be defined as an increase of at least one point on the 8-point scale compared to the 
baseline value (e.g. from 4 to 5) and the time to improvement will be defined as the elapsed time (in 
days) from baseline to the earliest day of observed improvement. 
Any subjects that are lost to follow-up or terminated early prior to an observed improvement will be 
censored at the day of their last observed assessment.  
 
3.1.4 
EXTRAPULMONARY MANIFESTATIONS 
 
The presence of the extrapulmonary manifestation of disease during the course of hospitalization will be 
assessed and reported at discharge.  These tables will be reported with stratification by the participant’s 
baseline clinical status. Specifically, clinical organ failure is defined by development of any one or more of 
the following clinical events: 
 
a. Respiratory dysfunction: 
1. Respiratory failure defined as receipt of high flow nasal oxygen, noninvasive 
ventilation, invasive mechanical ventilation or ECMO 
 
b. Cardiac and vascular dysfunction: 
1. Myocardial infarction 
2. Myocarditis or pericarditis 
3. Congestive heart failure: new onset NYHA class III or IV, or worsening to class III or IV 
4. Hypotension requiring institution of vasopressor therapy 
 
c. Renal dysfunction: 
1. New requirement for renal replacement therapy 
 
d. Hepatic dysfunction: 
1. Hepatic decompensation 
 
e. Neurological dysfunction 


 
 
 
 
 
 
 
 
Statistical Analysis Plan (ACTIV-1 IM) 
 
 
16 
CONFIDENTIAL 
1. Acute delirium 
2. Cerebrovascular event (stroke, cerebrovascular accident [CVA]) 
3. Transient ischemic events (i.e., CVA symptomatology resolving <24 hrs) 
4. Encephalitis, meningitis or myelitis 
 
f. Hematological dysfunction: 
1. Disseminated intravascular coagulation 
2. New arterial or venous thromboembolic events, including pulmonary embolism and 
deep vein thrombosis 
3. Major bleeding events (>2 units of blood within 24 hours, bleeding at a critical site 
(intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with 
compartment syndrome, or retroperitoneal), or fatal bleeding). 
 
 g. Secondary infection / superinfection: 
1. Intercurrent, at least probable, documented serious disease caused by an infection 
other than SARS-CoV2, requiring antimicrobial administration and care.  
2. A complete list of secondary infections / superinfections is provided in the study 
manual of procedures. 
 
3.1.5 
NATIONAL EARLY WARNING SCORE (NEWS) 
 
Vital signs and other clinical assessments are collected for the calculation of the NEWS, and include 
temperature, systolic blood pressure, heart rate, respiratory rate, O2 saturation and level of 
consciousness. Vital signs collected per standard of care can be used. NEWS has demonstrated an ability 
to discriminate subjects at risk of poor outcomes. (Smith, Prytherch et al. 2016). This score is based on 7 
clinical parameters (see Table 2). The NEWS is being used as an exploratory efficacy measure. The 
components of NEWS should be evaluated daily while hospitalized. It can be performed concurrently 
with the Ordinal Scale. This should be evaluated at a consistent time for each study day and prior to 
administration of study product. The 7 parameters can be obtained from the hospital chart or electronic 
medical record (EMR) using the last measurement prior to the time of assessment (including parameters 
collected prior to the time of consent) and a numeric score is given for each parameter (e.g., a 
respiratory rate [RR] of 9 breaths per minute 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 will be 


 
 
 
 
 
 
 
 
Statistical Analysis Plan (ACTIV-1 IM) 
 
 
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used to obtain NEWS for Day 3). ECMO and mechanically ventilated participants should be assigned a 
score of 3 for RR (RR ≤8 breaths per minute) regardless of the ventilator setting. Participants on ECMO 
should get a score of 3 for heart rate since they are on cardiopulmonary bypass. 
 
Table 2. National Early Warning Score (NEWS) 
PHYSIOLOGICAL 
PARAMETERS 
3 
2 
1 
0 
1 
2 
3 
Respiration Rate 
(breaths per minute) 
≤8 a 
 
9 – 11 
12 – 20 
 
21 – 24 
≥25 
Oxygen Saturation 
(%) 
≤91 
92 – 93 
94 – 95 
≥96 
 
 
 
Any Supplemental 
Oxygen 
 
Yes 
 
No 
 
 
 
Temperature (oC) 
≤35.0 
 
35.1 – 
36.0 
36.1 – 
38.0 
38.1 – 
39.0 
≥39.1 
 
Systolic Blood 
Pressure (mm Hg) 
≤90 
91 – 100 
101 – 110 
111 – 219 
 
 
≥220 
Heart Rate 
(beats per minute) 
≤40 b 
 
41 – 50 
51 – 90 
91 – 110 
111 – 130 
≥131 
Level of 
Consciousness 
 
 
 
A 
 
 
V, P, U 
Level of consciousness = alert (A), and non-alert and arousable only to voice (V) or pain (P), and unresponsive (U).  
a If the participant is on ECMO or invasive mechanical ventilation, they will be given a score of 3 (≤8 breaths per 
minute) for respiratory rate regardless of ventilator setting.  
b Participants on ECMO will also receive a score of 3 (≤40 beats per minute) for heart rate. 
 
 


 
 
 
 
 
 
 
 
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3.2 
POWER AND SAMPLE SIZE 
 
ACTIV-1 is an event-driven trial based on the number of observed recovery events. The effectiveness of 
each therapeutic agent as add-on therapy to SoC will be evaluated based on the primary endpoint of 
time to recovery through Day 28.  The Fine-Gray approach will be used to compare each test agent + SoC 
vs. SoC-alone with respect to the cumulative incidence of recovery, accounting for the semi-competing 
risk of mortality (Fine and Gray 1999). The approach is similar to using a log-rank test on time to 
recovery, retaining in the risk set people who die.  The two key determinants of power are the total 
number of events (i.e., recoveries) and the treatment-to-control recovery rate ratio (RRR).  
 
Overall study sample size requirements are based on the number of agents being evaluated and the 
ability to pool control patients for analysis. Initial sample size estimates are derived assuming three 
agents are ready for testing at study start and will remain in the study for evaluation at the final analysis 
stage. If newly emergent therapies are entered into the master protocol after study start, sample size 
requirements will be adjusted accordingly. 
 
Table 3 provides the numbers of recoveries and of patients required to provide 85% power for a single 
pairwise comparison of test drug versus control assuming a 73% recovery rate and various RRRs. The 
assumed 73% recovery rate is based on the Kaplan-Meier recovery rate from ACTT-1. Note that the 
recovery rate is the analogue of the hazard for each test agent or control treatment, and the RRR is the 
analogue of the hazard ratio for a test agent relative to control in this setting. Approximately 347 
recoveries are required to detect a 40% increase in the rate of recovery (𝜃= 1.40) from control. An RRR 
of 1.40 is similar to, but slightly higher than the figure of 1.31 reported in Cao et al. (2020) for a 
lopinavir/ritonavir trial that used time to improvement by 2 categories as primary endpoint (Cao, Wang 
et al. 2020). A total of 436 recoveries is needed for an RRR of 1.35 with 85% power.  
Table 3. Number of recoveries and number of patients 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 
Sample Size assuming 73% recovery 
rate (1 test agent vs SoC) 
1.25 
788 
1,080 
1.30 
570 
781 
1.35 
436 
598 
1.40 
347 
476 
 
The sample size requirements are based on the ability to detect a moderate improvement in time to 
recovery for each agent. After accounting for the proposed interim efficacy and futility monitoring rules, 


 
 
 
 
 
 
 
 
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a total of 788 recoveries are required for each comparison to provide approximately 85% power to 
detect a RRR of 1.25. Assuming 73% of participants achieve recovery in 28 days, consistent with the 
ACTT-1 results (Beigel, Tomashek et al. 2020), the total sample size to evaluate 1, 2, and 3 agents in 
ACTIV-1 IM is approximately 1080, 1620, and 2160, respectively.  
 
The proposed power and sample size requirements also provide adequate power to detect differences 
in the key secondary endpoints of clinical improvement and mortality. Based on the formulas from 
Whitehead (1993), a sample size of 1,080 (540 participants / group) ) gives approximately 95% or 85% 
power to detect a common odds ratio of 1.50 of clinical improvement (the observed odds ratio in the 
ACTT-1 trial) or 1.40 using a 2-tailed test at level α=0.05. The 28-day mortality probability in the 
remdesivir arm of ACTT-1 was approximately 12%. The power for comparing 28-day mortality is 90% for 
a 50% relative reduction (from 12% to 6%) and 80% to detect a difference of 12.0% vs. 6.8%. 
 
3.3 
RANDOMIZATION SCHEME 
 
Randomization will be stratified by: 
 
Geographic Region  
o USA – Northeast 
 
Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, 
Pennsylvania, Rhode Island, Vermont 
o USA - Midwest 
 
Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, North Dakota, 
Nebraska, Ohio, South Dakota, Wisconsin 
o USA – South 
 
Alabama, Arkansas, Delaware, District of Columbia, Florida, Georgia, Kentucky, 
Louisiana, Maryland, Mississippi, North Carolina, Oklahoma, South Carolina, 
Tennessee, Texas, Virginia, West Virginia 
o USA – West 
 
Alaska, Arizona, California, Colorado, Hawaii, Idaho, Montana, New Mexico, 
Nevada, Oregon, Utah, Wyoming, Washington 
o Argentina 
o Brazil 
o Peru 
o Mexico 
o Additional countries will be treated as separate regions 
 
Severity of illness at enrollment (by ordinal scale) 
o Severe disease: 


 
 
 
 
 
 
 
 
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 
Hospitalized, on invasive mechanical ventilation or ECMO, or  
 
Hospitalized, on non-invasive ventilation or high flow oxygen devices.  
o Moderate disease: 
 
Hospitalized, requiring supplemental oxygen, or  
 
Hospitalized, not requiring supplemental oxygen.  
Conceptually, randomization will proceed in two steps. At the first step, each participant will be assigned 
(open-label) with equal probability to one of the agents available at the time the patient is enrolled and 
for which the patient is eligible to receive, after applying any agent-specific safety exclusions. At the 
second step, each participant will be assigned to either the test agent or its matching placebo in an n:1 
ratio, where n = the number of agents currently active in the master protocol and for which the patient 
is eligible to receive.  
With SoC and three agents active simultaneously, if the participant meets each of the agent-specific 
criteria, this procedure results in the randomization ratio of 1:1:1:1. If 3 agents are available, but a 
patient is only eligible to receive 2 of them, the allocation ratio at the first step will be 1:1, and at the 
second step will be 2:1 (agent vs placebo). Inclusion of a matching placebo for each agent enables 
masking of study participants and clinical personnel to treatment assignment at the second stage. Data 
from patients receiving SoC plus placebo will be pooled across agents for comparative analyses and 
hypothesis testing. Comparative analyses of a particular agent will include the subset of pooled placebo 
patients who enrolled concurrently with the particular agent and would have been eligible to receive the 
agent.  That is, patients enrolled to control arm prior to a new agent entering the trial will not be 
included in comparative analyses of that newly added investigation agent. 
 
3.4 
INTERIM ANALYSES AND DATA MONITORING 
 
A complete description of the interim analyses plans including mock tables, listings, and figures is 
included in a separate DSMB guidance document. Briefly, unblinded interim analyses are planned to (i) 
assess the futility of each agent, with the goal of discontinuing those with lower probabilities of success 
to more effectively utilize trial resources for the remaining agents and (ii) review comparative analyses 
for each test agent to assess early stopping for efficacy.  
 
Alpha spending functions will be used to appropriately control the probability of making an erroneous 
conclusion across interim and final efficacy analyses at α = 0.05 (two-sided) for each agent.  The 
familywise error rates will be controlled at the two-sided 0.05 level for the primary endpoint and the 
two key secondary endpoints. Briefly, a gatekeeper approach will be used to test the primary 
hypothesis.  As described in Hung, Wang and O’Neill (2007), the null hypotheses for the two key 
secondary endpoints are tested only if the null hypothesis is rejected for the primary endpoint.  At the 
second level, the two key secondary endpoints are evaluated using a Pocock-type boundary with a Holm 


 
 
 
 
 
 
 
 
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procedure used to control the type I error for the two secondary endpoints (Tamhane, Mehta, Liu 2010; 
Holm 1979). 
 
3.4.1 
INTERIM SAFETY ANALYSES 
 
Safety analyses will evaluate Grade 3 and 4 AE and SAEs by treatment arm. Safety monitoring will be 
ongoing. The unblinded statistical team will prepare these reports for review by the DSMB. More details 
will be provided in a separate DSMB guidance document. 
 
3.4.2 
INTERIM ANALYSES FOR FUTILITY AND EFFICACY REVIEW 
 
Interim analyses for futility and efficacy were planned at three times during the study corresponding to 
the availability of approximately 25%, 50%, and 75% of total information. The planned randomization 
algorithm ensures approximately equal allocation to each test agent or control assuming that 
participants are eligible for all available agents. It is anticipated that the interim analyses for each agent 
will occur at the same time, and the DSMB will make recommendations for all agents at their scheduled 
meetings. If recovery rates vary substantially by agent; however, it may be necessary to let the interim 
analysis times also vary by agent. Because Type I error probabilities are controlled for each agent, 
independently of the other agents, the need for additional DSMB reviews due to differential information 
accrual across agents should not pose any issues other than logistical ones. 
 
The Lan-DeMets spending function analog with the O’Brien-Fleming boundaries will be used to monitor 
the primary endpoint as a guide for the DSMB. This spending function is conservative in that priority is 
given to preserving power for the final analysis with the use of stringent stopping rules early in the 
study. 
 
In contrast, moderately aggressive stopping rules for futility will be implemented to promote early 
discontinuation of agents with low probabilities for success. The futility stopping rules will be considered 
non-binding by the DSMB in their review of interim data. The futility boundaries are computed based on 
the gamma family of spending functions (Hwang, Shih, DeCani 1990). Figure 1 below illustrates the 
efficacy boundaries based on the Lan-DeMets spending function analog to O’Brien-Fleming and the 
futility boundaries based on a (Gamma=-2) spending function. 
 
 


 
 
 
 
 
 
 
 
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Figure 1: Stopping Boundaries for Efficacy (blue shading) and Futility (pink shading). 
 
As can be seen from the figure, an RRR showing no more than a small amount of improvement in 
recovery time (RRR ≤ 1.04) will result in early discontinuation of the agent mid-way through information 
accrual in the study (Table 4). When the null hypothesis is true (RRR = 1), the probability of discontinuing 
an agent at this point is 66%, but under the alternative, this probability is 4%.  
 
Table 4.  Efficacy and futility boundaries expressed in terms of z-scores and recovery rate ratios (RRRs).  
Conditional power corresponding to futility boundaries is also shown, and is computed under the 
originally hypothesized RRR of 1.25.  For the interim analyses, conditional power will be calculated under 
additional scenarios including the current trend and the null hypothesis. 
 
Efficacy Boundary 
Futility Boundary 
Information 
Fraction 
Z-score 
RRR 
Z-score 
RRR 
Conditional 
Power 
0.25 
4.3326 
1.8540 
-0.5854 
0.9200 
0.52 
0.50 
2.9631 
1.3479 
0.3791 
1.0389 
0.40 
0.75 
2.3590 
1.2142 
1.2187 
1.1055 
0.36 
1.00 
2.0141 
1.1543 
2.0141 
1.1543 
NA 
 
If the primary endpoint is declared to be statistically significant in the favorable direction, the two key 
secondary endpoints will be tested according to a Pocock-like boundary with the Holm procedure used 
to control for the two key secondary endpoint comparisons (Holm 1979). See Table 5 for the details of 
these procedures. 
 


 
 
 
 
 
 
 
 
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Table 5. Efficacy boundaries for the two key secondary endpoints assuming 3 equally spaced interim 
reviews and a final analysis. 
Information 
Fraction 
If the primary endpoint is 
declared significant, the larger 
absolute Z-statistic (smaller 
nominal p-value) is compared 
against … 
│Z│ (one-sided p-value) 
If the primary and other key secondary 
endpoint is declared statistically significant, the 
smaller absolute Z-statistic (larger p-value) is 
compared against … 
│Z│ (one-sided p-value) 
0.25 
2.62 (0.0043)* 
2.36 (0.0091) 
0.50 
2.62 (0.0043) 
2.36 (0.0091) 
0.75 
2.62 (0.0043) 
2.36 (0.0091) 
1.00 
2.62 (0.0043) 
2.36 (0.0091) 
*Exact boundaries will be computed using a spending function approach with a Pocock-like bound. 
Please note that the DSMB meeting scheduled for the 0.25 information time occurred closer to 0.30 information fraction.  
Furthermore, the DSMB approval letter dated May 28, 2021 states the following … 
“The NIAID DCR Data and Safety Monitoring Board held a teleconference on May 6, 2021. After carefully reviewing the safety 
data and interim analyses, the DSMB identified no safety concerns and recommended that all sub-studies in ACTIV-1 continue 
as planned. The DSMB made other recommendations as noted in the summary and recommended that the next DSMB meeting 
should take placed when ACTIV-1 has reached 60% enrollment.” 
Following the September 2, 2021 DSMB meeting, the recommendations stated that “the Board recommends that no further 
interim analysis be done”.  This meeting was the second DSMB review of the unblinded study data. 1340 participants had been 
randomized across 70 sites in the U.S. and Latin America at the time of the data cut. 
 
3.4.3 
ADAPTATIONS 
 
The master protocol design with common data elements, procedures, etc., and adaptive platform design 
allows for seamless dropping or replacing of an arm by a new treatment. Only concurrent data will be 
used for comparisons. Thus, a new arm will be compared to controls enrolled on or after the time the 
new arm is added and determined to be eligible to receive the agent. It is anticipated that the DSMB will 
informally incorporate mortality and adverse event information into the decision making regarding 
stopping for efficacy and futility.  
Prior to the second interim analysis, there is a plan to have a blinded sample size re-estimation that 
allows for sample size increases of as much as 25% but no reduction.  This decision would be made by 
the members of the study team without access to the treatment codes (i.e. active or placebo) or the 
unblinded results. The formula of Whitehead (1993) was used to determine the expected power for the 
8-point scale.  That calculation includes a factor that depends on the marginal distribution of the 8-point 
scale lumped over the active and placebo arms.  Additionally, the recommendation for the sample size 
adjustment will examine the overall recovery rate through Day 28.  It is possible that the observed 


 
 
 
 
 
 
 
 
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recovery rates will be somewhat different from the ACTT-1 results due to changes in SoC, differences in 
participant mix, and random variability. Recommendations for the sample size adjustment will be based 
on trying to maintain ≥ 85% power for the primary endpoint and ≥ 70% power for the key secondary 
endpoints. 
Approximately 2 weeks prior to the data cut for the second interim analysis, the blinded statistical team 
will conduct a review of marginal event rates and endpoint distributions.  The goals of the blinded 
review are to assure that there is adequate power for the primary and two key secondary endpoints 
under various extreme scenarios.  Namely, the team would like to maintain 85% power for the primary 
endpoint and >70% power for the two key secondary endpoints.  The blinded statistics team will have 
access to limited data including the marginal 28-day mortality rate and the 14-day 8-point ordinal scale 
lumped across the three sub-studies.  As noted in Table 6 below, the power for these endpoints does 
depend on these marginal distributions. 
 
Table 6.  Outline of the Power Calculations for the Primary and Two Key Secondary Endpoints 
Endpoint 
Assumptions under the 
Null Hypothesis (H0) 
 
Assumptions under 
the Alternative 
Hypothesis (Ha) 
Notes 
Time-to-
recovery 
RRR = 1.0 
RRR = 1.25 
Each sub-study plans to observe >788 recovery events for the 
primary endpoint, which provides 85% power under the alternative 
hypothesis. 
8-Point Ordinal 
Score at 14-days 
Common Odds Ratio = 
1.00 
Common Odds Ratio 
= 1.50 
The power for this statistical comparison is highly dependent on the 
marginal distribution of the 8-ordered categories. For example, if 
the placebo group distribution includes 12.5% for each category, a 
common odds ratio of 1.50 with sample sizes of 540/group will yield 
approximately 97% power with two-sided Type I error of 0.05.  By 
comparison, a placebo distribution with 10% in category 1, 84% in 
category 8, and 1% each in categories 2 to 7, would yield only 63% 
power under the same conditions. 
Mortality at 28 
days (binary 
endpoint) 
Odds Ratio = 1.00 
Odds Ratio < 1.00 
(e.g. 50% relative 
reduction) 
12% (placebo) vs. 6% (active) with 540 participants per group will 
provide 88% power with Type 1 error (two-sided) of 0.025.  By 
comparison, 6% (placebo) vs. 3% (active) will yield the only 55% 
power under the same conditions. 
 
Tables 7 and 8 provide an example of the power calculations that will be conducted to determine 
whether there is adequate power to detect 50% reductions in 28-day mortality rates. In the example 
below there would be adequate power (i.e. >70% power) to detect large relative differences. With a 
much lower pooled mortality rate, the power would decrease. 
 
 
 


 
 
 
 
 
 
 
 
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Table 7. Four scenarios for the treatment mortality rates with marginal mortality rates of 10%. 
Scenario 1 
Scenario 2 
Scenario 3 
Scenario 4 
No effective 
treatments 
1 effective 
treatment 
2 effective 
treatments 
3 effective 
treatments 
Placebo 
10% 
11.43% 
13.33% 
16.00% 
Active Drug 1 
10% 
5.71% 
6.67% 
8.00% 
Active Drug 2 
10% 
11.43% 
6.67% 
8.00% 
Active Drug 3 
10% 
11.43% 
13.33% 
8.00% 
Total 
10.00% 
10.00% 
10.00% 
10.00% 
 
Table 8. Power calculations to detect 50% relative reductions for the 28-day mortality endpoint. 
Placebo Group Rate 
Active Group Rate 
Power with Type I 
Error of 0.05 (two-
sided) 
Power with Type I 
Error of 0.025 (two-
sided) 
11.43% 
5.71% 
92% 
86% 
13.33% 
6.67% 
95% 
92% 
16.00% 
8.00% 
98% 
96% 
Assuming approximately 540 participants per group 
 
A similar approach will be used with the marginal distribution on the 8-point scale.  If these plausible 
scenarios provide greater than 70% power to detect a common odds ratio of 1.50, the sample size will 
not be increased. 
 
3.5 
DATA SOURCES 
 
At each study site, data will be entered on the electronic Case Report Forms (eCRFs) stored in Medidata 
Rave. Prior to database lock, programmed computer edit checks will be run against the database to 
identify discrepancies and verify reasonableness of the data. Queries to resolve discrepancies will be 
generated and resolved by the sites. As needed, DCRI Statistics will be able to directly download the 
eCRF database from Rave using SAS on Demand as Clinical Data Interchange Standards Consortium 
Study Data Tabulation Model (CDISC SDTM version 3.2) datasets. CDISC Analysis Data Model (ADaM 
version 2.1) datasets will be created by DCRI Statistics for production of final tables, figures, and listings. 


 
 
 
 
 
 
 
 
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All planned reporting will be based off of CDISC datasets, but in the case of emergent safety data, some 
reporting may occur from the raw eCRF data. All programs written to create analysis datasets and 
perform analyses will be validated according to SOPs established by the DCRI Statistical Programming 
group.  
 
3.6 
DOCUMENTATION CONVENTION 
 
The statistical analyses described in this SAP, as well as production of tables, listings, and figures will be 
performed using SAS®, version 9.4 or higher (SAS Institute, Cary, NC). Additional statistical software may 
be used as needed. 
 
3.7 
VERIFICATION OF RESULTS 
 
All tables, listings, and graphs will be verified and reviewed before considered final. The verification 
process will ensure that the numbers are produced by a statistically valid method and that the execution 
of the computations is correct. Qualified statisticians or statistical programmers employed by the DCRI 
who have not been previously involved in the production of the original programming will perform the 
verification procedures. Methods of verification include independent programming, prior to issuance of 
the draft statistical report, of all analysis datasets/ADaM and comparison to data listings. Tables, listings, 
and figures will be reviewed for accuracy, consistency with this analysis plan, consistency within 
tables/listings/figures, and consistency with corresponding output. Once verification is complete, all 
documentation of the verification process will be filed as required by the Statistical Standard Operations 
Procedures of the DCRI.  
 
3.8 
SUBJECT DISPOSITION 
 
The disposition of subjects (number randomized, number who received any amount of the randomly 
assigned treatment, number completing study drug administration, number who withdrew consent or 
discontinued from study drug early, and number lost to follow-up, and number who completed the trial) 
will be summarized by treatment group. The number of subjects screened for inclusion and a 
breakdown of reasons for exclusion will be summarized. The timing and reasons for early 
discontinuation of study drug and/or withdrawal from the study will be summarized by treatment 
group. For the calculation of percentages, subjects who die will not be included in the denominators for 
visits/assessments beyond their death. Treatment compliance (e.g. number of subjects who had their 
required infusions halted/slowed and the number of subjects with missed doses) will be summarized by 


 
 
 
 
 
 
 
 
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treatment group. A subject listing of analysis population eligibilities will be generated. A listing of all 
subjects discontinued from the study after enrollment, broken down by site and treatment group will be 
provided. The listing will include: reason for discontinuation, treatment group, duration of treatment, 
and whether or not the blind was broken. Also, for subjects who discontinued from the study after 
enrollment, a listing of adverse events will be provided. Subject-specific protocol deviations will be 
summarized by the reason for the deviation, the deviation category, treatment group, disease severity 
and (separately) site for all subjects. All subject-specific protocol deviations and non-subject specific 
protocol deviations will be included in listings. 
 
3.9 
POPULATIONS FOR ANALYSES 
 
The primary analysis will be based on an intent-to-treat (ITT) population, including all participants 
randomized. Similarly, safety analyses will be based on a modified intention-to-treat (MITT) population 
consisting of all participants who received at least one dose or injection of each drug administered in the 
randomization arm (e.g. investigational agent/placebo plus SoC). Each substudy will define separate ITT 
and MITT populations due to the shared SoC plus placebo (or control) group. The primary analysis will 
be based on those participants randomized in order to achieve 788 recoveries for each pairwise 
comparison. Subsequent analysis will be performed on all randomized participants. 
 
 


 
 
 
 
 
 
 
 
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4.0 
STATISTICAL ANALYSES 
 
4.1 
GENERAL APPROACH 
 
o Statistical significance: Statistical comparisons will be performed using two-sided significance 
tests. An alpha level of 0.05 will determine significance (unless otherwise noted) for each agent. 
Analyses will be carried out separately for each test agent. 
 
o Descriptive statistics:  
o Continuous variables will be presented as n, mean, standard deviation, median, Q1, Q3, 
and minimum and maximum. For comparisons of treatment groups, we will use the 
non-parametric Wilcoxon-Mann-Whitney rank-sum test. 
o Categorical variables will be presented as percentage (number). Group comparisons will 
use the conventional chi-square test. 
o Binary variables will be presented as percentage (number). Group comparisons will use 
the conventional chi-square test or Fisher’s Exact Test. 
 
o When death is not a competing risk (for example, the endpoint includes death in the 
composite), differences in time-to-event endpoints by treatment will be summarized with 
Kaplan-Meier curves, log-rank tests, stratified log-rank tests, and hazard ratios from Cox 
proportional hazards models.  When death is a competing risk (for example, time to at least a 
one-category improvement in ordinal scale, and time to at least a two-category improvement), 
the same competing risk approach will be used as for the primary analysis and results will be 
summarized by the hazard ratio from the Fine-Gray model. 
 
o Covariate adjustment clarification – for some of the models described below, it might be 
necessary to combine regions and / or disease severity levels to meet modeling assumptions. 
 
o Unblinding for the final analysis of a study agent: 
 
Unblinding of study data for final analysis will occur for each test agent independently of other 
agents, consistent with the master protocol design. That is, once the planned number of 
recoveries required for a particular agent’s comparative analysis are observed, study close-out 


 
 
 
 
 
 
 
 
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procedures for that agent are applied for all study visits and data elements associated with the 
participants receiving the test agent as well as participants receiving SoC plus placebo during the 
randomization period for that agent (i.e., concurrently controlled participants) subset to those 
eligible to receive the agent.  
 
Once the study visits are monitored, data edits are completed, queries are resolved, the 
database is locked, and treatment assignments are unmasked for that comparative analysis 
only. Note that, because placebo control participant data are shared across agents, procedures 
for unmasking data for one agent’s final analysis will be established to protect the ability to 
continue the ongoing study in a double-blinded manner for the remaining agents. It may be that 
recovery rates are similar enough across all agents in the study to enable a single study close-
out with standard procedures. Any necessary modifications or updates to the statistical analysis 
should be made prior to the study unblinding. 
 
o Handling of Missing Data: 
 
Efforts to minimize loss-to-follow-up will be considerable. However, small amounts of missing 
data may occur. The plans for handling missing data follow the approach taken in the ACTT-1 
study (Beigel, Tomashek et al. 2020). 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, participants who are lost to follow-up or terminate the study prior 
to Day 28 and prior to observing/experiencing the event will be censored at the time of their last 
observed assessment.  
 
For the analyses of the secondary outcomes described in Section 4.3, the following imputation 
rules will be used for participants 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 3 or 2 at the last observed assessment, then the 
subject will be considered to be on non-invasive ventilation/high-flow oxygen through 


 
 
 
 
 
 
 
 
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Day 28. 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 2 at the last observed assessment, then the subject 
will be considered to be on ventilation/ECMO through Day 28. 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 28. 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 4, 3, or 2 at the last observed assessment, then the 
subject will be considered to be on oxygen through Day 28. 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 28. Thus, no additional imputed days will 
be added to the number of days recorded on available assessments.  
 
• Days of Hospitalization  
 
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.  
 
 NEWS - There will be no imputation for incomplete components of the NEWS score. 
 


 
 
 
 
 
 
 
 
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4.2 
ANALYSIS OF THE PRIMARY AND KEY SECONDARY EFFICACY ENDPOINTS 
 
o 
Primary Endpoint – Time to Recovery through Day 28  
 
The primary efficacy analysis for the comparison of each test agent plus SoC versus SoC plus placebo is a 
stratified test based on the Fine-Gray proportional hazards approach, where stratification is according to 
geographic region and baseline disease severity on the 8-point ordinal scale (i.e. 2 or 3 or 4 or 5). Other 
covariates in the model will include age, and sex. The approach is similar to using a stratified log-rank 
test on time to recovery, providing an estimate of the cumulative incidence of recovery while accounting 
for the competing risk of death. The primary quantity of interest is the RRR.  With no censoring, the 
hazard rate in each arm can be thought of as the hazard for recovery, treating deaths as never having 
recovered (Fine and Gray 1999, Gooley, Leisenring et al. 1999). The median time to event and 95% 
confidence interval will be summarized by treatment arm. Cumulative incidence curves for each 
treatment arm will be presented, supplemented with the RRR estimate, p-value, along with the number 
of subjects at risk in each arm at Days 0 (baseline), 2, 4, 7, 10, 14, 21, and 28.  
 Sensitivity Analyses 
Gray’s test on time to recovery will be calculated to obtain the p-value with fewer parametric 
assumptions (Gray 1988). 
As a sensitivity analysis, the main analysis of the primary and two key secondary endpoints (described 
below) will be repeated in the MITT population. 
 
 Supplemental Analyses 
A supplemental analysis will examine the Day 28 binary response of ‘recovered’ or ‘not recovered’ which 
aligns with the 8-point ordinal score at Day 28.  Approximately, 95% of study participants are expected 
to have complete information on this endpoint.  
For individuals with a recovery event but missing 8-point ordinal score at Day 28 (~3% of the study 
population), a multiple imputation approach will be applied to impute those missing values.  For each 
missing observation, 10 imputed observations will be randomly drawn from the subset of individuals 
with complete data who had a recovery event.   
For individuals without a recovery event but missing 8-point ordinal score at Day 28 (~2% of the study 
population), a multiple imputation approach will be applied to impute those missing values.  For each 
missing observation, 10 imputed observations will be randomly drawn from the subset of individuals 
with complete data and the same baseline 8-point ordinal score (i.e. 2 or 3 or 4 or 5).  Results from the 
10 imputed datasets will be combined using Rubin’s rule to obtain the point estimate, 95% confidence 
interval, and p-value. 


 
 
 
 
 
 
 
 
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Those individuals in categories 6-8 would be considered as recovered and those in categories 1-5 are 
‘not recovered’.  The point estimate will be based on a difference in the probability estimates for active 
vs. control and the 95% CI will be constructed (and p-value obtained) using the Wald method. 
Additionally, for each participant, a count of the number of days recovered and out-of-hospital will be 
computed.  The treatment effect will be summarized by the mean difference between groups. This 
outcome will be analyzed using a linear model with adjustment for geographic region and baseline 
disease severity on the 8-point ordinal scale (i.e. 2 or 3 or 4 or 5) and an indicator for active vs. placebo 
treatment.  An additional supplemental analysis will analyze this outcome variable using a Wilcoxon-
Mann-Whitney test. 
Analyses that take into account concomitant medication will be performed. The primary analysis will be 
repeated, where subjects who take prohibited medications will be treated as treatment failures and will 
be censored at the time of medication use. Other censoring techniques and additional analyses may be 
performed. 
 
o 
Key Secondary Endpoint #1 - Clinical status (8-point ordinal scale) at Day 14 
 
The ordinal scale will be used to estimate a proportional odds model by disease strata and region. We 
will perform a covariate adjusted test to evaluate whether the common odds ratio for treatment is 
equal to one. The model covariates will include baseline severity (2, 3, 4, or 5), region, sex, and age 
(continuous). The distribution of severity results will be summarized by treatment group as percentages. 
The treatment odds ratio, 95% CI, and p-value estimated from the model will be presented.   
Supplemental analyses will examine the clinical status using the 8-point ordinal scale at Day 28.  This 
endpoint is expected to be bimodal with individuals more likely to be at the extremes of the scale 
compared to the Day 14 version.  
Analyses of the Day 14 and Day 28 clinical status score will be conducted using multiple imputation.  The 
~2% of participants who recovered prior to Day 14 but have missing data for the 8-point ordinal scale 
collected at Day 14 will have 10 observations imputed using randomly selected data from other 
participants who had complete data for their clinical status (8-point ordinal scale) at Day 14 and a 
recovery event prior to Day 14.   
Participants without a recovery and with missing data for the 8-point ordinal scale at Day 14 (~2% of 
participants) will have 10 imputed values randomly drawn from the subset of individuals with complete 
data and the same baseline 8-point ordinal scale. A similar approach will be taken for the Day 28 clinical 
status score.  Results from the 10 imputed datasets will be combined using Rubin’s rule. 
The number and proportion of subjects along with 95% confidence intervals by category of clinical status 
will be presented by treatment arm at Days 0 (baseline), 2, 4, 7, 10, 14, 21, and 28. A figure will present 
stacked bar charts by day with side by side bars for each treatment arm. Histograms will be generated to 
display the ordinal scale value distributions over time in each treatment group. 


 
 
 
 
 
 
 
 
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o 
Key Secondary Endpoint #2 - Mortality through Day 28  
 
Mortality through Day 28 will be analyzed as a binary endpoint, using a logistic regression model with an 
indicator variable for the treatment group.  Other variables in the regression model will include the 8-
point ordinal scale at baseline (2, 3, 4, or 5), region, sex, and age (continuous).  The odds ratio from this 
model will be supplemented with event rates at 14 and 28-days along with a difference between 
treatment groups and 95% confidence intervals (and p-values) obtained using the Wald method.  The 
number and percentage of subjects who die within 14- and 28-days following randomization will be 
presented by treatment arm (denominator for the percentages will be the number of subjects in the ITT 
population in each treatment arm).  
Approximately, 95% of study participants are expected to have complete information on this endpoint.  
For individuals with a recovery event but missing mortality status at Day 28 (~3% of the study 
population), a multiple imputation approach will be applied to impute those missing values.  For each 
missing observation, 10 imputed observations will be randomly drawn from the subset of individuals 
with complete data who had a recovery event.   
For individuals without a recovery event but missing mortality status at Day 28 (~2% of the study 
population), a multiple imputation approach will be applied to impute those missing values.  For each 
missing observation, 10 imputed observations will be randomly drawn from the subset of individuals 
with complete data and the same 8-point ordinal scale baseline score.   
Results from the 10 imputed datasets will be combined using Rubin’s rule to obtain the point estimate, 
95% confidence interval, and p-value. 
 
o 
Tipping Point Sensitivity Analyses for the Primary and Key Secondary Endpoints  
 
Tipping point sensitivity analyses that systematically and comprehensively vary assumptions about the 
missing outcomes on the two treatment arms will be applied. These analyses will be two-dimensional 
and will allow assumptions about the missing outcomes on the two arms to vary independently.  These 
scenarios will include those where dropouts on active drug tend to have worse outcomes than dropouts 
on placebo. The goal is to explore the plausibility of missing data assumptions under which the 
conclusions change, i.e., under which there is no longer evidence of efficacy. 
Among randomized participants, approximately 5% or participants have missing data for the primary or 
the two key secondary endpoints (Table 9).  There are two distinct types of missing data for these 
endpoints: 
1) participants with almost no information (n~42) and  


 
 
 
 
 
 
 
 
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2) those with missing data following a recovery event (n~60). 
Among the 1308 randomized participants with a recovery event prior to Day 14, the vast majority 
(~98%) had complete data for the ordinal score at Day 14 and approximately 99% of those individuals 
had a score of 7 or 8.  Similarly, among the 1527 randomized participants with a recovery event prior to 
Day 28, only 8 (<1%) died prior to Day 28. 
Table 9. Summary of Missing Data by Type for the Primary and Two Key Secondary Endpoints (data as of 
March 28, 2022) 
Endpoint 
Total Participants 
with Missing Data 
(N=1971) 
Post-Recovery 
Missing Data 
(N=1971) 
Missing Data Prior 
to a Recovery 
(N=1971) 
Primary Endpoint – Time to Recovery 
through Day 28 
42* (2.1%) 
n/a 
42 (2.1%) 
Key Secondary Endpoint #1 - Clinical 
status (8-point ordinal scale) at Day 14 
77 (3.9%) 
35 (1.8%) 
42 (2.1%) 
Key Secondary Endpoint #2 - Mortality 
through Day 28 
102 (5.2%) 
60** (3.0%) 
42 (2.1%) 
* 5 (11.4%) participants had > 3 days of follow-up and 11 (25%) received any of their randomized study drug 
**of the 1527 participants who recovered prior to Day 28, 8 (<1%) were determined to have died prior by Day 28. 
 
To create an imputation strategy that maintains consistency between the primary and two key 
secondary endpoints, we will first impute the ‘mortality status at day 28’ endpoint, then the ‘8-point 
ordinal scale at 14 days’, and finally, the ‘time-to-recovery through day 28’ primary endpoint.  This 
structure will help us avoid illogical scenarios such as having the same participant with the following 
imputed values …  
 
- Death at Day 6 
 
- Recovery at Day 10 
 
- Day 14 8-point ordinal scale of 2 (hospitalized, on invasive mechanical ventilation or ECMO) 
Clearly, a participant who dies on Day 6 cannot have a recovery on Day 10.   
An ordinal logistic regression model will be fitted to the entire ACTIV1 cohort of randomized 
participants.  The outcome variable will be the participant’s status at Day 28 and will have three levels.  
The worst value of the outcome is death, the best value of the outcome is recovery prior to Day 28, and 
the intermediate value is for those participants who are alive without a recovery by Day 28. The logistic 
regression imputation model will include covariates for region and severity of illness ordinal score at the 
time of randomization.  A parameter, Ɵ, will vary from 0.1 to 10 and correspond to an odds ratio 
parameter for the ordinal logistic model.  Values of Ɵ less than 1.0 will be associated with better than 
average outcomes and values great than 1.0 will have worse than average outcomes.  Specifically, for 
each level of the ordered response, the value of log(Ɵ) will be added to the logit function with the 
covariates associated with the participants with missing data.  Then a random uniform variable will be 


 
 
 
 
 
 
 
 
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generated and compared to the imputed probability distribution.  With the imputed outcome of either 
‘death’, ‘recovery’, or ‘alive without recovery’, the time-to-recovery and the Day 14 8-point ordinal scale 
response will be imputed by selecting a participant at random with the same severity of illness at 
randomization, region, and corresponding status at Day 28 (e.g. ‘death’, ‘recovery’, or ‘alive without 
recovery’).  
On average, a value of Ɵ = 0.1 will correspond to an expected Day 28 mortality of < 1% whereas a value 
of Ɵ = 10 will correspond to an expected Day 28 mortality of ~ 49% (see Table 10).  As special cases, 
values are Ɵ = 0 and Ɵ = ∞ will be used to denote the special cases of ‘best possible outcome’ and 
‘worst possible outcome’, respectively. As an example, for a participant who withdrew on Day 3, the 
best possible outcome (i.e. Ɵ = 0) would correspond to: Recovery at 3, Day 14 8-point ordinal scale of 8, 
and Alive at Day 28.  Similarly, for a participant who withdrew on Day 3, the worst possible outcome (i.e. 
Ɵ = ∞) would correspond to: Death at Day 3 and Day 14 8-point ordinal scale of 1. 
Table 10. Probability, on average, of recovery and death by Day 28 for various parameter settings 
Parameter Setting 
Recovery through Day 28 
Death through Day 28 
Ɵ = 0 “Best Case” 
100% 
0% 
Ɵ = 0.1 
98%* 
1% 
Ɵ = 0.2 
95% 
2% 
Ɵ = 0.5 
90% 
6% 
Ɵ = 1 “Missing at Random” 
82% 
10% 
Ɵ = 2 
71% 
18% 
Ɵ = 5 
51% 
34% 
Ɵ = 10 
35% 
49% 
Ɵ = ∞ “Worst Case” 
0% 
100% 
*the exact values will depend on the participant’s covariates 
For each parameter setting, 10 imputed datasets will be constructed for each individual with missing 
data for the primary endpoint.  For each imputed dataset, the primary and two key secondary analyses 
will be re-run and the results of the 10 models will be combined using Rubin’s rules.  The results of the 
tipping point analysis will allow for a comparison of point estimates and p-values across the various 
values of Ɵ (see Table 11 for an example). 
Table 11 will be repeated for the two key secondary endpoints, and this analysis will be repeated for the 
comparison of each study drug vs. the corresponding placebo. Separate models will be constructed for 
participants with incomplete data following a recovery event (e.g. withdrawal of consent after discharge 
from the hospital). 
 
 


 
 
 
 
 
 
 
 
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Table 11. Example summary of the tipping point analysis for the time-to-recovery endpoint 
RRR* 
95% CI 
p-value 
 
 
 
 
 
Active 
 
 
 
 
 
 
Ɵ = 0 
Ɵ = 0.1 
Ɵ = 0.2 
Ɵ = 0.5 
Ɵ = 1.0 
Ɵ = 2 
Ɵ = 5 
Ɵ = 10 
Ɵ = ∞ 
 
Ɵ=0 
 
 
 
 
 
 
 
 
 
 
Ɵ=0.1 
 
 
 
 
 
 
 
 
 
 
Ɵ=0.2 
 
 
 
 
 
 
 
 
 
 
Ɵ=0.5 
 
 
 
 
 
 
 
 
 
Placebo Ɵ=1 
 
 
 
 
 
 
 
 
 
 
Ɵ=2 
 
 
 
 
 
 
 
 
 
 
Ɵ=5 
 
 
 
 
 
 
 
 
 
 
Ɵ=10 
 
 
 
 
 
 
 
 
 
 
Ɵ=∞ 
 
 
 
 
 
 
 
 
 
*the values within each cell will correspond to the estimated RRR, 95% CI, and p-value for the particular parameter setting (e.g. 
Ɵ Placebo=1, Ɵ Active=10). 
The above description of the tipping point analysis has focused on the missing data of the subset of 
participants with no recovery.  For the two key secondary endpoints, it is expected that 2-3% of 
participants will have some missing data following a recovery event. 
For individuals with a recovery event but missing mortality status at Day 28 (~3% of the study 
population) or the Day 14 clinical status score, a multiple imputation approach will be applied to impute 
those missing values.  For each missing observation, 10 imputed observations will be randomly drawn 
from the subset of individuals with complete data who had a recovery event, and the imputed datasets 
will be combined as described above.   
 
4.3 
ANALYSIS OF THE OTHER SECONDARY EFFICACY ENDPOINTS 
 
o 
Time to improvement of one and two categories in ordinal scale 
 
Two separate endpoints are considered here.  The first endpoint will examine the time to a one category 
improvement in the 8-point ordinal scale.  The second endpoint will examine the time to a two category 
improvement in the 8-point ordinal scale.  These time-to-event endpoints will be computed through Day 
28 will also be analyzed using the same Fine-Gray proportional hazards approach as for the primary 
efficacy endpoint and stratification using the randomization factors. Proportions of one and two 
category improvements at 14 and 28-days along with 95% confidence intervals overall for each 
treatment arm along with a difference between treatment arms and 95% confidence intervals obtained 


 
 
 
 
 
 
 
 
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using the Miettinen-Nurminen method.  Calculations of these endpoints will rely on the 8-point ordinal 
scale that is collected on a daily basis while the participant is hospitalized. 
 
o 
Mean change in ordinal scale at specific time points 
 
Change in clinical status scale from baseline 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). A table 
will present the proportion of people on Days 2, 4, 7, 10, 14, 21, and 28 within each category of change 
by treatment arm along with 95% confidence intervals. The mean change in the ordinal scale difference 
between treatment arms along with 95% confidence interval will also be reported. Additionally, side-by-
side histograms (of an agent versus control) of the proportions with various changes will be presented. 
 
o 
Differences in total severity score (TSS) over time 
 
Differences in total severity score (TSS) over time will assessed by fitting a longitudinal Markov model to 
a modified version of the 8-point clinical scale value on a daily basis between days 1 and 28. The average 
difference across days in study (analogous to the area under the severity curve) will be estimated with 
95% confidence limits in the context of the longitudinal model.  The longitudinal mixed model will be 
developed as follows. The value of the ordinal scale on day 𝑡 will be assumed to depend on the patient's 
prior outcome trajectory only through the prior day's value, and treatment group assignment. The 
general form of the model will be: 
Pr(𝑌𝑖𝑡≤𝑘| 𝐻𝑖,𝑡−1, 𝑌𝑖.𝑡−1 = 𝑥, 𝑍𝑖= 𝑧, 𝜶, 𝜷, 𝜸, 𝑒𝑖) ≡𝜋𝑖𝑡𝑘|𝑥𝑧, 
log
𝜋𝑖𝑡𝑘|𝑥𝑧
1 −𝜋𝑖𝑡𝑘|𝑥𝑧
= 𝛼𝑘𝑥+ 𝑡𝛽1 + 𝑡2𝛽2 + 𝑧(𝛾0 + 𝑡𝛾1 + 𝑡2𝛾2), 
 
where 𝑌𝑖𝑡 is outcome of the 𝑖-th patient on day 𝑡, 𝐻𝑖,𝑡−1 = (𝑌𝑖1, … , 𝑌𝑖,𝑡−1) is the patient's outcome 
trajectory through day 𝑡−1, 𝑍𝑖 is a binary indicator of treatment group assignment (1=active agent plus 
SoC, 0=placebo plus SoC), and the symbols 𝛼𝑘𝑥, 𝛽1, 𝛽2, 𝛾0, 𝛾1𝛾2 represent unknown fixed effect 
parameters to be estimated from the data. The model assumes that on each day, the odds of an 
outcome in one of the 𝑘 lowest categories depends jointly on treatment assignment, days since 
randomization, and x is the patient's prior day outcome category. Parameters will be estimated by 
maximum likelihood using 1 record per patient per day from the first day post-randomization until the 
earlier of day 28, death or loss to follow-up. Days between death and day 28 do not contribute to the 
likelihood because death is an absorbing state and hence 𝛼11 = ∞ and 𝛼21 = 𝛼31 ⋯= 𝛼81 = −∞. The 
estimation procedure will assume that loss to follow-up is conditionally ignorable given treatment 
assignment and the patient's current observed outcome trajectory. A feature of the trial's outcome 
assessment schedule is that only patients who are hospitalized have their outcome assessed on days 


 
 
 
 
 
 
 
 
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other than 7, 10, 14, 21, and 28. If a patient is not hospitalized, the patient's outcome category will be at 
least 7 but the exact value (7 versus 8) will only be collected on days 7, 10, 14, 21, and 28. To mitigate 
potential bias from informatively missing data, categories 7 and 8 will be combined into a single 
category for this analysis. This modification guarantees that a patient will have non-missing data on all 
days 1 through 28 if the patient's vital status and hospitalization status is known on each day and the 
patient's outcome is assessed per protocol on each day that the patient is alive and in-hospital.  
 
o 
Days alive and free of supplemental oxygen 
 
Days alive and free of supplemental oxygen and its components, duration of oxygenation days and total 
days alive, will be summarized in a table using mean (median) and standard deviations (quartiles) by 
treatment arm. Point estimates for the difference between active and placebo for days alive and free of 
supplemental oxygen and associated 95% confidence intervals will be obtained using a linear model with 
treatment group and baseline 8-point ordinal score (i.e. 2 or 3 or 4 or 5) as categorical predictors.  The 
duration of oxygenation days will be computed using the 8-point ordinal scale that is collected each day 
the participant is hospitalized.  If a participant is rehospitalized after an initial recovery and the 8-point 
ordinal scale is not available, the participant will be assumed to have an 8-point ordinal score value of 2 
for all days of the rehospitalization. 
The incidence of new oxygen use will be analyzed by treatment arm. This will only include subjects in 
ordinal scale category 5 at enrollment (i.e. 5: Hospitalized, not requiring supplemental oxygen – 
requiring ongoing medical in-patient care). New use will be identified by a post-enrollment score of 4 or 
3 or 2. The number and percent of subjects reporting new use and 95% confidence interval will be 
reported. Comparisons between treatment arms will be presented as differences in proportions with 
95% confidence intervals using the Miettinen-Nurminen method. 
 
o 
Days alive and free of non-invasive ventilation/high flow oxygen 
 
Days alive and free of non-invasive ventilation/high flow oxygen and its components, duration of non-
invasive ventilation/high flow oxygen days will be summarized in a table using mean (median) and 
standard deviations (quartiles) by treatment arm. Point estimates and associated 95% confidence 
intervals will be obtained using a linear model with treatment group and baseline 8-point ordinal score 
(i.e. 2 or 3 or 4 or 5) as categorical predictors.  The duration of non-invasive ventilation/high flow oxygen 
days will be computed using the 8-point ordinal scale that is collected each day the participant is 
hospitalized.  If a participant is rehospitalized after an initial recovery and the 8-point ordinal scale is not 
available, the participant will be assumed to have an 8-point ordinal score value of 2 for all days of the 
rehospitalization. 
The incidence of new Non-Invasive Ventilation/High Flow Oxygen use will be analyzed by treatment arm. 
This will only include subjects in category 4 or 5 at enrollment. New use will be identified by a post-


 
 
 
 
 
 
 
 
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enrollment score of 3 or 2. Comparisons between treatment arms will be presented as differences in 
proportions with 95% confidence intervals using the Miettinen-Nurminen method. 
 
o 
Days alive and free of invasive mechanical ventilation/ECMO 
 
Days alive and free of invasive mechanical ventilation / ECMO and its components, total days alive and 
duration of invasive mechanical ventilation/ECMO days, will be summarized in a table using mean 
(median) and standard deviations (quartiles) by treatment arm. Point estimates for differences in the 
days alive and free of invasive mechanical ventilation / ECMO and associated 95% confidence intervals 
will be obtained using a linear model with treatment group and baseline 8-point ordinal score (i.e. 2 or 3 
or 4 or 5) as categorical predictors.  The duration of invasive mechanical ventilation/ECMO days will be 
computed using the 8-point ordinal scale that is collected each day the participant is hospitalized.  If a 
participant is rehospitalized after an initial recovery and the 8-point ordinal scale is not available, the 
participant will be assumed to have an 8-point ordinal score value of 2 for all days of the 
rehospitalization. 
The incidence of new Invasive Mechanical Ventilation/ECMO use will be analyzed by treatment arm. This 
will only include subjects in category 5, 4, or 3 at enrollment. New use will be identified by a post-
enrollment score of 2. The number and percent of subjects reporting new use and the 95% confidence 
interval will be reported. Comparisons between treatment arms will be presented as differences in 
proportions with 95% confidence intervals using the Miettinen-Nurminen method. 
 
o 
Days alive and out of hospitalization 
 
Days alive and out of hospital along with its components, duration of hospitalizations and total days 
alive, will be summarized in a table using mean (median) and standard deviations (quartiles) by 
treatment arm. Point estimates for the difference between active and placebo agents for days alive and 
out of hospital and associated 95% confidence intervals will be obtained using a linear model with 
treatment group and baseline 8-point ordinal score (i.e. 2 or 3 or 4 or 5) as categorical predictors.   
 
4.4 
SAFETY ANALYSES 
 
Safety endpoints include death through Day 28 (as assessed at Day 29), SAEs, and Grade 3 and 4 AEs. 
These events will be analyzed individually and as a composite endpoint. The time to this composite 
endpoint will be defined as the elapsed time (in days) from baseline to the earliest date of any of the 
events. Any subjects that are lost to follow-up or terminated early prior to experiencing any of the 
events will be censored at the day of their last observed assessment. Subjects who complete follow-up 


 
 
 
 
 
 
 
 
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but do not experience any of the events will be censored at the day of their Day 29 visit.  Time-to-event 
methods will be used for death and the composite endpoint. A table will present the hazard ratio 
estimate with 95% confidence intervals and log rank p-values. Differences in time-to-event endpoints by 
treatment will be summarized with cumulative incidence curves. In addition, risk differences between 
treatment groups and 95% CIs using the Miettinen-Nurminen method will be estimated for each type of 
event. 
Similar analyses will be conducted for the following AEs:  
 
Any Grade 2 suspected drug-related hypersensitivity reactions associated with study product 
administration will be reported as an AE. 
 
Any newly diagnosed infection (other than COVID-19) at any time during the study.  
 
Any AEs leading to dose modification  
 
Any AEs leading to discontinuation from the study. 
AEs will be coded in accordance with the current version of the Medical Dictionary for Regulatory 
Activities (MedDRA). AEs will be graded with regard to severity according to criteria defined in the 
Common Terminology Criteria for Adverse Events version 5.0 (CTCAE) and relationship to COVID-19 or 
study intervention. Each AE will be counted once only for a given participant. AEs will be presented by 
system organ class, preferred term (PT), duration (in days), start- and stop-date. AEs leading to 
premature discontinuation from the study intervention and serious AEs will be presented in a listing.  
 
4.4.1 
LABORATORY DATA 
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, differential, 
Hgb, PLT, creatinine, glucose, total bilirubin, AST, ALT, ALP, PT or INR, d-dimer, cardiac troponin, and C-
reactive protein.  
 
Descriptive statistics for baseline and post-baseline time points will be generated. Additionally, shift 
tables will be presented. The shift tables tabulate the number of lab values determined to be “Normal” 
and “Abnormal” at baseline and post-baseline time points. The classifications on shift tables will 
categorize lab values as “Normal” when they are in acceptable range. Laboratory values outside the 
normal range will be graded on the Labs Listing as >1x, >2x, >3x, >5x, or >10x the upper limit (or <0.1x, 
<0.5x, <1x the lower limit) of normal value based on appropriate increases or decreases. Laboratory data 
will also be summarized graphically to show the magnitude and changes in individual subject values over 
time relative to normal ranges. Details of any abnormalities will be listed. 
 


 
 
 
 
 
 
 
 
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4.4.2 
VITAL SIGNS 
 
Vital sign measurements include pulse, systolic blood pressure, respiratory rate, SpO2 and oral 
temperature.  
 
4.4.3 
PRIOR AND COMCOMITANT MEDICATIONS 
 
Concomitant medications will be coded to the Anatomical Therapeutic Classification using the WHO 
Drug Dictionary. The use of prior, concomitant medications taken, and changes in concomitant 
medications during the study will be recorded on the CRFs. The use of concomitant medications during 
the study will be summarized by ATC1, ATC2 code, and treatment group for the ITT population. The 
summaries will be repeated for each test agent. 
 
4.4.4 
TREATMENT COMPLIANCE 
 
Treatment compliance will be assessed based upon the administration rules for each of the test agents. 
For treatments that are one-time infusions (e.g. infliximab or abatacept), compliance will be summarized 
by the percentage of participants starting the infusion, the mean duration of the infusion, and the total 
amount of drug received (mg).  For oral medications (e.g. cenicriviroc), compliance will be summarized 
by the percentage of participants taking the loading dose and starting the maintenance dose, mean 
number of maintenance doses, and mean duration (days) of the oral medication.  
 
4.4.5 
PREGNANCY TESTS 
 
A set of listings of pregnancies and outcomes will be presented.   
 
4.5 
EXPLORATORY ANALYSES 
 
The probability of falling into category “i” or better will be compared between arms for each baseline 
severity score category. Exploratory analyses will also compare the difference between each test agent 
plus SoC and SoC plus placebo in the 8-point ordinal scale at each study day for which the clinical scale is 
administered (in-hospital and at Days 14, 21, and 28).  


 
 
 
 
 
 
 
 
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A set of Bayesian analyses will be conducted for the primary endpoint using informative, enthusiastic, 
and skeptical priors as described in Wijeysundera et al. (2009) and Zampieri et al. (2021). Three different 
prior distributions will be assumed for the odds ratio parameter for the treatment effect in the 
proportional odds model.  For the informative prior distribution, the log odds ratio (active drug vs. 
placebo) will have a mean of 0 and a standard deviation of 10 on the log-odds scale.  For the skeptical 
prior, the log odds ratio will have a mean of 0 and a standard deviation for the log-odds ratio that 
provides 5% probability for a response that is better than the assumed alternative hypothesis (e.g. 
OR=1.25).  For the enthusiastic prior, the assumed log-odds ratio will use the treatment effect assumed 
for the estimation of the sample size (e.g. OR~1.25) and a standard deviation that provides 5% 
probability of no benefit (e.g. OR<=1.00).  Similar analyses will be conducted for the 28-day mortality 
binary endpoint.  For these analyses, the enthusiastic prior will correspond to an odds ratio < 1.0 
indicating treatment benefit for the active drug. 
A separate statistical analysis plan will be created for the analyses of biomarkers.  
 
4.6 
BASELINE DESCRIPTIVE STATISTICS 
 
Baseline characteristics will be summarized by test agent versus control for each agent and study 
population. 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). 
Baseline characteristics will include age, sex, race, ethnicity, symptom duration, hypertension, obesity, 
diabetes, coronary disease, history of heart failure, history of cancer, asthma, COPD, chronic pulmonary 
disease, tuberculosis, HIV, severe liver disease, severe kidney disease, days since hospitalization, and 
baseline 8-point ordinal score. 
 
4.7 
SUB-GROUP ANALYSES 
 
The following subgroups have been pre-specified for the primary outcome and the two key secondary 
outcomes: 
 
Geographic region 
 
Duration of symptoms prior to randomization (<= Median; > Median) 
 
Duration of symptoms prior to randomization (based on quartiles) 
 
Hospitalization duration prior to randomization (<= Median, > Median) 
 
Baseline disease severity based on the 8-point ordinal scale 


 
 
 
 
 
 
 
 
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 
Age (<40; 40-64; 65 and older) 
 
Race (White; Black/African American; Asian; Other) 
 
Ethnicity (Hispanic, non-Hispanic) 
 
Sex (Female; Male) 
 
Comorbidities: 0, 1, 2, 3+ 
 
Baseline use of dexamethasone 
 
Co-enrollment in any ACTIV trial prior to randomization in ACTIV-1 IM 
 
Individual comorbidities: hypertension, obesity, diabetes, coronary disease, history of heart failure, 
history of cancer, asthma, COPD, chronic pulmonary disease, severe liver disease, severe kidney 
disease  
Any subgroup that has a frequency <5% will not be generated. Subgroups with frequencies <10% may 
also have issues with model convergence that dictate that they cannot be generated. 
The primary analysis will also be repeated for the primary endpoint and the two key secondary 
endpoints using the subgroups defined above.  Each subgroup will be considered separately and the 
tabular and graphical summaries described in the previous section will be replicated for each subgroup. 
In addition, a forest plot will be generated to display the overall treatment hazard ratio (or RRR) 
estimate and CI from each of the within-stratum analyses. These analyses will be performed in the ITT 
and MITT populations.  
Interaction tests will be conducted to determine whether the effect of treatment varies by subgroup.  
In addition to the subgroup analyses described above, primary and key secondary and safety analyses 
will be performed within additional subgroups as outlined in Appendix 2. 
 
 


 
 
 
 
 
 
 
 
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4.8 
REFERENCES 
 
Beigel, J. H., K. M. Tomashek, L. E. Dodd, A. K. Mehta, B. S. Zingman, A. C. Kalil, E. Hohmann, H. Y. Chu, A. 
Luetkemeyer, S. Kline, D. Lopez de Castilla, R. W. Finberg, K. Dierberg, V. Tapson, L. Hsieh, T. F. 
Patterson, R. Paredes, D. A. Sweeney, W. R. Short, G. Touloumi, D. C. Lye, N. Ohmagari, M. D. Oh, G. M. 
Ruiz-Palacios, T. Benfield, G. Fätkenheuer, M. G. Kortepeter, R. L. Atmar, C. B. Creech, J. Lundgren, A. G. 
Babiker, S. Pett, J. D. Neaton, T. H. Burgess, T. Bonnett, M. Green, M. Makowski, A. Osinusi, S. Nayak and 
H. C. Lane (2020). "Remdesivir for the Treatment of Covid-19 - Preliminary Report." N Engl J Med. 
Cao, B., Y. Wang, D. Wen, W. Liu, J. Wang, G. Fan, L. Ruan, B. Song, Y. Cai, M. Wei, X. Li, J. Xia, N. Chen, J. 
Xiang, T. Yu, T. Bai, X. Xie, L. Zhang, C. Li, Y. Yuan, H. Chen, H. Li, H. Huang, S. Tu, F. Gong, Y. Liu, Y. Wei, 
C. Dong, F. Zhou, X. Gu, J. Xu, Z. Liu, Y. Zhang, H. Li, L. Shang, K. Wang, K. Li, X. Zhou, X. Dong, Z. Qu, S. Lu, 
X. Hu, S. Ruan, S. Luo, J. Wu, L. Peng, F. Cheng, L. Pan, J. Zou, C. Jia, J. Wang, X. Liu, S. Wang, X. Wu, Q. 
Ge, J. He, H. Zhan, F. Qiu, L. Guo, C. Huang, T. Jaki, F. G. Hayden, P. W. Horby, D. Zhang and C. Wang 
(2020). "A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19." N Engl J Med 
382(19): 1787-1799. 
Fine, J. P. and R. J. Gray (1999). "A Proportional Hazards Model for the Subdistribution of a Competing 
Risk." Journal of the American Statistical Association 94(446): 496-509. 
Gooley, T. A., W. Leisenring, J. Crowley and B. E. Storer (1999). "Estimation of failure probabilities in the 
presence of competing risks: new representations of old estimators." Stat Med 18(6): 695-706. 
Gray RJ (1988). “A class of K-sample tests for comparing the cumulative incidence of a competing risk.” 
Ann Stat 16:1141-1154. 
Holm SA. (1979) “A simple sequentially rejective multiple test procedure.” Scandanavian Journal of 
Statistics; 6: 65-70. 
Huang, C., Y. Wang, X. Li, L. Ren, J. Zhao, Y. Hu, L. Zhang, G. Fan, J. Xu, X. Gu, Z. Cheng, T. Yu, J. Xia, Y. 
Wei, W. Wu, X. Xie, W. Yin, H. Li, M. Liu, Y. Xiao, H. Gao, L. Guo, J. Xie, G. Wang, R. Jiang, Z. Gao, Q. Jin, J. 
Wang and B. Cao (2020). "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, 
China." Lancet 395(10223): 497-506. 
Hung J, Wang S-J, O'Neill R (2007). “Statistical considerations for testing multiple endpoints in group 
sequential or adaptive clinical trials.” J Biopharm Stat; 17(6):1201-10. 
Hwang IK, Shih WJ, J S De Cani JS (1990). “Group sequential designs using a family of type I error 
probability spending functions” Stat Med; 9(12):1439-45. 
Smith, G. B., D. R. Prytherch, S. Jarvis, C. Kovacs, P. Meredith, P. E. Schmidt and J. Briggs (2016). "A 
Comparison of the Ability of the Physiologic Components of Medical Emergency Team Criteria and the 


 
 
 
 
 
 
 
 
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U.K. National Early Warning Score to Discriminate Patients at Risk of a Range of Adverse Clinical 
Outcomes." Crit Care Med 44(12): 2171-2181. 
Tamhane AC, Mehta CR, Liu L (2010) “Testing a Primary and a Secondary Endpoint in a Group Sequential 
Design.“ Biometrics; 66(4): 1174–1184. 
Whitehead J. (1993) “Sample Size Calculations for Ordered Categorical Data.” Stat Med; vol. 12, 2257-
2271. 
Wijeysundera DN, Austin PC, Hux JE, Beattie WS, Laupacis A (2009). “Bayesian statistical inference 
enhances the interpretation of contemporary randomized controlled trials.” J Clin Epidemiol; 62: 13-21 
e15. 
Zampieri FG, Casey JD, Shankar-Hari M; Harrell Jr. FE, and Harhay MO (2021). “Using Bayesian 
Methods to Augment the Interpretation of Critical Care Trials: An Overview of Theory and Example 
Reanalysis of the Alveolar Recruitment Trial.” Am J Resp Crit Care Med. Am J Respir Crit Care Med; 
203(5): 543-552. 
 
 


 
 
 
 
 
 
 
 
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4.9 
APPENDICES 
 
APPENDIX 1. ACTIV-1 Roster of Statisticians 
 
Team 
Name 
Email 
Attends DSMB 
Meetings 
Unblinded Statistical 
Team 
Michael Proschan 
proscham@niaid.nih.gov 
 
X 
 
Tyler Bonnet 
tbonnett@uw.edu 
 
X 
 
Jyotsna Garg 
jyotsna.garg@duke.edu 
 
X 
 
Eric Yow 
eric.yow@duke.edu 
 
X 
 
Zhen Huang 
zhen.huang@duke.edu 
 
 
 
Hwasoon Kim 
hwasoon.kim@duke.edu 
 
 
 
Hussein Al-Khalidi 
hussein.al-khalidi@duke.edu 
 
X 
 
Sean O’Brien 
sean.m.obrien@duke.edu 
 
X 
 
 
 
 
Blinded Statistical 
Team 
Lisa LaVange 
lisa.lavange@unc.edu 
 
X 
 
 
Steven McNulty 
steven.mcnulty@duke.edu 
 
X 
 
Adam Silverstein 
adam.silverstein@duke.edu 
 
 
 
Jun Wen 
jun.wen@duke.edu 
 
 
 
Pearl Zakroysky 
pearl.zakroysky@duke.edu 
 
X 
 
Susan Halabi 
susan.halabi@duke.edu 
 
X 
 
Kevin Anstrom 
kevin.anstrom@unc.edu 
 
X 
 
 
 
 


 
 
 
 
 
 
 
 
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APPENDIX 2. Additional Tables and Listings 
Table 
Demographic and Baseline Characteristics – US 
Intent-to-Treat Population 
Table 
Demographic and Baseline Characteristics – Latin America 
Intent-to-Treat Population 
Table 
Demographic and Baseline Characteristics by Geographic Region - 
Argentina 
Intent-to-Treat Population 
Table 
Demographic and Baseline Characteristics by Geographic Region - Brazil 
Intent-to-Treat Population 
Table 
Demographic and Baseline Characteristics by Geographic Region - Mexico 
Intent-to-Treat Population 
Table 
Demographic and Baseline Characteristics by Geographic Region - Peru 
Intent-to-Treat Population 
Table 
Demographic and Baseline Characteristics by Geographic Region – USA – 
Northeast 
Intent-to-Treat Population 
Table 
Demographic and Baseline Characteristics by Geographic Region – USA – 
Midwest 
Intent-to-Treat Population 
Table 
Demographic and Baseline Characteristics by Geographic Region – USA – 
South 
Intent-to-Treat Population 
Table 
Demographic and Baseline Characteristics by Geographic Region – USA – 
West 
Intent-to-Treat Population 
Table 
Demographic and Baseline Characteristics – Moderate Disease Severity at 
Baseline 
Intent-to-Treat Population 
Table 
Demographic and Baseline Characteristics – Severe Disease Severity at 
Baseline 
Intent-to-Treat Population 
Table 
Time to Recovery by US vs. Latin America 
Intent-to-Treat Population 
Table 
Time to Recovery by Disease Severity at Baseline (Moderate vs. Severe) 
Intent-to-Treat Population 
Table 
Time to Recovery by Remdesivir Use at Randomization 
Intent-to-Treat Population 
Table 
Time to Recovery by Steroid Use at Randomization 
Intent-to-Treat Population 
Table 
Time to Recovery by Immune Modulator Use at Randomization 
Intent-to-Treat Population 
Table 
Time to Recovery by Anticoagulant Use at Randomization 
Intent-to-Treat Population 
Table 
Time to Recovery by Baseline CRP (<=75 mg/L; >75 mg/L) 
Intent-to-Treat Population 
Table 
Proportional Odds Model of Clinical Status Score at Day 14 by US vs. Latin 
America 
Intent-to-Treat Population 
Table 
Proportional Odds Model of Clinical Status Score at Day 14 by Disease 
Severity at Baseline (Moderate vs. Severe) 
Intent-to-Treat Population 


 
 
 
 
 
 
 
 
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Table 
Proportional Odds Model of Clinical Status Score at Day 28 by US vs. Latin 
America 
Intent-to-Treat Population 
Table 
Proportional Odds Model of Clinical Status Score at Day 28 by Geographic 
Region 
Intent-to-Treat Population 
Table 
Proportional Odds Model of Clinical Status Score at Day 28 by Disease 
Severity at Baseline (Moderate vs. Severe) 
Intent-to-Treat Population 
Table 
28-Day Mortality by US vs. Latin America 
Intent-to-Treat Population 
Table 
28-Day Mortality by Disease Severity at Baseline (Moderate vs. Severe) 
Intent-to-Treat Population 
Table 
28-Day Mortality by Remdesivir Use at Randomization 
Intent-to-Treat Population 
Table 
28-Day Mortality by Steroid Use at Randomization 
Intent-to-Treat Population 
Table 
28-Day Mortality by Immune Modulator Use at Randomization 
Intent-to-Treat Population 
Table 
28-Day Mortality by Anticoagulant Use at Randomization 
Intent-to-Treat Population 
Table 
28-Day Mortality by Baseline CRP (<=75 mg/L; >75 mg/L) 
Intent-to-Treat Population 
Table 
14-Day and 28-Day Mortality Rates by US vs. Latin America 
Intent-to-Treat Population 
Table 
14-Day and 28-Day Mortality Rates by Geographic Region 
Intent-to-Treat Population 
Table 
14-Day and 28-Day Mortality Rates by Disease Severity at Baseline 
(Moderate vs. Severe) 
Intent-to-Treat Population 
Table 
14-Day and 28-Day Mortality Rates by Baseline CRP (<=75 mg/L; >75 
mg/L) 
Intent-to-Treat Population 
Table 
Overview of Safety Composite, Individual Endpoints, and Adverse Events 
through Day 28 - US 
Modified Intent-to-Treat 
Population 
Table 
Overview of Safety Composite, Individual Endpoints, and Adverse Events 
through Day 28 – Latin America 
Modified Intent-to-Treat 
Population 
Table 
Overview of Safety Composite, Individual Endpoints, and Adverse Events 
through Day 28 by Geographic Region - Argentina 
Modified Intent-to-Treat 
Population 
Table 
Overview of Safety Composite, Individual Endpoints, and Adverse Events 
through Day 28 by Geographic Region – Brazil 
Modified Intent-to-Treat 
Population 
Table 
Overview of Safety Composite, Individual Endpoints, and Adverse Events 
through Day 28 by Geographic Region – Mexico 
Modified Intent-to-Treat 
Population 
Table 
Overview of Safety Composite, Individual Endpoints, and Adverse Events 
through Day 28 by Geographic Region – Peru 
Modified Intent-to-Treat 
Population 
Table 
Overview of Safety Composite, Individual Endpoints, and Adverse Events 
Modified Intent-to-Treat 


 
 
 
 
 
 
 
 
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through Day 28 by Geographic Region – USA – Northeast 
Population 
Table 
Overview of Safety Composite, Individual Endpoints, and Adverse Events 
through Day 28 by Geographic Region – USA – Midwest 
Modified Intent-to-Treat 
Population 
Table 
Overview of Safety Composite, Individual Endpoints, and Adverse Events 
through Day 28 by Geographic Region – USA – South 
Modified Intent-to-Treat 
Population 
Table 
Overview of Safety Composite, Individual Endpoints, and Adverse Events 
through Day 28 by Geographic Region – USA – West 
Modified Intent-to-Treat 
Population 
Table 
Overview of Safety Composite, Individual Endpoints, and Adverse Events 
through Day 28 – Moderate Disease Severity at Baseline 
Modified Intent-to-Treat 
Population 
Table 
Overview of Safety Composite, Individual Endpoints, and Adverse Events 
through Day 28 – Severe Disease Severity at Baseline 
Modified Intent-to-Treat 
Population 
Table 
Most Common Adverse Events through Day 28 Occurring in >10% of 
Infliximab Subjects 
Modified Intent-to-Treat 
Population 
Table 
Most Common Adverse Events through Day 60 Occurring in >10% of 
Infliximab Subjects 
Modified Intent-to-Treat 
Population 
Listing 
Prior Medications 
Intent-to-Treat Population 
Listing 
Concomitant Medications 
Intent-to-Treat Population 

Prot_001.pdf: 
CONFIDENTIAL 
Page 1 of 94 
Randomized Master Protocol for Immune Modulators for Treating COVID-19  
 
Short Title: ACTIV-1 IM 
 
 
 
 
Protocol ID: ACTIV-1 IM 
 
Version Number: 2.0 
 
02 December 2020 
 
 
 
 
Sponsor: 
 
Daniel K. Benjamin, MD, MPH, PhD 
Kiser-Arena Distinguished Professor, Duke University Pediatrics 
Duke Clinical Research Institute 
300 W. Morgan Street, Suite 800 
Durham Center 
Durham, NC 27701 
Tel: 919-668-7081 
Fax: 919-681-9457 
E-mail: danny.benjamin@duke.edu  
 
Supported by: 
 
The National Center for Advancing Translational Sciences (NCATS) with funding  
from the Biomedical Advanced Research and Development Authority (BARDA) of the U.S. Department of 
Health and Human Services Office of the Assistant Secretary for Preparedness and Response 
 
Protocol Chair:  
 
William G. Powderly, MD 
J. William Campbell Professor of Medicine 
Larry J. Shapiro Director, Institute for Public Health 
Director, Institute of Clinical and Translational Sciences 
Co-Director, Division of Infectious Diseases 
Washington University in St. Louis 


Protocol # ACTIV-1 IM 
Version 2.0 
02 December 2020 
ACTIV-1 IM: Randomized Master Protocol for Immune Modulators for Treating COVID-19  
 
 
 
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Page 2 of 94 
 
 
STATEMENT OF COMPLIANCE 
Each institution engaged in this research will hold a current Federalwide Assurance (FWA) issued by the U.S. 
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 Harmonization 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 signature below provides the necessary assurance that this study will be conducted according to all stipulations 
of the protocol including statements regarding confidentiality, and according to local legal and regulatory 
requirements, US federal regulations, and ICH E6(R2) GCP guidelines. 
 
Site Investigator Signature: 
 
 
Signed: 
 
Date: 
 
 
Name and Title 
 
 
 
 


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Table of Contents 
STATEMENT OF COMPLIANCE .................................................................................................2 
1. 
PROTOCOL SUMMARY ..........................................................................................10 
1.1. 
ACTIV-1 IM – Synopsis ............................................................................................10 
1.1.1. 
Study Overview ...........................................................................................................10 
1.1.2. 
Enrollment Period ......................................................................................................10 
1.1.3. 
General .......................................................................................................................10 
1.1.4. 
Study Population .........................................................................................................11 
1.1.5. 
Inclusion Criteria ........................................................................................................11 
1.1.6. 
Exclusion Criteria at Screening..................................................................................11 
1.1.7. 
Study Intervention .......................................................................................................12 
1.1.8. 
Schedule of Assessments .............................................................................................14 
2. 
INTRODUCTION ......................................................................................................17 
2.1. 
Background .................................................................................................................17 
2.1.1. 
ACTIV-1 IM – Immune Modulators & Remdesivir Multi-arm Trial ..........................17 
2.2. 
Risk/Benefit Assessment ............................................................................................17 
2.2.1. 
Known Potential Risks of Study Participation............................................................17 
2.2.1.1. 
Risks to Privacy ..........................................................................................................17 
2.2.2. 
SoC - Remdesivir ........................................................................................................18 
2.2.2.1. 
Potential Risks of Remdesivir .....................................................................................18 
2.2.2.2. 
Potential Benefits of Remdesivir .................................................................................18 
2.2.2.3. 
Assessment of Potential Risks and Benefits of Remdesivir .........................................19 
2.2.3. 
Therapeutic Agents .....................................................................................................19 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................19 
4. 
STUDY DESIGN .......................................................................................................21 
4.1. 
Overall Design ............................................................................................................21 
4.2. 
Scientific Rationale for Study Design ........................................................................21 
4.3. 
Justification for Dose ..................................................................................................22 
4.3.1. 
Justification for Dose of Remdesivir ...........................................................................22 
4.3.2. 
Justification for Dose of Investigational Agents .........................................................22 
5. 
STUDY POPULATION .............................................................................................22 
5.1. 
Inclusion Criteria ........................................................................................................22 
5.2. 
Exclusion Criteria at Screening ..................................................................................23 
5.3. 
Exclusion of Specific Populations ..............................................................................24 
5.4. 
Inclusion of Vulnerable Subjects ................................................................................24 
5.5. 
Lifestyle Considerations .............................................................................................24 
5.6. 
Screen Failures ............................................................................................................24 
5.7. 
Strategies for Recruitment and Retention ...................................................................25 
5.7.1. 
Recruitment .................................................................................................................25 
5.7.2. 
Retention .....................................................................................................................25 
5.8. 
Compensation Plan for Subjects .................................................................................25 
5.9. 
Costs ...........................................................................................................................25 
6. 
STUDY PRODUCT ...................................................................................................25 
6.1. 
Study Product(s) and Administration .........................................................................25 


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6.1.1. 
Study Product Description ..........................................................................................26 
6.1.2. 
Dosing and Administration .........................................................................................26 
6.1.3. 
Dose Escalation ..........................................................................................................26 
6.1.4. 
Dose Modifications .....................................................................................................26 
6.1.5. 
Overdosage .................................................................................................................27 
6.1.6. 
Preparation/Handling/Storage/Accountability ...........................................................27 
6.1.6.1. 
Acquisition and Accountability ...................................................................................27 
6.1.6.2. 
Formulation, Appearance, Packaging, and Labeling ................................................27 
6.1.6.3. 
Product Storage and Stability .....................................................................................28 
6.1.6.4. 
Preparation .................................................................................................................28 
6.2. 
Measures to Minimize Bias: Randomization and Blinding ........................................28 
6.3. 
Study Intervention Compliance ..................................................................................29 
6.4. 
Concomitant Therapy .................................................................................................29 
6.4.1. 
Permitted Concomitant Therapy and Procedures ......................................................29 
6.4.2. 
Prohibited Concomitant Therapy ...............................................................................29 
6.4.3. 
Rescue Medicine .........................................................................................................30 
6.4.4. 
Non-Research Standard of Care .................................................................................30 
7. 
STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................30 
7.1. 
Halting Criteria and Discontinuation of Study Intervention .......................................30 
7.1.1. 
Individual Study Product Halting ...............................................................................30 
7.1.2. 
Study Halting ..............................................................................................................31 
7.2. 
Withdrawal from the Study ........................................................................................31 
7.3. 
Lost to Follow-Up.......................................................................................................31 
7.4. 
Readmission ................................................................................................................31 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................31 
8.1. 
Screening and Efficacy Assessments ..........................................................................31 
8.1.1. 
Screening Procedures .................................................................................................31 
8.1.2. 
Efficacy Assessments ..................................................................................................33 
8.1.3. 
Exploratory Assessments ............................................................................................35 
8.2. 
Safety and Other Assessments ....................................................................................36 
8.2.1. 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values 
or Abnormal Clinical Findings ...................................................................................38 
8.2.2. 
Unscheduled Visits ......................................................................................................38 
8.3. 
Adverse Events and Serious Adverse Events .............................................................38 
8.3.1. 
Definition of Adverse Event (AE) ...............................................................................38 
8.3.2. 
Definition of Serious Adverse Event (SAE) ................................................................39 
8.3.3. 
Suspected Unexpected Serious Adverse Reactions (SUSAR) .....................................39 
8.3.4. 
Classification of an Adverse Event .............................................................................40 
8.3.5. 
Time Period and Frequency for Event Assessment and Follow-Up ...........................40 
8.3.6. 
Serious Adverse Event Reporting ...............................................................................41 
8.3.7. 
Reporting of Pregnancy ..............................................................................................41 
8.4. 
Unanticipated Problems ..............................................................................................41 
8.4.1. 
Definition of Unanticipated Problems ........................................................................41 


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8.4.2. 
Unanticipated Problem Reporting ..............................................................................41 
9. 
STATISTICAL CONSIDERATIONS .......................................................................42 
9.1. 
Statistical Hypotheses .................................................................................................43 
9.2. 
Sample Size Determination ........................................................................................43 
9.3. 
Populations for Analyses ............................................................................................44 
9.4. 
Statistical Analyses .....................................................................................................45 
9.4.1. 
General Approach ......................................................................................................45 
9.4.2. 
Analysis of the Primary Efficacy Endpoint .................................................................45 
9.4.3. 
Analysis of the Secondary Endpoint(s) .......................................................................45 
9.4.4. 
Safety Analyses ...........................................................................................................46 
9.4.5. 
Baseline Descriptive Statistics ....................................................................................46 
9.4.6. 
Planned Early and Interim Analyses ..........................................................................46 
9.4.7. 
Sub-Group Analyses ...................................................................................................47 
9.4.8. 
Exploratory Analyses ..................................................................................................48 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS – ALL STAGES ......................................................................48 
APPENDIX 1 – SUB-STUDY 1 – INFLIXIMAB (REMICADE) ...............................................49 
1. 
SUB-STUDY SUMMARY .......................................................................................49 
1.1. 
Sub-study overview ....................................................................................................49 
1.2. 
Enrollment Period .......................................................................................................49 
1.3. 
General ........................................................................................................................49 
1.4. 
Study Population .........................................................................................................49 
1.5. 
Inclusion Criteria ........................................................................................................49 
1.6. 
Agent Specific Exclusion Criteria at Randomization .................................................49 
1.7. 
Study Intervention ......................................................................................................49 
1.8. 
Schedule of Assessments ............................................................................................50 
2. 
JUSTIFICATION FOR SELECTION ...................................................................50 
3. 
INTRODUCTION ....................................................................................................51 
3.1. 
Risk/Benefit Assessment ............................................................................................51 
3.1.1. 
Remicade .....................................................................................................................51 
3.1.1.1. 
Potential Risks of Remicade .......................................................................................51 
3.1.1.2. 
Potential Benefits of Remicade ...................................................................................51 
3.1.1.3. 
Assessment of Potential Risks and Benefits of Remicade ...........................................51 
4. 
OBJECTIVES AND ENDPOINTS .........................................................................52 
5. 
SUB-STUDY DESIGN .............................................................................................52 
5.1. 
Justification for Dose ..................................................................................................52 
5.1.1. 
Justification for Dose of Remicade .............................................................................52 
6. 
STUDY POPULATION ...........................................................................................52 
6.1. 
Inclusion Criteria ........................................................................................................53 
6.2. 
Sub-Study Specific Exclusion Criteria .......................................................................53 
6.3. 
Exclusion of Specific Populations ..............................................................................53 
7. 
STUDY PRODUCT ..................................................................................................53 
7.1. 
Study Product(s) and Administration .........................................................................53 
7.1.1. 
Study Product Description ..........................................................................................53 


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7.1.2. 
Dosing and Administration .........................................................................................53 
7.1.3. 
Dose Escalation ..........................................................................................................54 
7.1.4. 
Dose Modifications .....................................................................................................54 
7.1.5. 
Overdosage .................................................................................................................54 
7.1.6. 
Preparation/Handling/Storage/Accountability ...........................................................54 
7.1.6.1. 
Acquisition and Accountability ...................................................................................54 
7.1.6.2. 
Formulation, Appearance, Packaging, and Labeling ................................................55 
7.1.6.3. 
Product Storage and Stability .....................................................................................55 
7.1.6.4. 
Preparation and Administration .................................................................................55 
7.2. 
Measures to Minimize Bias: Randomization and Blinding ........................................55 
7.3. 
Study Intervention Compliance ..................................................................................55 
7.4. 
Concomitant Therapy .................................................................................................55 
7.4.1. 
Permitted Concomitant Therapy and Procedures ......................................................55 
7.4.2. 
Prohibited Concomitant Therapy ...............................................................................56 
7.4.3. 
Rescue Medicine .........................................................................................................56 
7.4.4. 
Non-Research Standard of Care .................................................................................56 
8. 
STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ...............................................................56 
8.1. 
Halting Criteria and Discontinuation of Study Intervention .......................................56 
8.1.1. 
Individual Study Product Halting ...............................................................................56 
8.1.2. 
Study Halting ..............................................................................................................56 
8.2. 
Withdrawal from the Study ........................................................................................56 
8.3. 
Lost to Follow-Up.......................................................................................................56 
8.4. 
Readmission ................................................................................................................56 
9. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................57 
10. 
STATISTICAL CONSIDERATIONS ....................................................................57 
APPENDIX 2 – SUB-STUDY 2 – ABATACEPT (ORENCIA) ..................................................58 
1. 
SUB-STUDY SUMMARY .......................................................................................58 
1.1. 
Sub-study overview ....................................................................................................58 
1.2. 
Enrollment Period .......................................................................................................58 
1.3. 
General ........................................................................................................................58 
1.4. 
Study Population .........................................................................................................58 
1.5. 
Inclusion Criteria ........................................................................................................58 
1.6. 
Agent Specific Exclusion Criteria ..............................................................................58 
1.7. 
Study Intervention ......................................................................................................58 
1.8. 
Schedule of Assessments ............................................................................................59 
2. 
JUSTIFICATION FOR SELECTION ...................................................................59 
3. 
INTRODUCTION ....................................................................................................61 
3.1. 
Risk/Benefit Assessment ............................................................................................61 
3.1.1. 
Abatacept ....................................................................................................................61 
3.1.1.1. 
Potential Risks of Abatacept .......................................................................................61 
3.1.1.2. 
Potential Benefits of Abatacept ..................................................................................63 
3.1.1.3. 
Assessment of Potential Risks and Benefits of Abatacept ...........................................63 
4. 
OBJECTIVES AND ENDPOINTS .........................................................................63 


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5. 
STUDY DESIGN ......................................................................................................64 
5.1. 
Justification for Dose ..................................................................................................64 
5.1.1. 
Justification for Dose of Abatacept ............................................................................64 
6. 
STUDY POPULATION ...........................................................................................64 
6.1. 
Inclusion Criteria ........................................................................................................64 
6.2. 
Sub-Study Specific Exclusion Criteria .......................................................................64 
6.3. 
Exclusion of Specific Populations ..............................................................................64 
7. 
STUDY PRODUCT ..................................................................................................65 
7.1. 
Study Product(s) and Administration .........................................................................65 
7.1.1. 
Study Product Description ..........................................................................................65 
7.1.2. 
Dosing and Administration .........................................................................................65 
7.1.3. 
Dose Escalation ..........................................................................................................65 
7.1.4. 
Dose Modifications .....................................................................................................65 
7.1.5. 
Overdosage .................................................................................................................66 
7.1.6. 
Preparation/Handling/Storage/Accountability ...........................................................66 
7.1.6.1. 
Acquisition and Accountability ...................................................................................66 
7.1.6.2. 
Formulation, Appearance, Packaging, and Labeling ................................................67 
7.1.6.3. 
Product Storage and Stability .....................................................................................67 
7.1.6.4. 
Preparation .................................................................................................................67 
7.2. 
Measures to Minimize Bias: Randomization and Blinding ........................................68 
7.3. 
Study Intervention Compliance ..................................................................................68 
7.4. 
Concomitant Therapy .................................................................................................68 
7.4.1. 
Permitted Concomitant Therapy and Procedures ......................................................68 
7.4.2. 
Prohibited Concomitant Therapy ...............................................................................68 
7.4.3. 
Rescue Medicine .........................................................................................................68 
7.4.4. 
Non-Research Standard of Care .................................................................................68 
8. 
STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ...............................................................68 
8.1. 
Halting Criteria and Discontinuation of Study Intervention .......................................68 
8.1.1. 
Individual Study Product Halting ...............................................................................68 
8.1.2. 
Study Halting ..............................................................................................................69 
8.2. 
Withdrawal from the Study ........................................................................................69 
8.3. 
Lost to Follow-Up.......................................................................................................69 
8.4. 
Readmission ................................................................................................................69 
9. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................69 
10. 
STATISTICAL CONSIDERATIONS ....................................................................69 
APPENDIX 3 – SUB-STUDY 3 – CENICRIVIROC (CVC) .......................................................70 
1. 
SUB-STUDY SUMMARY .......................................................................................70 
1.1. 
Sub-study overview ....................................................................................................70 
1.2. 
Enrollment Period .......................................................................................................70 
1.3. 
General ........................................................................................................................70 
1.4. 
Study Population .........................................................................................................70 
1.5. 
Inclusion Criteria ........................................................................................................70 
1.6. 
Agent Specific Exclusion Criteria ..............................................................................70 


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1.7. 
Study Intervention ......................................................................................................70 
1.8. 
Schedule of Assessments ............................................................................................71 
2. 
JUSTIFICATION FOR SELECTION ...................................................................71 
3. 
INTRODUCTION ....................................................................................................73 
3.1. 
Risk/Benefit Assessment ............................................................................................73 
3.1.1. 
Cenicriviroc ................................................................................................................73 
3.1.1.1. 
Potential Risks of Cenicriviroc ...................................................................................73 
3.1.1.2. 
Potential Benefits of Cenicriviroc ..............................................................................74 
3.1.1.3. 
Assessment of Potential Risks and Benefits of Cenicriviroc .......................................74 
4. 
OBJECTIVES AND ENDPOINTS .........................................................................75 
5. 
STUDY DESIGN ......................................................................................................75 
5.1. 
Justification for Dose ..................................................................................................75 
5.1.1. 
Justification for Dose of Cenicriviroc ........................................................................75 
6. 
STUDY POPULATION ...........................................................................................78 
6.1. 
Inclusion Criteria ........................................................................................................78 
6.2. 
Sub-Study Specific Exclusion Criteria .......................................................................78 
6.3. 
Exclusion of Specific Populations ..............................................................................78 
7. 
STUDY PRODUCT ..................................................................................................78 
7.1. 
Study Product(s) and Administration .........................................................................78 
7.1.1. 
Study Product Description ..........................................................................................79 
7.1.2. 
Dosing and Administration .........................................................................................79 
7.1.3. 
Dose Escalation ..........................................................................................................80 
7.1.4. 
Dose Modifications .....................................................................................................80 
7.1.4.1. 
Dose Modifications for Adverse Events ......................................................................80 
7.1.5. 
Overdosage .................................................................................................................81 
7.1.6. 
Preparation/Handling/Storage/Accountability ...........................................................82 
7.1.6.1. 
Acquisition and Accountability ...................................................................................82 
7.1.6.2. 
Formulation, Appearance, Packaging, and Labeling ................................................82 
7.1.6.3. 
Product Storage and Stability .....................................................................................82 
7.1.6.4. 
Preparation .................................................................................................................82 
7.2. 
Measures to Minimize Bias: Randomization and Blinding ........................................83 
7.3. 
Study Intervention Compliance ..................................................................................83 
7.4. 
Concomitant Therapy .................................................................................................83 
7.4.1. 
Permitted Concomitant Therapy and Procedures ......................................................83 
7.4.2. 
Prohibited Concomitant Therapy ...............................................................................83 
7.4.3. 
Rescue Medicine .........................................................................................................85 
7.4.4. 
Non-Research Standard of Care .................................................................................85 
8. 
STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ...............................................................85 
8.1. 
Halting Criteria and Discontinuation of Study Intervention .......................................85 
8.1.1. 
Individual Study Product Halting ...............................................................................85 
8.1.2. 
Study Halting ..............................................................................................................85 
8.2. 
Withdrawal from the Study ........................................................................................85 
8.3. 
Lost to Follow-Up.......................................................................................................85 


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8.4. 
Readmission ................................................................................................................86 
9. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................86 
10. 
STATISTICAL CONSIDERATIONS ....................................................................86 
APPENDIX 4 – ACTIV-1 IM PROTOCOL TEAM ROSTER.....................................................87 
11. 
REFERENCES .........................................................................................................91 
 
 
 


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ACTIV-1 IM:  
RANDOMIZED MASTER PROTOCOL FOR IMMUNE MODULATORS 
FOR TREATING COVID-19  
 
 
1. 
PROTOCOL SUMMARY 
1.1. 
ACTIV-1 IM – Synopsis 
1.1.1. 
Study Overview 
ACTIV-1 IM is a master protocol designed to evaluate multiple investigational agents for the treatment of 
moderately or severely ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 
The research objectives are to evaluate each agent with respect to speed of recovery, mortality, illness severity, and 
hospital resource utilization. Each agent will be evaluated as add-on therapy to the standard of care (SoC) in 
accordance with national or local guidelines, which may include remdesivir. The SoC may change during the course 
of the study based on other research findings. Comparisons of the agents among themselves is not a research 
objective. 
The study population corresponds to moderately and severely ill patients infected with the coronavirus disease 2019 
(COVID-19) virus. Recruitment will target patients already hospitalized for treatment of COVID-19 infection as 
well as patients being treated for COVID-19 infection in Emergency Departments while waiting to be admitted to 
the hospital. Patients both in and out of the ICU are included in the study population. 
Enrollment began when 3 agents were selected for initial evaluation and available for testing. Up to 5 agents may be 
evaluated in ACTIV-1 IM. Appendices to this protocol describe each agent and any sub-study-specific procedures 
and considerations for that agent. 
The study period is 29 days, with assessments on each day of the hospital stay. Discharged patients will be followed 
with periodic follow-up assessments through Day 29. There will also be a safety and clinical status assessment at 60 
days.  Treatment periods may vary by agent. 
The trial is adaptive in that interim analyses are planned to assess the futility of each agent, with the goal of 
discontinuing those with lower probabilities of success to more effectively utilize trial resources for the remaining 
agents. Additionally, interim analyses are planned for early stopping for efficacy.  Alpha spending functions are 
used to appropriately control the probability of making an erroneous conclusion at the interim and final analyses. 
Safety monitoring will be performed throughout the trial, and formal stopping rules for each agent will be adopted. 
The Data and Safety Monitoring Board (DSMB) selected for ACTIV-1 IM has oversight responsibility for the study.  
1.1.2. 
Enrollment Period  
Enrollment began in October 2020. It is anticipated that enrollment will be completed in 4-6 months. 
1.1.3. 
General 
ACTIV-1 IM is a master protocol designed to evaluate immune modulators for the treatment of moderately or 
severely ill hospitalized patients infected with COVID-19. Trial participants will be assessed daily while 
hospitalized. If the participants are discharged from the hospital prior to Day 29, they will have follow-up study 
visits at Days 8, 11, 15, 22, and 29. For discharged participants, it is preferred that the Day 8, 11, 15, and 29 visits 
are in person to obtain safety laboratory tests and blood (serum/plasma) samples for secondary research as well as 
clinical outcome data. However, infection control or other restrictions may limit the ability of the participant to 
return to the clinic. In this case, these visits may be conducted by phone, and only clinical data will be obtained. The 
Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone. The Day 60 
assessment will be conducted by phone. 


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The effectiveness of each therapeutic agent as add-on therapy to SoC which may include remdesivir (provided) will 
be evaluated based on the primary endpoint of time to recovery by Day 29. The sample size requirements are based 
on the ability to detect a moderate improvement in time to recovery (3-4 fewer days) for each agent (see Section 
9.2). A total of 788 recoveries are required for each comparison to provide approximately 85% power to detect a 
recovery rate ratio of 1.25. Assuming 73% of participants achieve recovery in 28 days, consistent with the ACTT-1 
results, the total sample size to evaluate 1, 2, and 3 agents in ACTIV-1 IM is approximately 1080, 1620, and 2160, 
respectively. Because each agent is being compared to SoC with no between-agent comparisons, no multiplicity 
adjustments for multiple agents are planned. 
1.1.4. 
Study Population 
Hospitalized adults (≥18 years old) with COVID-19, including patients both in and out of the ICU. Patients seeking 
care for COVID-19 in an Emergency Department (ED) and waiting to be admitted to the hospital are included. 
1.1.5. 
Inclusion Criteria 
1. Admitted to a hospital or awaiting admission in the ED 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 (within 14 days prior to enrollment) SARS-CoV-2 infection as determined by 
PCR or other commercial or public health assay in any specimen.  
6. Ongoing illness of any duration, and at least one of the following: 
• 
Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR 
• 
Blood oxygen saturation (SpO2) ≤ 94% on room air, OR 
• 
Requiring supplemental oxygen, OR 
• 
Requiring mechanical ventilation or ECMO. 
7. Women of childbearing potential must agree to either abstinence or use of at least one primary form of 
contraception not including hormonal contraception from the time of screening through Day 60. 
8. Agrees not to participate in another interventional trial for the treatment of COVID-19 through Day 60.  
Exception 1:  Participant may co-enroll in ACTIV-4 (ACTIV-4A and ACTIV-4C).  
Exception 2:  Participants in ACTIV-2 who have been hospitalized may be enrolled in ACTIV-1 as long as 
ACTIV-2 study therapy has been discontinued. They will remain in ACTIV-2 follow-up. 
Exception 3:  If participant is already participating in a COVID-19 vaccine trial but develops COVID-19 
disease that requires hospitalization, participant is eligible for this study, assuming all other 
inclusion/exclusion criteria are met. 
1.1.6. 
Exclusion Criteria at Screening 
1. ALT or AST >10 times the upper limit of normal. 
2. Estimated glomerular filtration rate (eGFR) <30 mL/min (including patients receiving hemodialysis or 
hemofiltration). 
Exception:  Participants with an eGFR <30 mL/min may enroll as long as their renal insufficiency has been 
stable without renal replacement therapy for ≥1 month and they are not current candidates for renal 
replacement therapy.  These participants will not receive remdesivir. 
3. Neutropenia (absolute neutrophil count <1000 cells/μL) (<1.0 x 103/μL or <1.0 GI/L). 
4. Lymphopenia (absolute lymphocyte count <200 cells/μL) (<0.20 x 103/μL or <0.20 GI/L) 
5. Pregnancy or breast feeding. 
6. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 
hours. 
7. Known allergy to any study medication. 
8. Received targeted immune-modulator treatments (such as anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab 
or sarilumab], anti-IL-17, T-cell or B-cell targeted therapies [e.g., rituximab], JAK inhibitors [including 


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baricitinib], TNF inhibitors, or interferon) within 4 weeks or 5 half-lives prior to screening, whichever is 
longer. Steroid dependency, defined as need for prednisone at a dose >10 mg (or equivalent) for >1 month 
within 2 weeks of screening, is exclusionary.  
Exception 1: Dexamethasone is permitted for the treatment of COVID-19 in patients who are already 
mechanically ventilated and in patients who require supplemental oxygen at screening, but who are not 
mechanically ventilated in accordance with national guidelines.  
Exception 2: Infusion of convalescent plasma given for treatment of COVID-19 while on-study is also 
allowed.  
Exception 3: Monoclonal antibody therapy given for COVID-19 treatment at any time prior to enrollment 
is also allowed. 
9. Known or suspected history of untreated tuberculosis (TB).  TB diagnosis may be suspected based on 
medical history and concomitant therapies that would suggest TB infection. Participants are also excluded 
if they have known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per 
local guidelines (by history only, no screening required).  
10. Known or suspected serious, active bacterial, fungal, or viral infection (excepting SARS-CoV-2 and 
including, but not limited to, active HBV, HCV, or HIV with the latter defined as a CD4 count <200 or an 
unsuppressed HIV viral load), or other infection (besides COVID-19) that in the opinion of the investigator 
could constitute a risk when taking investigational product.  
Note:  Broad-spectrum empiric antibiotic usage does not exclude participation. 
11. Have received any live vaccine (or live attenuated) within 3 months before screening, or intend to receive a 
live vaccine (or live attenuated) during the study.  
Exception: Use of prior non-live (inactivated) vaccinations is allowed for all participants, including any 
vaccine for COVID-19.  
12. Severe hepatic impairment (defined as liver cirrhosis Child stage C). 
13. Known severe heart failure (New York Heart Association [NYHA] III-IV) or new-onset left-systolic or 
global cardiac dysfunction in the setting of COVID-19. 
Exception: Right-sided heart dysfunction or pulmonary hypertension thought related to COVID-19 is 
permitted.  
14. In the Investigator’s judgment, the patient has any advanced organ dysfunction that would not make 
participation appropriate. 
1.1.7. 
Study Intervention 
Immune-modulating agents will be evaluated as an add-on therapy to SoC. Participants will be randomly assigned to 
receive either SoC (which may include remdesivir) plus one of the test agents or SoC (which may include 
remdesivir) plus placebo. Randomization will proceed in two stages via a web-based central randomization system. 
At the first stage (open label), each participant will be assigned to one of the sub-studies with equal probability. At 
the second stage (blinded), each participant will be assigned to either the test agent or its matching placebo in an n:1 
ratio, where n = the number of agents currently active in the master protocol and for which the patient is eligible to 
receive. With three agents and SoC, for example, this procedure results in a randomization ratio of 1:1:1:1 if the 
participant is eligible to receive all three agents (see Section 6.2). 
Inclusion of a placebo for each agent enables masking of study participants and clinical personnel to treatment 
assignment at the second stage. Data from participants receiving SoC plus placebo will be pooled across agents for 
comparative analyses and hypothesis testing. 
If there are supply limitations on any test agent, the sub-study containing that product, or its matching placebo, will 
be temporarily closed to enrollment.  
The initial SoC may include remdesivir in accordance with local or national guidelines, based on the results of the 
ACTT-1 study. Participants will receive remdesivir according to the FDA-approved package insert as follows:  
• 
For participants not already receiving remdesivir, remdesivir will be administered as a 200 mg intravenous 
(IV) loading dose on Day 1, followed by a 100 mg once-daily IV maintenance dose.  


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• 
Participants who have already been receiving remdesivir as SoC prior to Day 1 will continue to receive a 
100 mg once-daily IV maintenance dose up to a total of 10 days (inclusive of the days of treatment prior to 
Day 1). 
Duration of SoC therapy: 
• 
Remdesivir IV component – up to 10 days while hospitalized (see Section 6.1.2), per FDA package insert. 
• 
Other SoC as determined by the treating site in accordance with local or national guidelines 
 
 
 


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1.1.8. 
Schedule of Assessments 
In addition to the table below, please consult the appropriate appendix for each sub-study (Section 1.8 of 
Appendices 1, 2, and 3) for additional agent- and sub-study-specific assessments.  Also see Table 8-2 for a schedule 
of blood collections. 
Participants may be discharged from the hospital early, but should be present in the clinic for in-person (outpatient) 
follow-up visits according to the schedule in Table 1-1 below. These should occur on Day 8, Day 11, Day 15, and 
Day 29 and every effort should be made to encourage participants to return to the study site for these visits. (A 
telephone follow-up is scheduled for Day 22.) Participants who are discharged at any time are considered to have 
met the study endpoint and will continue to be followed via the scheduled outpatient visits and/or telephone calls. 
Participants who are transferred to another hospital that is not a study site will be followed by telephone calls; if the 
participant is enrolled in a sub-study involving self-administered medication, the participant will be given a supply 
of that medication and instructed to continue taking it. It is anticipated that transfer to another hospital will be an 
extremely rare occurrence.  
Day 29 assessments should not be performed earlier than Day 29 (to assess Day 28 endpoints), with a visit window 
of +3 days; therefore, the Day 29 visit may be conducted on Day 29 through Day 32.


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Table 1-1. Schedule of Assessments (SOA) 
  
Screen 
Baseline 1  
Study Intervention Period 
(while hospitalized) 
Follow-up Visits After Discharge 2 
Day 
(± Window) 
−1 or 1 
1 1 
 
8  
(± 1) 
11 
(± 1) 
15 
(± 2) 
22 3 
(± 3) 
29 
(+ 3) 
60 4 
(± 5) 
ELIGIBILITY 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics & Medical History 
X 
 
 
 
 
 
 
 
 
Review SARS-CoV-2 results 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Administration of investigational 
agents 
 
• Remdesivir: if included as SoC, given 
as daily infusion up to a total of 10 days 
or discharge.  
• Immune-modulator: See corresponding 
sub-study for dosing schedule. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY PROCEDURES 
 
 
 
 
 
 
 
 
 
Targeted physical exam 
X 
 
 
 
 
 
 
 
 
Vital signs including SpO2 5 
 
X 
Daily through hospital 
discharge or Day 29 6 
X 
X 
X 
 
X 
 
Clinical data collection 7 
 
X 
Daily through hospital 
discharge or Day 29 6 
X 
X 
X 
X 
X 
X 
Adverse event evaluation (including 
AESI) 8 
 
X 
Daily through hospital 
discharge or Day 29 6 
X 
X 
X 
X 
X 
X 
Prior/concomitant medications review 
X (from 
Day –7) 
X 
Daily through hospital 
discharge or Day 29 6 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
SAFETY LABORATORY 
 
 
 
 
 
 
 
 
 
Safety hematology, chemistry and 
liver function tests 
X 9 
X 
Day 3, 5, 8, 11, 15 (all ±1 
day) if hospitalized 10 
X 10,11 
X 11 
X 11 
 
X 11 
 
Pregnancy test and counseling for 
females of childbearing potential 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOKINETICS 
 
 
 
 
 
 
 
 
 
Blood sample for serum or plasma 
(pharmacokinetics)   
 
X 
Day 8 (±1 day) 
if hospitalized 10 
X 10 
 
 
 
X 10 
 


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Screen 
Baseline 1  
Study Intervention Period 
(while hospitalized) 
Follow-up Visits After Discharge 2 
Day 
(± Window) 
−1 or 1 
1 1 
 
8  
(± 1) 
11 
(± 1) 
15 
(± 2) 
22 3 
(± 3) 
29 
(+ 3) 
60 4 
(± 5) 
 
 
 
 
 
 
 
 
 
 
RESEARCH LABORATORY  
 
 
 
 
 
 
 
 
 
Blood for serum and plasma (future 
secondary research) 12 
 
X 
Day 3, 8, 15 (all ± 1 day) if 
hospitalized 
X 
 
X 
 
X 
 
Whole blood for genetic testing 12 
 
X 
 
 
 
 
 
 
 
Notes: 
1 Baseline assessments should be performed within 24 hours prior to first study product administration. Results of Day 1 (baseline) laboratory assessment 
do not need to be reviewed to determine if initial study product should be given.  
2 In-person follow-up visits for Days 8, 11, 15, and 29 are strongly preferred and should be encouraged by any means. If a participant cannot return to the 
site, a telephone follow-up visit (see footnote 3) will assess adverse events, clinical status (ordinal scale), readmission to a hospital, concomitant 
medications, and mortality only. If the participant is still hospitalized on any of these days, then the inpatient “daily until discharge” assessments 
(including concomitant medications) will be performed. 
3 Day 22 telephone-only follow-up will assess adverse events, clinical status (ordinal scale only), readmission to a hospital, concomitant medications, and 
mortality in participants who have been discharged from the hospital. If the participant is still hospitalized on Day 22, then the inpatient “daily until 
discharge” assessments (including concomitant medications) will be performed. 
4 Day 60 telephone-only follow-up will assess adverse events, clinical status (ordinal scale only), readmission to a hospital, and mortality.  
5 Vital 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. Height/weight will be assessed at baseline only. 
6 Daily until hospital discharge or through Day 29, whichever comes first.  
7 Refer to Sections 8.1.2 and 8.1.3 of the protocol for details of clinical data to be collected including ordinal scale, NEWS, oxygen requirement, 
mechanical ventilator requirement, extrapulmonary manifestations, etc. During telephone-only follow-ups, only ordinal scale will be collected.  
8 Secondary infections/superinfections are considered AEs of special interest (AESI) and are captured on the appropriate case report form. See Section 
8.3.2. 
9 Laboratory tests performed in the 48 hours prior to enrollment will be accepted for determination of eligibility. See Section 8.2 for the complete list of 
safety laboratory parameters to be assessed at each time point. 
10 If discharged before Day 8 or Day 29, blood for the corresponding PK assessments may be drawn shortly before discharge.  PK sample may be drawn 
at time of routine phlebotomy. All efforts will be made to collect the PK samples. If the samples are not collected due to complication or collected 
outside the window, this will not be considered a deviation. 
11 For outpatient visits (returning to clinic), any laboratory tests performed as part of routine clinical care within the specified visit window can be used 
for safety laboratory testing. 
12 Blood samples for future research, including genetic testing, are mandatory at all CTSA sites, and optional at all other US sites. These samples will not 
be collected at non-US sites.  
 


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Study Schema 
 
 
2. INTRODUCTION 
2.1. 
Background 
2.1.1. 
ACTIV-1 IM – Immune Modulators & Remdesivir Multi-arm Trial 
A preliminary review of data from ACTT-1 occurring after 606 recoveries and 103 deaths (approximately 67% of 
the 1,063 subjects enrolled) demonstrated that subjects that received remdesivir had a 31% faster time to recovery 
(11 vs 15 days, recovery rate ratio 1.312 (1.119, 1.541), p<0.001), and a decrease in mortality (8.0% vs 11.6%, p = 
0.059). The DSMB asked that the sponsor be unblinded early given the public health implications of the results as 
well as the implications for the design and conduct of ACTT-2. Based on the ACTT-1 results, the Emergency Use 
Authorization (EUA) from FDA, and the subsequent (as of 22 October 2020) FDA approval for COVID-19 
treatment in hospitalized adults, remdesivir is now considered the SoC in the US for hospitalized COVID-19 
patients. Note, however, that while remdesivir has demonstrated efficacy in the treatment of COVID-19, the 
mortality rate is still high. Infection by pathogenic coronaviruses (e.g. SARS and SARS-CoV–2) often results in 
excessive cytokine and chemokine action with the development of acute respiratory distress syndrome (ARDS) (33-
35). It is postulated that this dysregulated inflammatory immune response is contributing to the excessive mortality 
and targeting this response will further improve outcomes. 
2.2. 
Risk/Benefit Assessment 
2.2.1. 
Known Potential Risks of Study Participation 
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 2.2.2.1), and breach of confidentiality. 
Drawing blood may cause transient discomfort and fainting. Fainting is usually transient and managed by having the 
participant lie down and elevate his/her legs. Bruising at the blood collection sites may occur but can be prevented 
or lessened by applying pressure to the blood draw site for a few minutes after the blood is taken. IV catheterization 
may cause insertion site pain, phlebitis, hematoma formation, and infusate extravasation; less frequent but 
significant complications include bloodstream and local infections. The use of aseptic (sterile) technique will make 
infection at the site where blood will be drawn or at catheter site less likely. 
2.2.1.1. Risks to Privacy  
Participants 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 
participant’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 participants. 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/EC, NCATS, and applicable regulatory agencies (e.g., FDA).  


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2.2.2. 
SoC - Remdesivir  
2.2.2.1. Potential Risks of Remdesivir  
Remdesivir has been approved in the US for the treatment of COVID-19 in hospitalized adults and pediatric patients 
≥12 years of age and weighing ≥40 kg. It is still considered an investigational therapeutic in other regions including 
South America. Of 138 healthy adults dosed with remdesivir in four Phase 1 clinical trials, few subjects to date 
experienced constipation, heartburn, itching, unusual feelings in the ear, dizziness, loss of appetite, nausea, 
vomiting, shaking of the leg and arm, headache, loose stool, or upset stomach. These AEs were temporary, lasting 
only a few days, and none were serious. In clinical studies, transient elevations in ALT and AST have been observed 
with single doses of remdesivir up to 225 mg and multiple once daily doses of remdesivir 150 mg for up to 14 days. 
Mild (Grade 1) reversible PT prolongation was also noted in some subjects but without any clinically significant 
change in INR or other evidence of hepatic effects. The mechanism of these elevations is currently unknown. Based 
on these clinical observations, patients with ALT or AST >10 times the upper limit of normal will not be eligible for 
study enrollment. Regular laboratory assessments will be performed in order to monitor hepatic function and PT. 
Any observed liver function-related laboratory abnormalities or possibly related AEs will be treated appropriately 
and followed to resolution.  
In nonclinical animal studies, toxicity studies found dose-dependent and reversible kidney injury and dysfunction. In 
clinical studies, no evidence of nephrotoxicity has been observed with single doses of remdesivir up to 225 mg or 
multiple once daily doses of remdesivir 150 mg for up to 14 days. A 150-mg dose of the solution and lyophilized 
formulations of remdesivir contains 9 g and 4.5 g, respectively, of sulfobutylether-beta-cyclodextrin (SBECD), for 
which the maximum daily recommended daily dose (based on a European Medicines Agency (EMA) safety review) 
is approximately 250 mg/kg. Because SBECD is renally cleared, participants 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 and requiring hemodialysis or hemofiltration will not be eligible for study enrollment.  Patients with eGFR 
<30 mL/min may enroll to the trial as long as their renal insufficiency has remained stable for at least 1 month and 
they are not on hemodialysis/hemofiltration, though these participants will not be treated with remdesivir. 
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. Drug-drug interaction trials of remdesivir and other concomitant medications have 
not been conducted in humans. See the FDA product label and the IB for full discussions 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.  
2.2.2.2. Potential Benefits of Remdesivir  
A preliminary review of data from ACTT-1 occurring after 606 recoveries and 103 deaths (approximately 67% of 
the 1063 subjects enrolled) demonstrated that subjects that received remdesivir had a 31% faster time to recovery 
(11 vs 15 days, recovery rate ratio 1.312 (1.119, 1.541), p<0.001), and a decrease in mortality (8.0% vs 11.6%, p = 
0.059). The DSMB asked that the sponsor be unblinded early given the public health implications of the results and 
implications for the design and conduct of ACTT-2. Based on the ACTT-1 results, remdesivir is now considered the 
standard of care for Covid-19 infected hospitalized patients. As a result, all subjects in ACTIV-1 IM will be given 
remdesivir as part of SoC, and the new therapeutic agents will be evaluated as add-on therapies to SoC including 
remdesivir. 
This is a benefit to participation as remdesivir will be provided to all participants without contraindications as part of 
the study.  In addition, society may benefit from their participation in this study resulting from insights gained about 
the efficacy of remdesivir combined with the new agents. Determining if additional clinical benefit can be realized 
by combining the antiviral with one of the new therapeutic agents being evaluated in ACTIV-1 IM for the treatment 
of COVID-19 may benefit society during this global COVID-19 pandemic. 


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2.2.2.3. Assessment of Potential Risks and Benefits of Remdesivir  
Remdesivir is generally a well-tolerated medication. There are liver toxicities and minor (grade 1-2) increases in 
prothrombin time (PT) 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 
from remdesivir treatment those with elevated liver transaminases and decreased kidney function (eGFR <30 
mL/min or requires hemodialysis or hemofiltration), and appropriate monitoring during the study (including 
assessment of PT/INR), we can minimize the risk to participants. While there may not be benefits for an individual 
participant, there may be benefits to society if a safe, efficacious therapeutic agent can be identified during this 
global COVID-19 pandemic. The potential risks therefore are thought to be acceptable given the potential benefits.  
2.2.3. 
Therapeutic Agents 
For each of the therapeutic agents under investigation, findings from the preclinical and clinical studies are briefly 
described in the agent-specific appendices, including a summary of the findings described in the Investigator 
Brochures (IBs). The potential risks and benefits of the therapeutic agents are also summarized in the appendices. 
 
3. OBJECTIVES AND ENDPOINTS 
The overall objective of the study is to evaluate the clinical efficacy and safety of different investigational 
therapeutic agents relative to the control arm among hospitalized adults who have COVID-19. 
 
Table 3-1. Trial objectives and measured endpoints 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
Primary 
 
To evaluate the clinical efficacy of different 
investigational therapeutics relative to the control arm 
in adults hospitalized with COVID-19 with respect to 
time to recovery by Day 29. 
Day of recovery is defined as the first day on which the 
participant satisfies one of the following three 
categories from the ordinal scale: 
• 
Hospitalized, not requiring supplemental oxygen – 
no longer requires ongoing medical in-patient care; 
• 
Not hospitalized, limitation on activities and/or 
requiring home oxygen; 
• 
Not hospitalized, no limitations on activities. 
Recovery is evaluated up until Day 29. 
Key Secondary 
 
• 
To evaluate the clinical efficacy of different 
investigational therapeutics relative to the control 
arm in adults hospitalized with COVID-19 
according to: 
• 
Clinical status (8-point ordinal scale) assessed 
on Day 15 and Day 29 for the previous day 
 
 
 
 
 
 
 
 
1. Death; 
2. Hospitalized, on invasive mechanical ventilation or 
ECMO; 
3. Hospitalized, on non-invasive ventilation or high 
flow oxygen devices; 
4. Hospitalized, requiring supplemental oxygen; 
5. Hospitalized, not requiring supplemental oxygen – 
requiring ongoing in-patient medical care (COVID-
19 related or otherwise); 
6. Hospitalized, not requiring supplemental oxygen – 
no longer requires ongoing in-patient medical care 
(i.e., in hospital for social reasons, infection control, 
etc.); 
7. Not hospitalized, limitation on activities and/or 
requiring home oxygen; 
8. Not hospitalized, no limitations on activities. 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
• 
Mortality 
o 
14-day mortality 
o 
28-day mortality 
 
 
• 
Date and cause of death (if applicable) 
 
Additional Secondary  
 
To evaluate the clinical efficacy of different 
investigational therapeutics relative 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 8-point ordinal scale. 
 
Subject clinical status using 8-point ordinal 
scale at Days 3, 5, 8, 11, 15, 22, and 29.  
 
Mean change in the 8-point ordinal scale 
from Day 1 to Days 3, 5, 8, 11, 15, 22, and 
29. 
 
Total severity score (TSS): 8-point ordinal 
scale summarized as a daily score (for days 
collected) averaged over time from Day 1 
through Day 29 
 
 
 
• Clinical outcome assessed using ordinal scale daily 
while hospitalized and on Days 15, 22, and 29. 
 
 
 
 
 
 
o 
Oxygenation: 
 
Oxygenation use up to Day 29. 
 
Incidence and duration of new oxygen use 
during the study. 
 
• Days alive and free 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 alive and free 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 alive and free of invasive mechanical 
ventilation/ECMO (if applicable) up to Day 29 
 
• 
Hospitalization 
o 
Duration of hospitalization (days).  
 
• Days alive and out of hospitalization up to Day 29 
To evaluate clinical Status at Day 60 
• 8-point Ordinal Scale 
To evaluate the safety of different investigational 
therapeutics relative 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) 
 
 
• SAEs 
• Grade 3 and 4 AEs  
• WBC with differential, hemoglobin, platelets, 
creatinine, glucose, total bilirubin, ALP, ALT, and 
AST on Days 1, 3, 5, 8, 11, 15, and 29. 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
• 
Changes in white blood cell (WBC) count with 
differential, hemoglobin, platelets, creatinine, 
glucose, total bilirubin, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), 
prothrombin time (PT reported as INR), d-dimer, 
and C-reactive protein (CRP) over time (analysis 
of lab values in addition to AEs noted above). 
• PT/INR, d-dimer, troponin, and CRP on Days 1 
and 8. 
 
• 
To evaluate the impact of different investigational 
therapeutics relative to the control arm of 
extrapulmonary manifestations of COVID-19. 
Incidence of individual and “any” specified 
manifestations at Day 29. 
Exploratory  
 
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 feasible. 
Collect blood samples for future research. 
Blood draws on Days 1, 3, 8, 15, and 29. 
  
4. STUDY DESIGN 
4.1. 
Overall Design 
ACTIV-1 IM is a master protocol designed to evaluate multiple therapeutic agents for the treatment of moderately or 
severely ill hospitalized patients infected with COVID-19. Participants will be assessed daily while hospitalized. If 
the participants are discharged from the hospital, they will have a study visit at Days 8, 11, 15, 22, and 29. For 
discharged participants, it is preferred that the Day 8, 11, 15, and 29 visits are in person to obtain safety laboratory 
tests and blood (serum and plasma) samples for secondary research as well as clinical outcome data. However, 
infection control or other restrictions may limit the ability of the participant to return to the clinic. In this case, these 
visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory 
tests or collection of samples and is conducted by phone. The Day 60 assessment will be conducted by phone. The 
primary outcome is time to recovery by Day 29 (see Table 3-1 for definition of recovery based on the 8-point 
ordinal scale). Key secondary outcomes include treatment-related improvements in the 8-point ordinal scale at Day 
15, evaluation of safety, and 14-day and 28-day mortality.   
4.2. 
Scientific Rationale for Study Design 
ACTIV-1 IM utilizes a master protocol to evaluate multiple therapeutic agents for the treatment of COVID-19 
infection in hospitalized patients. Approximately 400 agents were identified and screened for clinical readiness by a 
panel of experts, and 170 agents were selected for further evaluation based on mechanism of action and need for 
further clinical testing (i.e., not previously studied or plan for study in other trials or trial networks). From this 
triaging exercise, three agents were initially selected for study in the ACTIV-1 IM master protocol. All three agents 
are immune modulators with substantial clinical experience available. Details about the initial set of selected agents 
are provided elsewhere (see Sections 2 and 4 and Appendices 1-3); additional agents may be entered into the 
ACTIV-1 IM master protocol after the study begins, depending on availability and network capacity. In that case, 
agent-specific information will be appended to the protocol for any new agents entering the study, and the 
randomization algorithm will be adjusted accordingly. 
ACTIV-1 IM builds upon findings and the model used for ACTT-1 and -2.  Including multiple therapeutic agents 
under a single protocol avoids duplication of effort in terms of infrastructure, trial governance, information systems 
(EDC, web-based randomization, etc.) and other aspects of study management. Implementation of the master 


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protocol facilitates discontinuation of less promising agents and addition of possibly newly emergent agents that 
become available after the study begins, without stopping and starting the study itself for extended pauses. 
All test agents are evaluated as add-on therapies to the local SoC at each clinic. The master protocol design allows 
for the efficacy and safety of each agent to be determined based on comparisons with a pooled control group, 
consisting of patients receiving SoC plus placebo. Sharing control patients across all test agents substantially 
reduces the sample size requirements for the study. 
4.3. 
Justification for Dose 
4.3.1. 
Justification for Dose of Remdesivir 
The dose of remdesivir used in this study is the dose specified on its FDA-approved product label, and the same 
dose that was used in the ACTT-1 and ACTT-2 trials.  
4.3.2. 
Justification for Dose of Investigational Agents 
The dose of each investigational agent is provided in the agent-specific appendices to this master protocol. 
 
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 90 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 
participant is approximately 60 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 participant is eligible for study enrollment. 
There is no exclusion for receipt of SARS-CoV-2 vaccine (experimental or licensed). 
Following are the inclusion and exclusion criteria for the master protocol population. These criteria apply to all 
patients enrolled, regardless of therapeutic agent to be assigned for treatment. Any agent-specific exclusion criteria 
that are required will be applied during recruitment in addition to these common criteria and are described in the 
appendices corresponding to each agent under study. 
5.1. 
Inclusion Criteria 
1. Admitted to a hospital or awaiting admission in the ED 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 (within 14 days prior to enrollment) SARS-CoV-2 infection as determined by 
PCR or other commercial or public health assay in any specimen.  
6. Ongoing illness of any duration, and at least one of the following: 
• 
Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR 
• 
Blood oxygen saturation (SpO2) ≤ 94% on room air, OR 
• 
Requiring supplemental oxygen, OR 
• 
Requiring mechanical ventilation or ECMO. 
7. Women of childbearing potential must agree to either abstinence or use of at least one primary form of 
contraception not including hormonal contraception from the time of screening through Day 60. 
8. Agrees not to participate in another interventional trial for the treatment of COVID-19 through Day 60.  
Exception 1:  Participant may co-enroll in ACTIV-4 (ACTIV-4A and ACTIV-4C).  
Exception 2: Participants in ACTIV-2 who have been hospitalized may be enrolled in ACTIV-1 as long as 
ACTIV-2 study therapy has been discontinued. They will remain in ACTIV-2 follow-up. 


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Exception 3: If participant is already participating in a COVID-19 vaccine trial but develops severe 
COVID-19, participant is eligible for this study, assuming all other inclusion/exclusion criteria are met. 
 
5.2. 
Exclusion Criteria at Screening 
1. ALT or AST >10 times the upper limit of normal. 
2. Estimated glomerular filtration rate (eGFR) <30 mL/min (including patients receiving hemodialysis or 
hemofiltration). 
Exception:  Participants with an eGFR <30 mL/min may enroll as long as their renal insufficiency has been 
stable without renal replacement therapy for ≥1 month and they are not current candidates for renal 
replacement therapy.  These participants will not receive remdesivir. 
3. Neutropenia (absolute neutrophil count <1000 cells/μL) (<1.0 x 103/μL or <1.0 GI/L). 
4. Lymphopenia (absolute lymphocyte count <200 cells/μL) (<0.20 x 103/μL or <0.20 GI/L) 
5. Pregnancy or breast feeding. 
6. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 
hours. 
7. Known allergy to any study medication. 
8. Received targeted immune-modulator treatments (such as anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab 
or sarilumab], anti-IL-17, T-cell or B-cell targeted therapies [e.g., rituximab], JAK inhibitors [including 
baricitinib], TNF inhibitors, or interferon) within 4 weeks or 5 half-lives prior to screening, whichever is 
longer. Steroid dependency, defined as need for prednisone at a dose >10 mg (or equivalent) for >1 month 
within 2 weeks of screening, is exclusionary.  
Exception 1: Dexamethasone is permitted for the treatment of COVID-19 in patients who are already 
mechanically ventilated and in patients who require supplemental oxygen at screening, but who are not 
mechanically ventilated in accordance with national guidelines.  
Exception 2: Infusion of convalescent plasma given for treatment of COVID-19 while on-study is also 
allowed.  
Exception 3: Monoclonal antibody therapy given for COVID-19 treatment at any time prior to enrollment 
is also allowed. 
9. Known or suspected history of untreated tuberculosis (TB).  TB diagnosis may be suspected based on 
medical history and concomitant therapies that would suggest TB infection. Participants are also excluded 
if they have known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per 
local guidelines (by history only, no screening required).  
10. Known or suspected serious, active bacterial, fungal, or viral infection (excepting SARS-CoV-2 and 
including, but not limited to, active HBV, HCV, or HIV with the latter defined as a CD4 count <200 or an 
unsuppressed HIV viral load), or other infection (besides COVID-19) that in the opinion of the investigator 
could constitute a risk when taking investigational product.  
Note:  Broad-spectrum empiric antibiotic usage does not exclude participation. 
11. Have received any live vaccine (or live attenuated) within 3 months before screening, or intend to receive a 
live vaccine (or live attenuated) during the study.  
Exception: Use of prior non-live (inactivated) vaccinations is allowed for all participants, including any 
vaccine for COVID-19.  
12. Severe hepatic impairment (defined as liver cirrhosis Child stage C). 
13. Known severe heart failure (New York Heart Association [NYHA] III-IV) or new-onset left-systolic or 
global cardiac dysfunction in the setting of COVID-19. 
Exception: Right-sided heart dysfunction or pulmonary hypertension thought related to COVID-19 is 
permitted.  
14. In the Investigator’s judgment, the patient has any advanced organ dysfunction that would not make 
participation appropriate. 
 


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5.3. 
Exclusion of Specific Populations 
Children and adolescents will not be included in this trial. The SoC, remdesivir, has only been used in a small 
number of pediatric patients, and does not have FDA approval for use in any patients under 12 years of age or in 
patients 12 years of age or older who weigh less than 40 kg. Initial information about the epidemiology of COVID-
19 indicates that the overwhelming burden of severe disease occurs among older adults, especially those with 
comorbidities. Given significant gaps in knowledge in this population, and a low incidence of severe morbidity/ 
mortality in children, and that none of the agents initially selected for study or likely to be selected in the future have 
had or will have demonstrated efficacy in COVID-19, this research is not known to have the prospect of direct 
benefit to individual child participants, and the risk/benefits do not warrant inclusion of this population into this trial 
at this time.  
In nonclinical reproductive toxicity studies, the SoC, 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. Information on nonclinical reproductive toxicity studies for the therapeutic agents 
selected for study is provided in the agent-specific appendices.  
In animal studies, remdesivir metabolites have been detected in the nursing pups of mothers given remdesivir. It is 
not known whether remdesivir is secreted in human milk. Because the effects of the SoC, remdesivir, on the 
breastfeeding infant is not known, and because the effects of one or more therapeutic agents selected for evaluation 
in this study may also be unknown, women who are breast feeding are not be eligible for the trial. 
5.4. 
Inclusion of Vulnerable Subjects 
Certain human subjects are categorized as vulnerable populations and require special treatment with respect to 
safeguards of their well-being. For this clinical trial, examples include cognitively impaired or mentally disabled 
persons and intubated individuals who are sedated. When it is determined that a potential research participant 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 participants using an 
IRB-approved protocol- specific process for consent using a LAR. 
 
For participants for whom a LAR gave consent, during the course of the study, if the participant regains the capacity 
to consent, informed consent must be obtained from the participant and the participant offered the ability to leave the 
study if desired. 
5.5. 
Lifestyle Considerations 
During this study, participants are asked to: 
• 
Avoid getting pregnant, breastfeeding, or impregnating their partner during the study from Day 1 through 
Day 60. 
• 
Agree not to participate in another interventional trial for the treatment of COVID-19 or SARS-CoV-2 
through Day 60, with the exception of ACTIV-4 (ACTIV-4A and ACTIV-4C). This includes interventional 
trials that evaluate treatment of SARS-CoV-2 infection as well as the disease pathogenesis (e.g., 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 SARS-CoV-2 
infection and follow-up from ACTIV-2 and COVID-19 vaccine studies is permitted; however, participation 
in both ACTIV-1 IM and other studies can only occur if the total recommended blood collection volumes 
are not exceeded.  
5.6. 
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 participant’s eligibility for the study. If there is any uncertainty, the PI 
should make the decision on whether a potential participant is eligible for study enrollment.  
 


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Only basic demographic information and the reason(s) for ineligibility will be collected on screen failures. 
Prospective participants 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. 
5.7. 
Strategies for Recruitment and Retention 
5.7.1. 
Recruitment 
It is anticipated that patients with COVID-19 will present to participating hospitals, and that no external recruitment 
efforts towards potential participants are needed. Recruitment efforts may also include dissemination of information 
about this trial to other medical professionals / hospitals.  
 
The hospitals that will constitute the ACTIV-1 IM network span the United States and South America. As the 
pandemic migrates to different locations during the coming months, we anticipate being able to effectively follow 
the migration and focus recruitment efforts at hot spots through our network hospitals in different locales. 
 
The IRB/EC will approve the recruitment process and all materials provided prior to any recruitment to prospective 
participants directly. 
 
Screening will begin with a brief discussion with study staff. Some patients 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 participants (or legally authorized representative) and questions will be asked to determine 
potential eligibility. Screening procedures can begin only after informed consent is obtained. 
5.7.2. 
Retention 
Retention of participants in this trial is very important for determining the primary endpoint of time to recovery by 
Day 29. As such, after hospital discharge, participants will be reminded of subsequent study visits and every effort 
will be made to accommodate the participant’s schedule to facilitate follow-up within the specified visit window. 
Additionally, there are many circumstances that influence the ability to obtain outcome information after discharge. 
Follow-up visits may be conducted by phone if in-person visits are not feasible.  
5.8. 
Compensation Plan for Subjects  
Compensation, if any, will be determined locally and in accordance with local IRB/EC requirements, and subject to 
local IRB/EC approval.  
5.9. 
Costs 
There is no cost to participants for the research tests, procedures/evaluations, and study product (including 
remdesivir) while taking part in this trial. Procedures and treatment for clinical care including costs associated with 
hospital stay may be billed to the participant, participant’s insurance, or third party. 
 
 
6. STUDY PRODUCT 
6.1. 
Study Product(s) and Administration  
Participants will first be randomized to one of the agents currently active in the study, and then to either the agent or 
its matching placebo. The dosing regimen and administration of each agent and matching placebo are described in 
the agent-specific appendices. 
If there are supply limitations on any product, the arms containing that product and the corresponding placebo will 
be temporarily closed to enrollment.  Currently, the trial team anticipates no difficulty in obtaining remdesivir for 


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the SoC for this study; however, if remdesivir supply should become limited for the trial, the treating physician 
should enroll the patient without remdesivir using local SoC. 
6.1.1. 
Study Product Description  
The SoC, 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 sterile, preservative-
free lyophilized formulation of remdesivir contains the following inactive ingredients: SBECD, and hydrochloric 
acid and/or sodium hydroxide. Use of remdesivir in this study is investigational. 
Descriptions of the therapeutic agents selected for evaluation in the study are provided in the agent-specific 
appendices. 
6.1.2. 
Dosing and Administration 
Participants who were enrolled with baseline eGFR <30 mL/min will not receive remdesivir. 
Participants who have not yet received remdesivir as SoC prior to enrollment 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 5 days during 
hospitalization for patients not requiring invasive mechanical ventilation and/or extracorporeal membrane 
oxygenation (ECMO).  If a patient does not demonstrate clinical improvement, treatment may be extended for up to 
5 additional days for a total treatment duration of up to 10 days.  For patients requiring invasive mechanical 
ventilation and/or ECMO, the recommended total treatment duration is 10 days.  
If a participant has been receiving remdesivir as SoC prior to enrollment, their first on-study dose will be the 100 mg 
(maintenance) dose to a maximum of 10 days total, as determined by the PI. Patients who have completed 5 days of 
remdesivir may, at the treating physician's discretion, receive no more remdesivir or continue to a total of 10 days. 
Patients who have completed 10 days of remdesivir should not receive any more doses. 
Dosing of the SoC and investigational agents should not occur at the same time.  In fact, no physical biochemical 
compatibility studies have been conducted to evaluate the co-administration of the remdesivir with other 
investigational agents.   
Any dose that is delayed may be given later that calendar day. Any dose that is missed (not given that calendar day) 
is not made up. The treatment course continues as described above even if the participant becomes SARS-CoV-2 
PCR negative.  
Dosing and duration of therapy of the therapeutic agents selected for study are described in the agent-specific 
appendices. 
6.1.3. 
Dose Escalation 
Not Applicable.  
6.1.4. 
Dose Modifications 
SoC (remdesivir): 
If the eGFR decreases to an eGFR <25 mL/min, the remdesivir infusion should not be given on that day. The 
infusion may be resumed on the next day if the eGFR returns to ≥30 mL/min. If the participant’s renal function 
worsens to the point that they require hemodialysis or hemofiltration, remdesivir will be discontinued. 
If the ALT increases to >10 times upper limits of normal, discontinue remdesivir.  If elevated ALT (>5 times upper 
limit of normal) is accompanied by signs or symptoms of liver inflammation, discontinue remdesivir without the 
option to restart. 
If any of the therapeutic agents selected for study require dose modifications based on biomarkers or safety signals, 
these adjustments are described in the agent-specific appendices. 


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6.1.5. 
Overdosage 
There is no known antidote for an overdose of remdesivir. In the case of overdose, the participant should receive 
supportive therapy based on the participant´s signs and symptoms. Availability of antidotes for study agents is 
discussed in the agent-specific appendices. 
6.1.6. 
Preparation/Handling/Storage/Accountability 
6.1.6.1. Acquisition and Accountability 
Investigational products (IP) will be shipped to the site either directly from participating companies, or from other 
regional or local drug repositories. SoC (remdesivir) will be provided to the sponsor’s designated distributor and the 
sponsor’s distributor will provide the SoC agent to the sites.  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. For IV infusion agents, drug preparation will be performed by 
the participating site’s unblinded research pharmacist on the same day of administration to the participant. For oral 
agents, the investigational agent and the placebo will be shipped to the site ready to administer.  The participating 
site’s unblinded research pharmacist will provide either the investigational agent or the placebo pill to the treating 
physician at the time of assignment to the sub-study and randomization to the appropriate arm.  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 participant 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 for any of the agents selected for study should be saved until instructed by 
sponsor. 
6.1.6.2. Formulation, Appearance, Packaging, and Labeling 
SoC (remdesivir): 
The lyophilized 100 mg single-dose vial formulation of remdesivir is a preservative-free, white to off-white to 
yellow, lyophilized powder to be reconstituted with 19 mL of sterile water for injection and immediately diluted into 
either a 100 mL or 250 mL 0.9% sodium chloride (NaCl) infusion bag prior to IV infusion. A clear solution should 
result. Following reconstitution, each vial contains a 5 mg/mL remdesivir concentrated solution with sufficient 
volume to allow withdrawal of 20 mL (100 mg of remdesivir).  


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It is supplied as a sterile product in a single-use, Type 1 clear glass vial. In addition to the active ingredient, the 
lyophilized formulation of remdesivir contains the following inactive ingredients: SBECD, hydrochloric acid, and/or 
sodium hydroxide. For more information, refer to the MOP. 
Remdesivir sourced for this study is labeled with the EUA label and will include the statement “Caution: New Drug 
Limited by Federal (USA) Law to Investigational Use.” 
Interventional Agents:  
Formulation, appearance, packaging, and labeling for each of the agents selected for study are described in the 
agent-specific appendices. 
6.1.6.3. Product Storage and Stability 
SoC (remdesivir): 
Ambient vials of the lyophilized formulation of remdesivir should be stored below 30°C (below 86°F). After 
reconstitution, use the vials immediately to prepare the diluted solution. The diluted solution in the infusion bags 
should not exceed 4 hours at room temperature (20°C to 25°C or 68°F to 77°F) prior to administration or 24 hours at 
refrigerated temperature (2°C to 8°C or 36°F to 46°F). See MOP for additional information. 
Interventional Agents:  
Product storage and stability for each of the agents selected for study are described in the agent-specific appendices. 
6.1.6.4. Preparation 
Refer to the protocol-specific MOP for details about preparation.  
SoC (remdesivir): 
Remdesivir does not meet the criteria for a hazardous compound as defined by NISOH and ASHP hazard 
classification systems. The SoC may be prepared in a clean room but do not need to be prepared or handled in a 
fume hood. 
Interventional Agents:  
Preparation of each of the agents selected for study are described in the agent-specific appendices. 
Measures that minimize drug contact with the body should always be considered during handling, preparation, and 
disposal procedures as indicated in the IB.  
 
6.2. 
Measures to Minimize Bias: Randomization and Blinding 
Randomization will be stratified by: 
• 
Geographic Region (regions will be identified in the Statistical Analysis Plan) 
• 
Severity of illness at enrollment (by ordinal scale) 
o 
Severe disease: 
 
Hospitalized, on invasive mechanical ventilation or ECMO, or  
 
Hospitalized, on non-invasive ventilation or high flow oxygen devices.  
o 
Moderate disease: 
 
Hospitalized, requiring supplemental oxygen, or  
 
Hospitalized, not requiring supplemental oxygen.  
 
Randomization will proceed in two steps, with stratification at each step. At the first step, each participant will be 
assigned with equal probability to one of the agents available at the time the patient is enrolled and for which the 
patient is eligible to receive, after applying any agent-specific safety exclusions. At the second step, each participant 
will be assigned to either the test agent or its matching placebo in an n:1 ratio, where n = the number of agents 


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currently active in the master protocol and for which the patient is eligible to receive. With SoC and three agents 
active simultaneously, and if the participant meets the criteria to receive all three agents, the allocation ratio at the 
first step will be 1:1:1 and the second step 3:1 (agent vs placebo) or overall randomization ratio of 1:1:1:1.  If 3 
agents are available, but a patient is only eligible to receive 2 of them, the allocation ratio at the first step will be 1:1, 
and at the second step will be 2:1 (agent vs placebo) or overall randomization of 1:1:1. Inclusion of a matching 
placebo for each agent enables masking of study participants and clinical personnel to treatment assignment at the 
second stage. Data from patients receiving SoC plus placebo will be pooled across agents for comparative analyses 
and hypothesis testing. Comparative analyses of a particular agent will include the subset of pooled placebo patients 
who enrolled concurrently with the new agent.  That is, patients enrolled to control arm prior to a new agent entering 
the trial will not be included in comparative analyses of that newly added investigation agent. 
Additional details of the randomization procedure will be described in the MOP.  
6.3. 
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 OR trained and qualified hospital personnel under the direction of the site 
investigator. Administration, including date and time, will be entered into the case report form (CRF). 
6.4. 
Concomitant Therapy 
6.4.1. 
Permitted Concomitant Therapy and Procedures 
Therapy prior to enrollment with any other experimental treatment or off-label use of marketed medications that are 
intended as specific treatment for COVID-19 or the SARS-CoV-2 infection (i.e., post-exposure prophylaxis [PEP]) 
are permitted (except as detailed in the inclusion/exclusion criteria) but must be discontinued on enrollment. For 
example: anti-SARS-CoV-2 monoclonal antibody allowed prior to screening but must be discontinued. Patients who 
were enrolled on ACTIV-2 and had their study treatment discontinued may enroll to ACTIV-1 IM while remaining 
in ACTIV-2 follow-up. 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.  
Participants who are taking other immunosuppressive or immunomodulatory drugs for other medical conditions 
except as noted below as prohibited medications, may continue with the treatment.  Agent specific appendices 
should be referenced for further prohibitions on concomitant therapies. 
Local standard of care per written policies or guidelines for treatment for supportive care of COVID-19 or SARS-
CoV-2 infection (i.e., not just an individual clinician decision) are permitted.  This includes the evolving SoC with 
anticoagulant therapies as well as co-enrollment to ACTIV-4 (ACTIV-4A and ACTIV-4C).  Dexamethasone is 
permitted for the treatment of COVID-19 in patients who are mechanically ventilated and in patients who require 
supplemental oxygen but who are not mechanically ventilated in accordance with national guidelines. Infusion of 
convalescent plasma is also allowed if it is standard of care at the treating site.  
Venous thromboembolism (VTE) prophylaxis is recommended for all patients unless there is a major 
contraindication such as active bleeding events or history of heparin-induced thrombosis. 
6.4.2. 
Prohibited Concomitant Therapy 
See Section 5.5 (Lifestyle Considerations) for details on allowable participation on other clinical trials. 
If there are NO written policies or guidelines for local standard of care, concomitant use of any other experimental 
treatment or off-label use of marketed medications intended as specific treatment for COVID-19 or SARS-CoV-2 
infection are prohibited. This includes medications that target the host immune response. 
Any immune-modulating therapies are prohibited. This includes, but is not limited to, TNF inhibitors, anti-
interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], anti-IL-17, T-cell or B-cell targeted therapies, JAK 
inhibitor(s) (including baricitinib), and interferon within 4 weeks or 5 half-lives prior to screening, whichever is 


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longer. Anti-SARS-CoV-2 monoclonal  antibody therapy given for COVID-19 treatment prior to enrollment is 
allowed. The use of any biologics prior to screening will be used to determine eligibility.  
Dexamethasone or other steroids are permitted for the treatment of COVID-19 in patients who are mechanically 
ventilated and in patients who require supplemental oxygen but who are not mechanically ventilated in accordance 
with national guidelines.  The use of corticosteroids outside of this indication is prohibited. 
The use of chloroquine or hydroxychloroquine for treatment of COVID-19 is prohibited. 
Other concomitant medications will be assessed only from 7 days prior to enrollment to Day 29 or upon discharge, 
whichever comes first. Report all prescription medications and vaccines (as well as over the counter, vitamins, 
herbal supplements, and/or cannabis or other specific categories of interest) taken during this time period. Record 
medications once regardless of the number of times it was given during the time period. For example, vasopressors 
or insulin should be recorded when first started (the start date) and end date if ended before Day 29 or discharge. 
Record all antipyretics and other medications given for symptomatic care, if they are administered while an 
inpatient. However, record these medications only once, even if given multiple times, as needed during hospital 
course. Do not report medications that the participant did not actually receive during study (e.g., prn medications 
that were never given).  
Medications must be recorded along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
The Sponsor’s Medical Safety Physician or equivalent representative should be contacted if there are any questions 
regarding concomitant or prior therapy. 
Due to potential interactions the additional medications may be disallowed for specific agents on the trial as detailed 
in the sub-study appendices. If there is a medical need to utilize any of the medications disallowed, then the 
Investigator should discuss appropriate steps with the Sponsor. 
6.4.3. 
Rescue Medicine 
Not Applicable. 
6.4.4. 
Non-Research Standard of Care 
Not Applicable. 
 
7. STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Halting Criteria and Discontinuation of Study Intervention 
7.1.1. 
Individual Study Product Halting  
Study product administration for any given participant may be stopped for SAEs, clinically significant adverse events, 
severe laboratory abnormalities, or any other medical conditions that indicate to the Investigator that continued dosing 
is not in the best interest of the patient. 
In addition, a participant in this clinical study may discontinue study drug at their request for any reason. Every 
effort should be made to encourage participants to remain in the study for the duration of their planned outcome 
assessments. Participants should be educated on the continued scientific importance of their data, even if they 
discontinue study drug.  
Unless the participant withdraws consent, those who discontinue study drug early will remain in the study. The reason 
for participant discontinuation of study drug should be documented in the case report form. 


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See Section 6.1.4 for information about dosing modifications of remdesivir due to laboratory abnormalities. 
7.1.2. 
Study Halting 
There will be close oversight by the protocol team and frequent DSMB reviews of the safety data. The DSMB may 
recommend halting one or more of the therapeutic agents due to safety, futility, or efficacy issues observed during 
the study, or they may recommend halting the study as a whole, if a safety issue or issue relating to the COVID-19 
pandemic that negatively impacts study continuation arises. 
A sub-study will be paused for new enrollment/study drug administration and will be reviewed by the DSMB if the 
following rule is met: 
• 
After a sub-study has enrolled at least 10% of its planned study population, the proportion of study 
participants who die within 14 days of study drug administration or first dose administration in the same 
sub-study exceeds 24% (based on the 11.9% death rate in the ACTT-1 placebo arm; Beigel et al. 2020). 
 
7.2. 
Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time upon request, without any consequence. 
Participants 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.  
Participants 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 participant withdrawal from the study 
will be recorded on the appropriate CRF. 
7.3. 
Lost to Follow-Up 
A participant 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 participant should be made and these efforts should be documented in the 
participant’s records.  
7.4. 
Readmission  
If a participant is discharged from the hospital and then readmitted prior to Day 14, they may be given the remainder 
of the study product (i.e., remdesivir for up to a total of 10 days). If the participant did not withdrawal his/her 
consent to participate in the study, there is no need to reconsent upon readmission to the study hospital. However, 
the site will need to inform them that since he/she was readmitted, study product administration will resume and 
confirm that they still agree to receive study product. If the participant is re-admitted with diminished mental 
capacity, the site should discuss continued study participation with a LAR. 
The site should not complete the Discontinuation of Treatment form since the participant came back to the study 
hospital to be readmitted. For all data collection procedures required for those readmitted, please see the MOP.  
 
8. STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Screening and Efficacy Assessments 
8.1.1. 
Screening Procedures 
Screening procedures may be done over one to two calendar days (from Day -1 to Day 1). However, in many cases 
all the screening assessments can be done in less than 24 hours. If that is the case, Day 1 pre-study product 
administration baseline assessments, specimen collection and the initial study product administration can occur on 
the same calendar day as the screening procedures.  


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After the informed consent, the following assessments are performed to determine eligibility and obtain baseline 
data: 
- 
Confirm the positive SARS-CoV-2 test result (per inclusion criteria).  
- 
Take a focused medical history, including the following information:  
• Day of onset of COVID-19 signs and symptoms. 
• History of vaccinations within 4 weeks before screening and planned vaccinations.  
• 
Exception:  COVID-19 vaccine should always be captured even if administered more than 4 
weeks before screening. Participants on COVID-19 vaccine trials are eligible for this trial if they 
develop severe COVID-19. 
• 
Exclusionary vaccine history includes: 
o 
Has received any live vaccine (or 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 participants.  
• History of chronic medical conditions including chronic oxygen requirement prior to onset of COVID-
19. See conditions included in exclusion criteria (Section 5.2) and on the Medical History (CMX) data 
collection form. 
• 
Exclusionary medical history includes: 
o 
Has diagnosis of current active tuberculosis (TB) or, if known, latent TB treated for less 
than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history 
only, no screening required). 
o 
Suspected serious, active bacterial, fungal, or viral (excepting SARS-CoV-2 and 
including, but not limited to, active HBV, HCV, or HIV with the latter defined as a CD4 
count <200 or an unsuppressed HIV viral load) infection, or other infection (besides 
COVID-19) that in the opinion of the investigator could constitute a risk when taking 
investigational product. 
• History of medication allergies. 
• Medications and therapies for this current illness taken in the 7 days prior to Day 1, and history of any 
medication listed in the exclusion criteria within the timelines described below (also see Section 1.1.6, 
and Section 5.2). 
• 
Exclusionary medication use includes: 
o 
Received targeted immune-modulating treatments (such as TNF inhibitors, anti-
interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], anti-IL-17, T-cell or B-cell 
targeted therapies (e.g., rituximab), JAK inhibitors including baricitinib, or interferon 
within 4 weeks or 5 half-lives prior to screening, whichever is longer.  
o 
Currently receiving corticosteroids at high doses (i.e., prednisone >10 mg per day or 
equivalent) for >1 month within 2 weeks of screening.  Dexamethasone is permitted for 
the treatment of COVID-19 in patients who are mechanically ventilated and in patients 
who require supplemental oxygen but who are not mechanically ventilated in accordance 
with national guidelines. 
• Ask if they are participating in another interventional trial or plan to enroll in another clinical trial in 
the next 60 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 60. 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; weight can be self-reported if not feasible to assess). 
- 
Results of recent radiographic imaging specific to chest (x-ray or CT scan). 


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- 
SpO2, including whether patient is on room air or receiving supplemental oxygen. 
- 
Blood for screening laboratory evaluations if not done as part of routine clinical care in the preceding 48 
hours prior to enrollment: 
 
CBC with differential  
• 
Evaluate if neutropenic (absolute neutrophil count <1000 cells/μL) (<1.0 x 103/μL or <1.0 GI/L) 
and/or lymphopenic (absolute lymphocyte count <200 cells/μL) (<0.20 x 103/μL or <0.20 GI/L) 
 
ALT and AST 
• 
Assess if ALT or AST >10 times the upper limit of normal.  
 
Creatinine (and calculated eGFR) 
• 
Determine if eGFR <30 mL/min or receiving hemodialysis or hemofiltration. 
• 
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 participants enrolled at the site for 
the duration of the study. 
• 
Patients with eGFR <30 mL/min may still enroll in this study (but not receive remdesivir) as long 
as their renal insufficiency has remained stable for at least 1 month without renal replacement 
therapy (and are not current candidates for renal replacement therapy). 
- 
Urine or serum pregnancy test (in women of childbearing potential). 
- 
Clinical screening laboratory evaluations will be performed locally by the site laboratory. The volume of 
venous blood to be collected is presented in Table 8-2. 
- 
A targeted physical examination will be performed at screening (Day -1 or Day 1) prior to initial study 
product administration on Day 1. No routine physical exam is needed for study visits after Day 1.  
o 
Study staff at some sites are not allowed into the participants’ 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 participants, physical exams can be performed by any licensed provider at the 
study hospital even if they are not study staff listed on the FDA form 1572. The study team can 
extract information from the hospital chart or EMR.  
 
The overall eligibility of the participant 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. 
8.1.2. 
Efficacy Assessments 
For all baseline assessments and follow-up visits, refer to the Schedule of Assessments (SOA) for procedure to be 
done, and details below for each assessment. 
Measures of clinical support, limitations and infection control 
The participant’s clinical status will be captured on each study day while hospitalized through Day 29. If a participant 
is discharged early, clinical status is collected on Day 8, Day 11, Day 15, and Day 29 if the participant returns for an 
in-person clinic visit or by phone if an in-person visit is not possible. Clinical status will also be captured on Day 22 
during a phone visit. Clinical status is largely measured by the 8-point ordinal scale and the NEWS. Unlike the NEWS, 
the ordinal scale can also be evaluated over the phone if the discharged participant is unable to return for visits on 
Days 8, 11, 15, or 29 as well as on Day 22.  
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 in-patient care preventing hospital discharge (COVID-19 related or other medical 
conditions). 
• 
Limitations of physical activity (self-assessed). 
• 
Isolated for infection control purposes. 
Ordinal Scale 
The ordinal scale is the basis for the primary and key secondary clinical outcomes in the study, namely, time to 
recovery, improvement in disease severity, and mortality.  
The scale used in this study is as follows (from worst to best): 
• 
Death; 
• 
Hospitalized, on invasive mechanical ventilation or ECMO; 
• 
Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
• 
Hospitalized, requiring supplemental oxygen; 
• 
Hospitalized, not requiring supplemental oxygen – requiring ongoing medical in-patient care (COVID-19 
related or otherwise); 
• 
Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical in-patient care; 
o 
This would include those kept in hospital for quarantine/infection control/social reasons, awaiting 
bed in rehabilitation facility or homecare, etc.  
• 
Not hospitalized, limitation on activities and/or requiring home oxygen; 
• 
Not hospitalized, no limitations on activities. 
To determine a participant’s clinical status using the ordinal scale: On Day 1, report their clinical status at 
randomization. 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 early, collect ordinal scale on follow-up Days 8, 11, 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 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 more information about the data collected 
for the ordinal scale, see the MOP. 
 
Extrapulmonary manifestations 
The presence of the extrapulmonary manifestation of disease during the course of hospitalization will be assessed and 
conditions present at any time during hospitalization will be reported at discharge.  Specifically, clinical organ failure 
defined by development of any one or more of the following clinical events (see Protocol Information Manual) for 
criteria for what constitutes each of these conditions): 
 
a. Respiratory dysfunction: 
1. Respiratory failure defined as receipt of high flow nasal oxygen, noninvasive ventilation, 
invasive mechanical ventilation or ECMO 
 
b. Cardiac and vascular dysfunction: 
1. Myocardial infarction 
2. Myocarditis or pericarditis 
3. Congestive heart failure: new onset NYHA class III or IV, or worsening to class III or IV 
4. Hypotension requiring institution of vasopressor therapy 
 
c. Renal dysfunction: 
1. New requirement for renal replacement therapy 
2. New occurrence of eGFR <30 mL/min (or, for participants admitted with baseline eGFR <30 
mL/min, an increase in serum creatinine to >1.5 times the baseline value) 
 


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d. Hepatic dysfunction: 
1. Hepatic decompensation 
 
e. Neurological dysfunction 
1. Acute delirium 
2. Cerebrovascular event (stroke, cerebrovascular accident [CVA]) 
3. Transient ischemic events (i.e., CVA symptomatology resolving <24 hrs) 
4. Encephalitis, meningitis or myelitis 
 
f. Hematological dysfunction: 
1. Disseminated intravascular coagulation 
2. New arterial or venous thromboembolic events, including pulmonary embolism and deep vein 
thrombosis 
3. Major bleeding events (>2 units of blood within 24 hours, bleeding at a critical site (intracranial, 
intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or 
retroperitoneal), or fatal bleeding). 
 
 g. Secondary infection/superinfection: 
1. New or worsening (post-randomization) intercurrent, at least probable, documented serious 
disease caused by an infection other than SARS-CoV2, requiring antimicrobial administration 
and care. 
2. A list of secondary infections/superinfections is provided in the study Manual of Operating 
Procedures (MOP). These are considered adverse events of special interest (AESI). 
  
Longer term follow-up 
Information on vital and clinical status and occurrence and duration of re-hospitalization will be captured by 
phone on Day 60. 
 
8.1.3. 
Exploratory Assessments 
Blood for serum, plasma, and whole blood (for future secondary research) 
Serum and plasma collected will be stored for future assessment of biomarkers of immune function including 
cytokines, and chemokines that may be associated with inflammation, anti-viral response, cytokine response 
syndrome (CRS) and secondary hemophagocytic lymphohistiocytosis (sHLH) during SARS-CoV-2 infection and 
genetic markers predicting disease progression and/or response to specific therapy.  The final decisions about the 
specific biomarkers will be determined later. 
An additional sample of whole blood will be collected at baseline for future genetic testing. 
• 
If the samples can be processed and stored, but not sent to the repository, the samples may be stored locally. 
• 
These samples will be collected at Clinical and Translational Science Awards (CTSA) Program sites. At all 
other US sites, this collection is optional. Samples will not be collected at non-US sites. 
• 
Samples may be collected at the time of routine phlebotomy. 
• 
See Section 8.2, Table 8-2 (Venipuncture Volumes) for the schedule of blood collections. 
 
National Early Warning Score (NEWS) 
Vital signs and other clinical assessments are collected for the calculation of the NEWS, and include temperature, 
systolic blood pressure, heart rate, respiratory rate, O2 saturation and level of consciousness. Vital signs collected 
per standard of care can be used. NEWS has demonstrated an ability to discriminate subjects at risk of poor 
outcomes. (Smith, 2016). This score is based on 7 clinical parameters (see Table 8-1). The NEWS is being used as 
an exploratory efficacy measure. The components of NEWS should be evaluated daily while hospitalized. It can be 
performed concurrently with the Ordinal Scale. This should be evaluated at a consistent time for each study day and 


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prior to administration of study product. The 7 parameters can be obtained from the hospital chart or electronic 
medical record (EMR) using the last measurement prior to the time of assessment (including parameters collected 
prior to the time of consent) and a numeric score is given for each parameter (e.g., a RR of 9 breaths per minute 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 will be used to obtain NEWS for Day 3). ECMO and mechanically ventilated 
participants should be assigned a score of 3 for RR (RR ≤8 breaths per minute) regardless of the ventilator setting. 
Participants on ECMO should get a score of 3 for heart rate since they are on cardiopulmonary bypass. 
 
Table 8-1. National Early Warning Score (NEWS) 
PHYSIOLOGICAL 
PARAMETERS 
3 
2 
1 
0 
1 
2 
3 
Respiration Rate 
(breaths per minute) 
≤8 a 
 
9 – 11 
12 – 20 
 
21 – 24 
≥25 
Oxygen Saturation 
(%) 
≤91 
92 – 93 
94 – 95 
≥96 
 
 
 
Any Supplemental 
Oxygen 
 
Yes 
 
No 
 
 
 
Temperature (oC) 
≤35.0 
 
35.1 – 36.0 36.1 – 38.0 38.1 – 39.0 
≥39.1 
 
Systolic Blood 
Pressure (mm Hg) 
≤90 
91 – 100 
101 – 110 
111 – 219 
 
 
≥220 
Heart Rate 
(beats per minute) 
≤40 b 
 
41 – 50 
51 – 90 
91 – 110 
111 – 130 
≥131 
Level of 
Consciousness 
 
 
 
A 
 
 
V, P, U 
Level of consciousness = alert (A), and non-alert and arousable only to voice (V) or pain (P), and unresponsive (U).  
a If the participant is on ECMO or invasive mechanical ventilation, they will be given a score of 3 (≤8 breaths per 
minute) for respiratory rate regardless of ventilator setting.  
b Participants on ECMO will also receive a score of 3 (≤40 beats per minute) for heart rate. 
 
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 
FDA form 1572 will be responsible for all trial-related medical decisions. 
Clinical laboratory evaluations: 
• 
Fasting is not required before collection of laboratory samples. 
• 
Blood will be collected at the time points indicated in the SOA and in Table 8-2.  
• 
Clinical safety laboratory tests will evaluate the following parameters at the following time points: 
• 
Screening:  CBC with differential (including absolute neutrophil count and absolute lymphocyte 
count), ALT, AST, ALP, total bilirubin, and creatinine (with calculated eGFR).  


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• 
Baseline: CBC with differential (including absolute neutrophil count and absolute lymphocyte 
count), ALT, AST, ALP, total bilirubin, creatinine (with calculated eGFR), glucose, PT/INR, 
troponin, d-dimer, and C-reactive protein.  Sites that do not have access to a test for PT will be 
allowed to report an international normalized ratio (INR). 
• 
Days 3, 5, 8, 11, 15, and 29:  WBC with differential, hemoglobin, platelets, ALT, AST, ALP, total 
bilirubin, creatinine (with calculated eGFR), and glucose.  
 
On Day 8 (or on day of discharge if prior to Day 8), the following additional parameters 
will be assessed:  PT/INR, troponin, d-dimer, and C-reactive protein.  Sites that do not 
have access to a test for PT will be allowed to report an international normalized ratio 
(INR). 
• 
Routine standard-of-care clinical laboratory bloodwork may be accepted for Screening if performed within 
the 48 hours prior to enrollment. 
• 
Baseline (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. 
• 
Laboratory tests performed as part of routine clinical care in the 48 hours prior to baseline visit 
will be accepted for the baseline safety laboratory tests.  
• 
Note that Day 1 PK assessments need to be drawn after 1st dose of study drug, so will need to be 
drawn separately from Baseline lab assessments. 
• 
Clinical laboratory testing will be performed at each clinical trial site in real time.  PK samples will be 
analyzed at a central facility at a future date. 
 
 
Table 8-2. Venipuncture Volumes 
 
Screen 
Baseline 
 
 
 
 
 
 
Day 
(± Window) 
−1 to 1 
1 
(± 1) 
3 
(± 1) 
5 
(± 1) 
8 
(± 1) 
11 
(± 1) 
15 
(± 2) 
29 
(+ 3) 
Safety hematology, 
chemistry and liver 
tests 1 
X 
10mL 
X 
10mL 
X 
10mL 
X 
10mL 
X 2 
10mL 
X 2 
10mL 
 X 2 
10mL 
X 2 
10mL 
Blood for Serum and 
Plasma (future and 
secondary research) 3 
 
X 3 
18mL 
X 3 
18mL 
 
X 3 
18mL 
 
X 3 
18mL 
X 3 
18mL 
Blood for Whole 
Blood (genetic 
testing) 3 
 
X 3 
8mL 
 
 
 
 
 
 
PK Assessments 4 
 
X 5 
4mL 
 
 
X 6 
4mL 
 
 
X 6 
4mL 
Total daily volume 7 
10mL 
40mL 
(14mL) 
28mL 
(10mL) 
10mL 
32mL 
(14mL) 
10mL 
28mL 
(10mL) 
32mL 
(14mL)  
Total all study days 7 
 
 
 
 
 
 
 
190 mL 
(92mL) 
PK = pharmacokinetic 
1. Routine clinical laboratory bloodwork may substitute for any post-baseline blood draws if drawn within the given 
window for the study days. At Screening and Baseline, routine clinical laboratory bloodwork may be accepted if 
performed within 48 hours prior to enrollment (Screening) or baseline visit (Baseline).  
2. Safety laboratory tests will be collected on Days 8, 11, 15, and 29 if the participant 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. 


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3. Blood collection for future secondary research, including genetic testing, is to be performed at CTSA sites; 
collection is optional at all other US sites. Ex-US sites will not collect blood for future secondary research. 
4. All efforts will be made to collect the PK samples. If the samples are not collected due to complication or 
collected outside the window, this will not be considered a deviation. See study Manual of Operating Procedures 
(MOP) and sub-study specific appendices for specific PK blood collection procedures. Participants on ECMO 
may have an additional blood draw at the given PK timepoint; please consult the MOP.  
5. Single blood draw, separate from Day 1 Baseline labs, within 24 hours post-dose (post-start of infusion or post-
ingestion of oral drug), with timing of drug administration and PK collection recorded.  In patients that received 
an infusion, sample should be collected from the arm contralateral to that used for IV infusion.  
6.  If hospital discharge occurs prior to visit, then the PK blood sample should be collected at discharge; this 
sample may be drawn at the time of routine phlebotomy. 
7. Values in parentheses indicate total volume of blood if blood for future secondary research (including genetic 
testing) is not collected.  
 
Additional PK blood collections from participants on ECMO: 
ECMO has been repeatedly shown to substantially and unpredictably alter drug disposition (Wildschut et al. 2010; 
Watt et al. 2011). For ACTIV-1 IM participants supported with ECMO, the PK sampling scheme depicted in Table 
8-2 will be augmented with a paired sample collected from the ECMO circuit. Please consult the study Manual of 
Operating Procedures (MOP). 
 
8.2.1. 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
If a physiologic parameter (e.g., vital signs, or laboratory value) is outside of the protocol-specified range, then the 
measurement may be repeated once if, in the judgment of the investigator, the abnormality is the result of an acute, 
short-term, rapidly reversible condition or was an error. A physiologic parameter may also be repeated if there is a 
technical problem with the measurement caused by malfunctioning or an inappropriate measuring device (i.e., 
inappropriate-sized BP cuff). 
8.2.2. 
Unscheduled Visits 
If clinical considerations require the participant to be contacted or seen prior to the next schedule assessment to 
assure the participant’s well-being, it is permissible in this protocol. However, no research data is collected at this 
visit.  
 
8.3. 
Adverse Events and Serious Adverse Events 
8.3.1. 
Definition of Adverse Event (AE) 
AE means any untoward medical occurrence associated with the use of an intervention in humans, whether or not 
considered intervention related. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of medicinal (investigational) 
product. If multiple abnormalities are part of the same clinical syndrome, they can be reported together as one AE 
under a unifying clinical diagnosis.  
Any medical condition that is present at the time that the participant 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, participants will have many symptoms and abnormalities in 
vital signs and laboratory values. All Grade 3 and 4 AEs will be reported in this trial. In addition, the following AEs 
will be reported: 


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• 
Any Grade 2 suspected drug-related hypersensitivity reactions associated with study product administration 
will be reported as an AE. 
• 
Any newly diagnosed infection (other than COVID-19) at any time during the study.  
• 
Any AEs leading to dose modification  
• 
Any AEs leading to discontinuation from the study. 
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.  
Serious or acute syndromes that arise during the course of the study should be treated and referred as necessary 
according to the standard of care prevailing at the local treatment site. 
 
8.3.2. 
Definition of Serious Adverse Event (SAE) 
An AE or suspected adverse reaction is considered serious (i.e., is an SAE) if, in the view of either the investigator 
or the Sponsor, it results in any of the following outcomes: 
• 
Death; 
• 
A life-threatening AE; 
• 
Inpatient hospitalization or prolongation of existing hospitalization; 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions; or 
• 
A congenital anomaly/birth defect. 
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 participant 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 participant. 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. 
SAEs will only be reported to the designated pharmacovigilance group (see Section 8.3.6 for reporting procedure) if 
they are considered related to the study product (serious adverse reaction [SAR]). 
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 the IND sponsor and will be sent to the DSMB (for periodic review), 
and the IRB/IEC.  All newly-diagnosed secondary infections/superinfections are regarded as adverse events of 
special interest (AESI) and will be reported to the DSMB. 
8.3.3. 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A SUSAR is any SAE where a causal relationship with the study product is at least reasonably possible but is not 
listed in the Investigator Brochure (IB), Package Insert, and/or Summary of Product Characteristics. 


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8.3.4. 
Classification of an Adverse Event 
The determination of seriousness, severity, and causality will be made by an on-site investigator who is qualified 
(licensed) to diagnose AE information, provide a medical evaluation of AEs, and classify AEs based upon medical 
judgment. This includes but is not limited to physicians, physician assistants, and nurse practitioners. 
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 participant. 
• 
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. 
 
8.3.5. 
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 informed consent is signed through 
the Day 60 ± 5-day telehealth visit will be documented, recorded, and reported. In addition, patients will be 
contacted at the end of the safety follow-up period required for each study agent (see appendices for details) to 
assess AEs and SAEs occurring after drug withdrawal. 
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. 
New secondary infections/superinfections will be recorded on the appropriate CRF.  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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8.3.6. 
Serious Adverse Event Reporting 
Investigator Reporting of SAEs 
Any AE that meets a protocol-defined criterion as a treatment related SAE (SAR) must be submitted within 24 hours 
of site awareness via an SAE form to the Technical Resources, International (TRI) Pharmacovigilance Group, at the 
following address:  TRISafetyOffice@tech-res.com. 
Other supporting documentation of the event may be requested by the TRI Pharmacovigilance Group and should be 
provided as soon as possible. The TRI Medical Monitor will review and assess the SAE for regulatory reporting and 
potential impact on study participant 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 participant’s participation in the study, the site PI or appropriate sub-investigator will report 
the event to the TRI Pharmacovigilance Group. 
Regulatory Reporting of SAEs 
Any event that requires expedited reporting to Regulatory Authorities (i.e, Serious Unexpected Suspected Adverse 
Reactions [SUSARs]) based on applicable national regulations will be forwarded to the IND sponsor in time to meet 
reporting requirements (e.g. 7 days for fatal and life-threatening initial reports, with follow up reports within another 
8 days, 15 days for all other SUSARs). The IND sponsor or its in-country representative as detailed in the Transfer 
of Regulatory Obligations (TORO) will submit safety reports (e.g. IND safety reports) to the regulatory agencies as 
necessary, and will inform the investigators of such regulatory reports. Site investigators must submit safety reports 
as required by their Institutional Review Board (IRB)/Ethics Committee (EC). Documentation of the submission and 
receipt by the IRB/REB must be retained for each expedited safety report. 
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/EC and/or national regulatory authority).  
8.3.7. 
Reporting of Pregnancy 
Pregnancy is not an AE. However, any pregnancy that occurs in a study subject during study participation should be 
reported to the Sponsor on the appropriate CRF.  Pregnancies should also be reported to the IRB/EC.  The Sponsor 
will report pregnancies to the DSMB.  Pregnancy should be followed to outcome.   
Pregnancy should also be reported in a partner of a male participant, though information may not be collected from 
the pregnant partner. 
 
8.4. 
Unanticipated Problems 
8.4.1. 
Definition of Unanticipated Problems 
An Unanticipated Problem (UP) is any event, incident, experience, or outcome that meets the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are described 
in the protocol-related documents, such as the IRB-approved research protocol and informed consent 
document; and (b) the characteristics of the subject population being studied; 
 
Related to participation in the research (meaning there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures involved in the research); and 
 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
8.4.2. 
Unanticipated Problem Reporting 
To satisfy the requirement for prompt reporting, all UPs will be reported using the following timeline: 


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 
UPs that are SAEs will be reported to the IRB/EC 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 
described SAE reporting process. 
 
Any other UP will be reported to the IRB/EC and to the SDCC/study Sponsor within 3 days of the 
investigator becoming aware of the problem. 
 
9. STATISTICAL CONSIDERATIONS 
The ACTIV-1 IM master protocol utilizes an adaptive platform trial design that allows for four types of adaptations: 
(1) early stopping of agents for futility, to allow more speedy accrual to other agents remaining in the trial; (2) early 
stopping for strong evidence of efficacy of a particular agent; (3) substitution of one of the test agents as standard of 
care for the remainder of the trial, should early evidence of superiority over SoC support such a change, and (4) 
addition of newly emergent agents, if they become available after study start. A brief summary is provided here. 
Details will be described in the statistical analysis plan (SAP).  
The total sample size for ACTIV-1 IM is based on the Kaplan-Meier estimate of the probability of recovery from 
ACTT-1. Preliminary data indicate this estimate is approximately 73% based on over 1,000 patients enrolled. 
Sample size requirements are based on the number of agents being evaluated and the ability to pool control patients 
for analysis. Initial sample size estimates are derived assuming three agents are ready for testing at study start and 
will remain in the study for evaluation at the final analysis stage. If newly emergent therapies are entered into the 
master protocol after study start, sample size requirements will be adjusted accordingly.  
The statistical analysis strategy calls for sharing of control participants across all agents available for study when 
enrollment begins. For agents added to the trial after study start, comparative analyses will be limited to those 
control patients enrolled concurrently with the new agent. That is, control participants enrolled prior to an agent 
entering the trial will not be included in comparative analyses of that agent. This approach was used in the recent 
PALM study in patients with Ebola virus disease (Mulangu et al. 2019). Although sharing of non-concurrently 
randomized control patients has been used successfully in studies of chronic diseases (DIAN-TU; 
https://clinicaltrials.gov/ct2/show/NCT01760005), it is not recommended here due to the evolving nature of the 
COVID-19 infection and treatment thereof. Exploratory analyses of the similarity between control participants 
enrolled early and late in the study, however, may be useful in informing the design of future master protocols in 
COVID-19.  
If early evidence of superiority of any one of the test agents relative to SoC (plus placebo) is observed during this 
trial, consideration will be given to replacing the SoC with the test agent for the remainder of the trial. Such a 
change is dependent on the safety of combining the remaining test agents with this new SoC and will complicate the 
final data analyses somewhat. Comparative analyses will need to account for this change in SoC through 
stratification or other model-based methods. Details will be provided in the statistical analysis plan. 
Preliminary reports of the completed RECOVERY Trial show that dexamethasone may reduce mortality in some 
hospitalized patients with COVID-19 (RECOVERY Collaborative Group, 2020).  If dexamethasone or steroid, or 
other agents, become part of standard of care (SoC) or are used in a substantial number of patients, the observed 
potential benefit of immunomodulators may be altered.  Nonetheless, ACTIV-1 IM is designed with high power to 
detect even a modest benefit of 25% for the primary outcome; attempting to detect smaller effects would cause a 
prohibitively large increase in sample size. Addition of dexamethasone or other agents to SoC may also affect the 
key secondary endpoint of mortality and alter the proportions of people in different cells of another key secondary 
endpoint, the 8-point ordinal scale. Accordingly, a blinded sample size re-estimation may be conducted at the 2nd 
interim analysis, after approximately one-half of the total number of expected recoveries has occurred. The purpose 
is to use the overall proportions of people in the different categories of the key secondary endpoint of the ordinal 
scale to recalculate power for that endpoint. If power for this key secondary endpoint is below 70%, the sample size 


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might be increased, but by at most 25%. The sample size would not be reduced based on this potential re-estimation. 
More details will be provided in the SAP. 
9.1. 
Statistical Hypotheses 
The primary null hypothesis being tested is that time-to-recovery does not differ between each test agent and the 
pooled control group, consisting of patients receiving SoC plus placebo. The alternative hypothesis is that the test 
agent and pooled control group differ in time-to-recovery. If Drug A, B, and C denote the initial set of agents to be 
tested in ACTIV-1 IM, and S denotes patients receiving SoC plus placebo, then the primary hypotheses are: 
H01: TRA = TRS vs  HA1: TRA ≠ TRS 
H02: TRB = TRS vs  HA2: TRB ≠ TRS 
H03: TRC = TRS vs  HA3: TRC ≠ TRS 
There are two key secondary endpoints that will be evaluated as supportive evidence: 
1. The distribution of the 8-point ordinal scale at Day 14 and Day 28 (assessed on Days 15 and 29 for the 
previous day). For this, the parameter of interest is the “common odds ratio,” which quantifies the shift in 
the severity distribution resulting from treatment. For an efficacious treatment, an odds ratio greater than 1 
quantifies an improvement in disease severity; a value of 2 indicates a bigger improvement than a value of 
1.25. The null hypothesis to be tested is that the odds of improvement on the ordinal scale is the same for 
the placebo and experimental treatment arms (i.e., the common odds ratio is 1). It is worth noting that, for 
large sample sizes, the test based on the proportional odds model is nearly the same as the Wilcoxon rank 
sum test. 
2. Mortality will be evaluated with standard survival analysis techniques. Kaplan Meier curves and 
associated log-rank statistics will be generated to compare mortality between each test agent and SoC. 
Mortality (14-day and 28-day)  will also be evaluated at Days 15 and 29. 
9.2. 
Sample Size Determination 
Primary endpoint: The Fine-Gray approach will be used to compare each test agent with SoC with respect to the 
cumulative incidence of recovery, accounting for the competing risk of mortality (Fine and Gray, 1999). The 
approach is similar to using a log-rank test on time to recovery, retaining in the risk set people who die.  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, RRR. Without accounting for futility monitoring, 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(𝑅𝑅𝑅𝑅𝑅𝑅)}2 , 
 
where 𝑧𝑧𝛽𝛽 is the 100(1 −𝛽𝛽)th percentile of the standard normal distribution.  The number of events must be 
increased to account for futility monitoring.  For 85% power, the 1.96 + 𝑧𝑧𝛽𝛽 in the above equation is replaced by 
3.1312. 
Table 9-1 provides the numbers of recoveries and of patients required to provide 85% power for a single pairwise 
comparison of test drug versus control assuming a 73% recovery rate and various recovery rate ratios (RRRs). Note 
that the rate of recovery is the analogue of the hazard for each test agent or control treatment, and the RRR is the 
analogue of the hazard ratio for a test agent relative to control in this setting. As can be seen from the table, 
approximately 347 recoveries are required to detect a 40% increase in the rate of recovery (𝜃𝜃= 1.40) from control. 
An RRR of 1.40 is similar to, but slightly higher than the figure of 1.31 reported in Cao et al. (2020) for a 
lopinavir/ritonavir trial that used time to improvement by 2 categories as primary endpoint. A total of 436 recoveries 
is needed for an RRR of 1.35 with 85% power. Sample size requirements for ACTT-1 assumed an RRR of 1.35, but 


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the study was over-enrolled (1,063 patients were enrolled, compared to N=572 needed) due to more rapid than 
anticipated accrual. Preliminary results from ACTT-1 show an RRR of 1.32 ([CI = [1.12,1.55]) for remdesivir vs 
placebo.  
Table 9-1. Number of recoveries and number of patients 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 
Sample Size assuming 
73% recovery rate (1 test 
agent vs SoC) 
1.25 
788 
1,080 
1.30 
570 
781 
1.35 
436 
598 
1.40 
347 
476 
 
The objective of ACTIV-1 IM is to provide evidence of efficacy and safety of selected agents that would support 
regulatory approval of their use in treating moderately to severely ill hospitalized Covid-19 patients. It was decided 
that a modest effect as low as a 25% improvement in recovery rate attributable to any one of the test agents in the 
study would be of interest to detect. Consequently, the sample size requirements are based on the ability to detect an 
RRR of 1.25 for each agent relative to SoC. 
A total of 788 recoveries is required for each comparison to provide approximately 85% power to detect a recovery 
rate ratio of 1.25 for the therapeutic agent relative to control, accounting for the interim analyses. Assuming 73% of 
participants achieve recovery in 28 days, consistent with the ACTT-1 results, the total sample size to compare 1, 2, 
or 3 agents to control in ACTIV-1 IM is approximately 1,080, 1,620, and 2,160, respectively. Because each agent is 
being compared to SoC with no between-agent comparisons currently planned, no multiplicity adjustments will be 
made, provided the number of agents assessed in ACTIV-1 IM is three or fewer. If more than three agents are 
evaluated, a minor multiplicity adjustment will be considered to aid in interpreting the results of the study. 
Key secondary endpoints: A sample size can be computed using an (assumed) ordinal scale distribution for the 
control and the odds ratio representing clinical improvement. The odds ratio represents the odds of improvement in 
the ordinal scale for treatment relative to control [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.  
A sample size of 1,080 for an (active, control) pair gives approximately 95% or 85% power to detect an odds ratio of 
1.50 (the observed odds ratio in the ACTT-1 trial) or 1.40 using a 2-tailed test at level α = 0.05. 
The 28-day mortality probability in the remdesivir arm of ACTT-1 was approximately 12%.  Power for comparing 
28-day mortality is 90% only for a 50% relative reduction (from 12% to 6%). 
9.3. 
Populations for Analyses 
The primary analysis will be based on an intention-to-treat population, including all participants randomized. 
Similarly, safety analyses will be based on a modified intention-to-treat population consisting of all participants who 
received at least one dose or injection of each drug administered in the randomization arm (e.g., test agent plus 
SoC). The primary analysis will be based on those participants enrolled in order to achieve 788 recoveries for each 
pairwise comparison as noted in section 9.1. Subsequent analysis will be performed on all enrolled participants.  


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9.4. 
Statistical Analyses 
9.4.1. 
General Approach 
This is a randomized, controlled, double-blinded trial testing a superiority hypothesis with respect to each 
therapeutic agent plus SoC versus SoC plus placebo with a two-sided Type I error probability of 5% for each agent. 
This is a randomized, controlled, double-blinded trial testing a superiority hypothesis with respect to each 
therapeutic agent plus SoC versus SoC plus placebo with a two-sided Type I error probability of 5% for each agent. 
Secondary hypotheses have been ordered according to relative importance, with key secondary hypotheses identified 
(corresponding to the odds ratio based on the 8-point clinical severity scale, and time to death). These will be 
described according to the appropriate summary statistics (e.g., proportions for categorical data, median for time-to-
event data).  
A statistical analysis plan will be developed and filed with the FDA prior to the first unblinded interim analysis.  
Unblinding of study data for final analysis will occur for each test agent independently of other agents, consistent 
with the master protocol design. That is, once the planned number of recoveries required for a particular agent’s 
comparative analysis are observed, study close-out procedures for that agent are applied for all study visits and data 
elements associated with the participants receiving the test agent as well as participants receiving SoC plus placebo 
during the randomization period for that agent (i.e., concurrently controlled participants). The study visits are 
monitored, data edits are completed, queries are resolved, database is locked, and treatment assignments are 
unmasked for that comparative analysis only. Note that, because control participant data are shared across agents, 
procedures for unmasking data for one agent’s final analysis will be established to protect the ability to continue the 
ongoing study in a double-blinded manner for the remaining agents. It may be that recovery rates are similar enough 
across all agents in the study to enable a single study close-out with standard procedures. Any necessary 
modifications or updates to the statistical analysis should be made prior to the study unblinding.  
9.4.2. 
Analysis of the Primary Efficacy Endpoint 
The primary efficacy analysis for the comparison of each test agent plus SoC versus SoC plus placebo is a stratified 
test based on the Fine-Gray proportional hazards approach, where stratification is according to region and baseline 
disease severity (i.e. protocol defined mild/moderate vs severe disease). The method provides an estimate of the 
cumulative incidence of recovery while accounting for the competing risk of death.  The hazard ratio can also be 
computed.  With no censoring, the hazard rate in each arm can be thought of as the hazard for recovery, treating 
deaths as never having recovered (see section 2 of Fine and Gray, 1999).  Every attempt will be made to complete 
final clinic visits for patients dropping out of the study prematurely. For those unable to complete the final visit, data 
collection will be attempted via telephone interview. At a minimum, vital status will be obtained. 
9.4.3. 
Analysis of the Secondary Endpoint(s) 
1) 
The ordinal scale will be used to estimate a proportional odds model by disease strata. We 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, participants 
without final outcome data will be excluded from the analysis. Sensitivity analyses will evaluate the impact 
of making different assumptions about missing observations. These analyses will be defined in the SAP.  
2) 
When death is not a competing risk (for example, the endpoint includes death in the composite), differences 
in time-to-event endpoints by treatment will be summarized with Kaplan-Meier curves and 95% confidence 
bounds.  When death is a competing risk (for example, time to at least a one-category improvement in 
ordinal scale, and time to at least a two-category improvement), the same competing risk approach will be 
used as for the primary analysis. 
3) 
Change in ordinal scale at specific time points will be summarized by proportions (e.g., proportion who 
have a 1-, 2-, 3-, or 4-point improvement or 1-, 2-, 3-, 4-point worsening).  
4) 
Differences in total severity score (TSS) over time will assessed by fitting a longitudinal mixed model to 
the 8-point clinical scale value on each day of assessment (in hospital plus Days 15, 22, 29). The average 


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difference across days in study (analogous to the area under the severity curve) will be estimated with 95% 
confidence limits in the context of the longitudinal model. 
5) 
Duration of event (e.g., duration of mechanical ventilation) will be summarized according to median days 
with quartiles. 
6) 
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. 
7) 
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 statistical analysis plan. 
9.4.4. 
Safety Analyses 
Safety endpoints include death through Day 28 (as assessed at 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 participant 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.  
9.4.5. 
Baseline Descriptive Statistics 
Baseline characteristics will be summarized by test agent versus control for each agent. For continuous measures the 
mean and standard deviation will be summarized. Categorical variables will be described by the proportion in each 
category (with the corresponding sample size numbers).  
9.4.6. 
Planned Early and Interim Analyses  
Data analyses will be conducted to monitor enrollment and follow-up rates and to summarize baseline characteristics 
throughout the course of the study. These early analyses will be conducted by the study team masked to treatment 
assignment. Summaries will be generated for each test agent separately. For agents entering the study at staggered 
times, data summaries (pooling test agent and control data in blinded fashion) will incorporate data from 
concurrently randomized control participants only. 
Unblinded interim analyses are planned to (i) assess the futility of each agent, with the goal of discontinuing those 
with lower probabilities of success to more effectively utilize trial resources for the remaining agents and (iii) review 
comparative analyses for each test agent to assess early stopping for efficacy. Alpha spending functions will be used 
to appropriately control the probability of making an erroneous conclusion across interim and final analyses at α = 
0.05 (two-sided) for each agent. 
A Data and Safety Monitoring Board (DSMB) will monitor ongoing results to ensure participant well-being and 
safety as well as study integrity. The DSMB will be asked to recommend early termination due to futility and early 
stopping for efficacy, only when stopping rules and conditions are clearly met. More details about the interim 
analyses are described in section 9.4.6.1 and 9.4.6.2 below as well as a separate guidance document for the DSMB.  
Interim Safety Analyses 
Safety analyses will evaluate Grade 3 and 4 AE and SAEs by treatment arm. Safety monitoring will be ongoing. The 
unblinded statistical team will prepare these reports for review by the DSMB.  
Interim Analyses for Futility and Efficacy Review 
Interim analyses for futility and efficacy are planned at three times during the study corresponding to the availability 
of approximately 25%, 50%, and 75% of total information. The planned randomization algorithm described above 


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(Section 6.2) ensures equal allocation to each test agent or control (e.g., 1:1:1:1 for 3 test agents and control). It is 
anticipated that the interim analyses for each agent will occur at the same time, and the DSMB will make 
recommendations for all agents at their scheduled meetings. If recovery rates vary substantially by agent, however, it 
may be necessary to let the interim analysis times also vary by agent. Because Type I error probabilities are 
controlled for each, independently of the other agents, the need for additional DSMB reviews due to differential 
information accrual across agents should not pose any issues other than logistical ones. 
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. This spending function is conservative in that priority is given to preserving 
power for the final analysis with the use of stringent stopping rules early in the study. 
In contrast, moderately aggressive stopping rules for futility will be implemented to promote early discontinuation 
of agents with low probabilities for success. The futility stopping rules will be considered non-binding by the DSMB 
in their review of interim data. The futility boundaries are computed based on the gamma family of spending 
functions α{1-exp(-γt)}/{1-exp(-γ)} (Hwang et al. 1990). Figure 1 below illustrates the efficacy stopping boundaries 
based on the Lan-DeMets spending function (in blue shading) and the futility boundaries based on a Gamma (-2) 
spending function (in pink shading).  
Figure 1: Stopping Boundaries for Efficacy (blue shading) and Futility (pink shading). 
 
As can be seen from the figure, an RRR showing no more than a small amount of improvement in recovery time 
(RRR ≤ 1.04) will result in early discontinuation of the agent mid-way through information accrual in the study. 
When the null hypothesis is true (RRR = 1), the probability of discontinuing an agent at this point is 66%, but under 
the alternative, this probability is 4%. In simulations, the average number of recoveries under these efficacy and 
futility boundaries is 587, and the maximum sample size is approximately 1,080 participants. 
The unblinded statistical team will prepare closed reports for each DSMB review meeting. 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. Unblinding codes will be provided to DSMB members who wish to be unblinded.  A DSMB 
charter will further describe procedures and membership. An additional document on statistical issues related to 
monitoring will be provided to the DSMB prior to the first interim analysis.  
9.4.7. 
Sub-Group Analyses 
Subgroup analyses for the primary outcomes will evaluate treatment effects across the following subgroups: 
geographic region, duration of symptoms prior to enrollment, baseline disease severity (stratification variable of 
mild/moderate and severe, as well as ordinal scale of 4/5 vs 6/7) age, race, sex and comorbidities. A forest plot will 


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display confidence intervals across subgroups. Interaction tests will be conducted to determine whether the effect of 
treatment varies by subgroup. These subgroup analyses will be carried out separately for each test agent. 
9.4.8. 
Exploratory Analyses 
An exploratory analysis will compare treatment efficacy estimates for each agent 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. Exploratory analyses will also compare the difference between each test agent plus SoC and SoC 
plus placebo in TSS at each study day for which the clinical scale is administered (in-hospital and at Days 15, 22, 
and 29). 
 
 
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 1 – SUB-STUDY 1 – INFLIXIMAB (REMICADE) 
1. SUB-STUDY SUMMARY 
1.1. 
Sub-study overview 
The sub-study population corresponds to moderately and severely ill patients infected with the COVID-19 virus. 
Recruitment will target patients already hospitalized for treatment of COVID-19 infection as well as patients being 
treated for COVID-19 infection in Emergency Departments while waiting to be admitted to the hospital. Patients 
both in and out of the ICU are included in the study population. 
Enrollment will begin as soon as all elements are met for the sub-study to activate. 
The study period is 29 days, with assessments on each day of the hospital stay. Patients will be followed after 
hospital discharge with periodic follow-up assessments through Day 29 and at Day 60.  
1.2. 
Enrollment Period  
Enrollment began in October 2020. It is anticipated that enrollment will be completed in 4-6 months. 
1.3. 
General 
This sub-study is designed to evaluate Remicade for the treatment of moderately or severely ill hospitalized patients 
infected with COVID-19. This sub-study will have the same assessments and procedures as the main protocol. 
The effectiveness of Remicade as add-on therapy to SoC will be evaluated based on the primary endpoint of time to 
recovery after 28 days. The sample size requirements are based on the ability to detect a moderate improvement in 
time to recovery (3-4 fewer days). 
1.4. 
Study Population 
Hospitalized adults (≥18 years old) with COVID-19, including patients both in and out of the ICU. Patients seeking 
care for COVID-19 in an Emergency Department (ED) and waiting to be admitted to the hospital are included. 
1.5. 
Inclusion Criteria 
Inclusion criteria are outlined in the main body of the ACTIV-1 IM protocol. 
1.6. 
Agent Specific Exclusion Criteria at Randomization 
1. Allergy to other monoclonal antibodies, or to any murine proteins.  
2. History of HSTL or other lymphoma within 5 years before screening; history of or current diagnosis of 
multiple sclerosis (MS) or other significant demyelinating condition (e.g., optic neuritis).   
1.7. 
Study Intervention 
Therapeutic agents will be evaluated as an add-on therapy to SoC.  The study intervention is as outlined in the main 
body of the ACTIV-1 IM protocol. 
For the Remicade component, participants will receive active product as follows: 
• 
Remicade will be administered as a single dose of 5 mg/kg (IV) on Day 1 in addition to SoC.  The 
administration window will be within 24 hours of randomization.  Infusion of Remicade and remdesivir 
should not be given concurrently in order not to confound attribution of possible infusion reactions or 
hypersensitivity events. 
 
Duration of therapy: 
• 
Remicade IV component – single dose on Day 1. 


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1.8. 
Schedule of Assessments 
Assessments will be performed according to Table 1-1 in 1.1.8 in the main body of the ACTIV-1 IM master 
protocol. 
In addition, TB and HBV testing should be performed on Day 1 to rule out latent TB and/or HBV infection. Results 
do not need to be available for the participant to initiate treatment with study medication on Day 1. Once results are 
communicated, if the participant tests positive for TB or HBV, consultation with an infectious disease specialist and 
treatment for latent TB or hepatitis B should be considered. 
 
2. JUSTIFICATION FOR SELECTION 
Respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality associated with 
COVID-19 infection (Ruan et al. 2020). 
Learnings from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), initial COVID-19 data (Conti, 
Ronconi et al. 2020; Prompetchara et al. 2020) and preclinical mouse model data indicate that many cytokines 
including tumor necrosis factor α (TNFα), interleukin (IL)-1, and IL-6, may be key drivers of the acute lung injury 
(ALI) and ARDS observed in COVID-19. Severe COVID-19 patients from an initial study in China had elevated 
levels of TNFα. (Huang, Wang et al. 2020) SARS-CoV, a virus closely related to SARS-CoV-2, has been directly 
implicated in stimulating TNFα generation. The virus' spike protein has been shown to interact with angiotensin-
converting enzyme 2 (ACE2) with consequent activation of TNFα converting enzyme (TACE), in a process that 
facilitates both viral entry into host cells and TNFα production (Haga et al. 2008). 
Excess TNFα has been associated with multiple inflammatory diseases and may be an initiating or contributing factor 
to disease pathology and progression (Braun and Sieper 2003). TNFα has been reported to be an amplifier of 
inflammation, and suppressing it has the potential to suppress multiple downstream cytokines such as IL-1 and IL-6, 
as well as decrease capillary leak, and leukocyte trafficking as has been shown in rheumatoid arthritis (RA) patients 
(Feldmann et al. 2020). 
Remicade binds to both soluble and transmembrane forms of TNFα and inhibits its functional activity. TNF antagonist 
therapy does not appear to be a risk factor for severe COVID-19 (Brenner et al. 2020). 
No efficacy data are available on the use of Remicade to treat COVID-19 induced ARDS. Remicade has been approved 
across the globe for the treatment of Crohn’s disease (adult and pediatric), RA, UC (adult and pediatric), psoriasis, 
PsA, and AS, although not all indications have been approved in all countries. Remicade has also been approved in 
Japan for use in some orphan indications including variants of psoriasis (psoriatic erythroderma and pustular 
psoriasis), Behçet’s disease (entero-, neuro-, vasculo-, and uveitis), and acute Kawasaki disease. 
Safety data from clinical studies are available from 6,122 Remicade-treated subjects including 2,363 with RA, 1,427 
with Crohn’s disease, 275 with AS, 191 with PsA, 1,373 with plaque psoriasis, and 493 with UC. Infusion-related 
reactions (e.g., dyspnea, flushing, headache and rash) were among the most common causes for discontinuation, except 
in UC, pediatric Crohn’s disease, and PsA. Remicade has been mainly studied in chronic use, and approximately 3 
million patients have been exposed to Remicade since its launch in August 1998.  
 


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3. INTRODUCTION 
3.1. 
Risk/Benefit Assessment 
3.1.1. 
Remicade 
3.1.1.1. Potential Risks of Remicade 
Risks that have been observed in patients with chronic use of Remicade but may also have relevance for single dose 
administration are the occurrence of serious infusion reactions, hypersensitivity, serious infections, liver enzymes 
increase, leukopenia or pancytopenia, and worsening of heart failure in those with NYHA Functional Class III/IV 
heart failure. Although there is a theoretical risk of cancer with the use of Remicade, this is felt to be of less concern 
with single dose administration. Of these, the most significant risks relate to the complications associated with 
immunosuppression, essentially mycobacterial, fungal, and viral infections. 
The following risk mitigations are in place: 
The inclusion/exclusion criteria prevent patients with pre-existing comorbidities (including non-COVID-19-related 
active infections, steroid dependency, being on renal replacement therapy, severe hepatic inflammation, history of 
HSTL or other lymphoma within 5 years before screening, current NYHA Functional Class III/IV heart failure) from 
participating.  
Remicade administered at a dose of 10 mg/kg at 0, 2 and 6 weeks post randomization has been associated with 
increased combined risk of death from any cause or hospitalization for heart failure (hazard ratio 2.84, 95% confidence 
interval 1.01 to 7.97; nominal p=0.043) in the ATTACH Trial, a randomized study evaluating the use of Remicade in 
participants with NYHA Functional Class III/IV heart failure. Remicade at a dose of 5 mg/kg did not increase risk of 
mortality or worsening of heart failure compared to placebo (Chung et al. 2003). 
Remicade may have a risk of reactivation of latent TB and chronic hepatitis B. Therefore, participants will be screened 
for both TB and hepatitis B. Results of these tests do not need to be available for the participant to initiate study 
medication. If the participant tests positive for TB or hepatitis B, consultation with an infectious disease specialist and 
treatment for latent TB or hepatitis B should be considered. 
To further protect the participants from the immunomodulatory effects of Remicade that may predispose them to 
infections, the investigators are referred to the local guidelines for the concomitant use of antibacterial and/or antiviral 
agents that are intended for management of community acquired pneumonia or secondary bacterial infections, and to 
inhibit SARS CoV-2 viral activity.  
3.1.1.2. Potential Benefits of Remicade 
The potential benefit of Remicade is to fulfill an urgent medical need for patients by shortening the period of 
hospitalization. 
3.1.1.3. Assessment of Potential Risks and Benefits of Remicade 
The potential benefits of treatment with Remicade are considered to outweigh any associated risks of treatment. This 
is based upon the following: 
The proposed target patient population consists of individuals who have hypoxemia and who are at risk of ARDS. 
These are the patients with the most urgent medical need who are at the greatest risk of dying. The current mortality 
due to COVID-19-associated pulmonary complications for hospitalized patients with hypoxemia and pulmonary 
involvement ranges from approximately 20-50% depending upon the age of the individual and pre-existing 
comorbidities.  
Access of patients to investigational therapeutics to mitigate the disease is limited in this pandemic setting, and this 
study will offer the potential to access a therapeutic in the context of a clinical study. 


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Remicade has been approved for more than 20 years and has accrued safety data from estimated marketing exposure of 
over 3 million patients encompassing over 7 million patient years of exposure. Remicade is contraindicated for CHF at 
a dose higher than 5 mg/kg. 
By excluding those with elevated liver transaminases, class 3 or 4 congestive heart failure or with concomitant 
infections, and with appropriate monitoring during the study as well as inclusion of an Independent Data Monitoring 
Committee (IDMC), risk to participants can be minimized. While there may not be benefits for an individual 
participant, there may be benefits to society if a safe, efficacious therapeutic agent can be identified during this global 
COVID-19 pandemic. The potential risks therefore are thought to be acceptable given the potential benefits. 
 
4. 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.  All the endpoints for the 
overall trial are defined in the body of the main ACTIV-1 IM protocol. 
 
5. SUB-STUDY DESIGN 
5.1. 
Justification for Dose 
5.1.1. 
Justification for Dose of Remicade 
Based on the findings reported, blood TNFα levels are significantly elevated in severe and critical COVID-19 
patients (Chen et al. 2020; Wu et al. 2020). In one study, blood TNFα levels were found to correlate with disease 
severity with a substantial proportion of severe and critical COVID 19 patients having TNFα levels exceeding 11 
pg/mL (Komatsu et al. 2001). Of note, median serum TNFα levels in patients with active inflammatory bowel 
disease (IBD; UC and CD) ranged between 9.5 to 14.0 pg/mL (Komatsu et al. 2001). Recent emerging data has 
suggested that levels of TNFα may reach roughly 100 pg/mL in critically ill COVID-19 patients (Huang et al. 2020). 
At these higher levels of TNFα, the Remicade 5 mg/kg dose provides substantial molar excess. Remicade exposure 
after a single dose of 5 mg/kg IV is predicted to yield roughly 100,000-fold molar excess at Tmax and 20,000 fold at 
14 days post-dose to plasma TNFα, assuming a ~100 pg/mL concentration of TNFα.Therefore, the Remicade dose 
proposed to be evaluated in severe or critical COVID-19 patients is 5 mg/kg administered as a single IV infusion. 
In the approved labeling, with the exception of patients with RA who start with a dose of 3 mg/kg Remicade in 
conjunction with methotrexate and have the option of increasing the Remicade dose up to 10 mg/kg, the standard 
recommended starting dose of Remicade is 5 mg/kg for all other indications. The safety and efficacy of the 5 mg/kg 
dose regimen of Remicade is well established in many immune-mediated disease populations such as patients with 
RA, Crohn’s disease, UC, and psoriasis. 
In a short-term study of patients with CD where single doses of 5 mg/kg, 10 mg/kg, or 20 mg/kg Remicade were 
evaluated, no apparent dose-response was observed for this range of doses with respect to either magnitude or 
duration of clinical response or CRP reductions. Accordingly, it is not anticipated that doses greater than 5 mg/kg 
would be needed for acute treatment of COVID-19.   
With respect to treatment duration, because the symptomatic phase of the disease lasts about 2 weeks (Zhou et al. 
2020), it is reasonable to use a single dose of 5 mg/kg Remicade which is expected to provide adequate exposure to 
suppress elevated TNFα levels for the duration of the symptomatic phase of COVID-19 infection. 
In summary, Remicade 5 mg/kg administered as a single IV infusion is expected to be effective with acceptable 
risks in rapidly suppressing the elevated TNFα levels in participants with confirmed severe or critical COVID-19. 
 
6. STUDY POPULATION 
The study population will adhere to the master protocol population, except for the noted additional exclusions and 
considerations below. 


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6.1. 
Inclusion Criteria 
The same as the master protocol. 
6.2. 
Sub-Study Specific Exclusion Criteria 
1. Allergy to other monoclonal antibodies, or to any murine proteins. 
2. History of HSTL or other lymphoma within 5 years before screening; history of or current diagnosis of MS 
or other significant demyelinating condition (e.g., optic neuritis).   
6.3. 
Exclusion of Specific Populations 
Since Remicade does not cross-react with TNFα in species other than humans and chimpanzees, animal 
reproduction studies have not been conducted with Remicade. No evidence of maternal toxicity, embryotoxicity, or 
teratogenicity was observed in a developmental toxicity study conducted in mice using an analogous antibody that 
selectively inhibits the functional activity of mouse TNFα. Doses of 10 mg/kg to 15 mg/kg in PD animal models 
with the anti-TNF analogous antibody produced maximal pharmacologic effectiveness. Doses up to 40 mg/kg were 
shown to produce no adverse effects in animal reproduction studies. It is not known whether Remicade can cause 
fetal harm when administered to a pregnant woman or can affect reproductive capacity. Remicade should be given 
to a pregnant woman only if considered that the benefits outweigh the risks. 
As with other IgG antibodies, Remicade crosses the placenta. Remicade has been detected in the serum of infants up 
to 6 months following birth. 
After in utero exposure to Remicade, infants may be at increased risk of infection, including disseminated infection 
that can become fatal. It is recommended that therapeutic infectious agents are not given concurrently with 
Remicade. 
It is not known whether Remicade is excreted in human milk or absorbed systemically after ingestion. Because 
many drugs and immunoglobulins are excreted in human milk, and because of the potential for ADRs in nursing 
infants from REMICADE, a decision should be made whether to discontinue nursing or to discontinue the drug, 
taking into account the importance of the drug to the mother. 
 
7. STUDY PRODUCT 
7.1. 
Study Product(s) and Administration  
Participants will be randomized according to the procedure described in the master protocol. 
 
If there are supply limitations on any product, the arms containing that product will be temporarily closed to 
enrollment and the corresponding placebo is not needed.  
7.1.1. 
Study Product Description  
Remicade is a chimeric human-murine IgG1γ monoclonal antibody that specifically binds to human TNFα. In 
addition to the active ingredient, the lyophilized formulation of Remicade contains the following inactive 
ingredients: water for injection, sucrose, polysorbate 80, monobasic sodium phosphate monohydrate, and dibasic 
sodium phosphate dihydrate. 
7.1.2. 
Dosing and Administration 
For the Remicade component, participants will receive either active product or placebo as follows: 
• 
Remicade will be administered as a single dose of 5 mg/kg (IV) on Day 1 in addition to SoC. 
• 
A placebo of IV saline will be given at an equal volume at the same schedule in addition to SoC. 


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The administration window will be within 24 hours of randomization. Any dose that is delayed may be given later 
that calendar day. Any dose that is missed (not given that calendar day) is not made up. The treatment course 
continues as described above even if the participant becomes PCR negative.  
 
Duration of therapy: 
• 
Remicade IV component or saline placebo – single dose on Day 1. 
7.1.3. 
Dose Escalation 
Not Applicable 
7.1.4. 
Dose Modifications 
For mild to moderate infusion reactions, the patient may improve following slowing or suspension of the infusion, 
and upon resolution of the reaction, re-initiation at a lower infusion rate and/or therapeutic administration of 
antihistamines, acetaminophen, and/or corticosteroids. For participants who do not tolerate the infusion following 
these interventions, Remicade should be discontinued. 
 
Participants who have severe infusion-related hypersensitivity reactions should be discontinued from further 
Remicade treatment. The management of severe infusion reactions should be dictated by the signs and symptoms of 
the reaction. Appropriate personnel and medication should be available to treat anaphylaxis if it occurs. 
 
7.1.5. 
Overdosage 
There is no known specific antidote for Remicade overdose. In the event of an overdose, the participant should be 
monitored for any signs or symptoms of adverse effects and institute appropriate symptomatic treatment 
immediately. 
7.1.6. 
Preparation/Handling/Storage/Accountability 
7.1.6.1. Acquisition and Accountability 
Investigational products (IP) will be shipped to the site either directly from participating companies, from the 
Sponsor, or from other regional or local drug repositories. All other supplies should be provided by the site. Multiple 
lots of each IP may be supplied. 
Study products received at the sites will be open label and not kit specific, unless specified in the protocol-specific 
Manual of Procedures (MOP) or pharmacy manual. Drug preparation will be performed by the participating site’s 
unblinded research pharmacist on the same day of administration to the participant. 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 participant 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.  


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Unused product at the end of the study should be saved until instructed by the Sponsor. 
7.1.6.2. Formulation, Appearance, Packaging, and Labeling  
Remicade component: The lyophilized formulation of Remicade is a preservative-free, white, lyophilized solid 
containing 100 mg of Remicade to be reconstituted with 10 mL of sterile water for injection and diluted into IV 
infusion fluids prior to IV infusion. Following reconstitution, each vial contains a 10 mg/mL Remicade concentrated 
solution. 
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 Remicade contains the following inactive ingredients: water for injection, sucrose, 
polysorbate 80, monobasic sodium phosphate monohydrate, and dibasic sodium phosphate dihydrate. For more 
information, refer to the MOP. 
Injectable placebo component: 
Injectable placebo will be IV normal saline (0.9% NaCl) made up unblinded by the resident pharmacist and blinded 
to the study team.  Note that the type of infusion bag used for placebo should be identical to that used for the 
preparation of the Remicade infusion in order to ensure the blind in the study. 
7.1.6.3. Product Storage and Stability 
Study intervention must be stored at controlled temperatures as indicated on the product label and should not be 
used beyond the expiration date. 
Refer to the MOP for additional guidance on study intervention storage. 
7.1.6.4. Preparation and Administration 
Refer to the protocol-specific MOP for details about preparation.  
Remicade 5 mg/kg will be administered to the participant via an IV infusion at a rate of not more than 100 mL/h 
over a time period of not less than 2 hours using a total volume of 250 mL. Placebo participants will receive the IV 
infusion of 250 mL normal saline at the same rate. Aseptic procedures must be used during the study agent infusion. 
Remicade must not be infused with other agents in the same infusion line. Generally, lines should be flushed before 
and after use if to be used for administration of other medications.  In addition, the infusion of Remicade should not 
be given concurrently with the infusion of remdesivir in order not to confound attribution of possible infusion 
reactions or hypersensitivity events. 
Refer to the MOP for additional guidance on study intervention preparation and handling. 
7.2. 
Measures to Minimize Bias: Randomization and Blinding 
Randomization will be performed as specified in the Master Protocol 
7.3. 
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 date and infusion start/stop times will be entered into the 
case report form (CRF). 
7.4. 
Concomitant Therapy  
7.4.1. 
Permitted Concomitant Therapy and Procedures  
All concomitant therapies permitted in the master protocol will be allowed for this sub-study. 
Of further note in regard to co-administration of corticosteroids, Remicade in combination with corticosteroids, 
including dexamethasone, has been used in clinical trials and 20+ years of post-marketing experience in several 


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immuno-mediated inflammatory diseases with an overall positive benefit-risk profile.  This profile was established 
in the context of long-term use of Remicade in patients without active infection at the time of initiation of treatment. 
7.4.2. 
Prohibited Concomitant Therapy 
All concomitant therapies prohibited in the master protocol will also be prohibited for this sub-study.   
Medications to be used with caution as their exposure could be modified by the study medication 
The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-1, IL-6, IL-
10, IFN) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine 
activity, such as Remicade, the formation of CYP450 enzymes could be normalized. Upon initiation of Remicade in 
patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., 
warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the 
drug product may be adjusted as needed.  
7.4.3. 
Rescue Medicine 
Not Applicable. 
7.4.4. 
Non-Research Standard of Care 
Not Applicable. 
 
8. STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
8.1. 
Halting Criteria and Discontinuation of Study Intervention 
8.1.1. 
Individual Study Product Halting  
Individual study product halting will be managed as specified in the Master Protocol. 
Remicade Halting 
For mild to moderate infusion reactions, the patient may improve following slowing or suspension of the infusion, 
and upon resolution of the reaction, re-initiation at a lower infusion rate and/or therapeutic administration of 
antihistamines, acetaminophen, and/or corticosteroids. For patients that do not tolerate the infusion following these 
interventions, Remicade should be discontinued. 
Patients who have severe infusion-related hypersensitivity reactions should be discontinued from further Remicade 
treatment. The management of severe infusion reactions should be dictated by the signs and symptoms of the 
reaction. Appropriate personnel and medication should be available to treat anaphylaxis if it occurs. 
8.1.2. 
Study Halting 
Study halting will be managed as specified in the Master Protocol. 
8.2. 
Withdrawal from the Study 
Sub-study will have the same requirements as the main study. 
8.3. 
Lost to Follow-Up 
Sub-study will have the same requirements as the main study. 
8.4. 
Readmission  
Sub-study will have the same requirements as the main study. 
 


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9. STUDY ASSESSMENTS AND PROCEDURES 
Sub-study will have the same assessments and procedures as the main protocol. 
 
10. STATISTICAL CONSIDERATIONS 
Statistical analysis will be performed as described within the main body of the ACTIV-1 IM master protocol. 


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APPENDIX 2 – SUB-STUDY 2 – ABATACEPT (ORENCIA) 
1. SUB-STUDY SUMMARY 
1.1. 
Sub-study overview 
The sub-study population corresponds to moderately and severely ill patients infected with the COVID-19 virus. 
Recruitment will target patients already hospitalized for treatment of COVID-19 infection as well as patients being 
treated for COVID-19 infection in Emergency Departments while waiting to be admitted to the hospital. Patients 
both in and out of the ICU are included in the study population. 
Enrollment will begin as soon as all elements are met for the sub-study to activate. 
The study period is 60 days, with assessments on each day of the hospital stay. Patients will be followed after 
hospital discharge with periodic follow-up assessments through Day 29 and at Day 60.  
1.2. 
Enrollment Period  
Enrollment began in October 2020. It is anticipated that enrollment will be completed in 4-6 months. 
1.3. 
General 
This sub-study is designed to evaluate abatacept for the treatment of moderately or severely ill hospitalized patients 
infected with COVID-19. Sub-study will have the same assessments and procedures as the main protocol. 
The effectiveness of abatacept as add-on therapy to SoC will be evaluated based on the primary endpoint of time to 
recovery after 28 days. The sample size requirements are based on the ability to detect a moderate improvement in 
time to recovery (3-4 fewer days). 
1.4. 
Study Population 
Hospitalized adults (≥18 years old) with COVID-19, including patients both in and out of the ICU. Patients seeking 
care for COVID-19 in an Emergency Department (ED) and waiting to be admitted to the hospital are included. 
1.5. 
Inclusion Criteria 
Inclusion criteria are outlined in the main body of the ACTIV-1 IM protocol. 
1.6. 
Agent Specific Exclusion Criteria 
There are no agent specific exclusion criteria for this sub-study.   
1.7. 
Study Intervention 
Therapeutic agents will be evaluated as an add-on therapy to SoC. The study intervention is as outlined in the main 
body of the ACTIV-1 IM protocol. 
For the abatacept component, the dose of abatacept will be 10 mg/kg with a maximum dose of 1000 mg. Study 
medication will be administered in a fixed volume of 100 mL at a constant infusion rate over approximately 30 
minutes. The IV line must be flushed with 25 mL of NS solution at the end of the infusion.  The administration 
window will be within 24 hours of randomization. 
Infusion of abatacept and remdesivir should not be given concurrently in order not to confound attribution of 
possible infusion reactions or hypersensitivity events. 
Duration of therapy: 
• 
Abatacept IV component –  single infusion on Day 1. 
 


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1.8. 
Schedule of Assessments 
Assessments will be performed according to Table 1-1 in 1.1.8 in the main body of the ACTIV-1 IM master 
protocol. 
 
 
2. JUSTIFICATION FOR SELECTION 
It is hypothesized that abatacept therapy can modulate the ongoing/emerging dysregulated immune response 
considered to be driving the progression of disease severity in COVID-19. Abatacept is not a therapy for neutralizing 
cytokines but for preventing further cellular activation (e.g., CD4+ T cells, B cells, macrophages) and production of 
cytokines and interrupting the feedforward pathological process. 
Appendix 2 Figure 1: 
Cellular interactions affected by abatacept 
 
In vitro evidence of abatacept impact on cytokine production by multiple cell types 
Abatacept was first studied in the setting of a pathological response to a viral infection in a murine model of influenza 
(Teijaro et al. 2009).  In this study, abatacept could prevent development of severe lung injury while not inhibiting an 
effective memory antiviral response in the setting of secondary infection. This study, along with others, have continued 
to evolve the understanding of the mechanism of action (MOA) of abatacept which has proven to be much more 
complex than initially envisioned. Although CTLA-4 is central to the regulation of T cell activation, CTLA-4Ig clearly 
has effect on other cell types. Since CTLA-4 regulates interactions with T cells and professional antigen presenting 
cells (APC), it is not surprising that effects on APC populations (i.e., dendritic cells, macrophages, B cells) can also 
be seen, in vitro and clinically (Chambers and Allison 1999). Indeed, in vitro work has demonstrated reverse signaling 
via CD80 or CD86 in APCs although the full impact of this is not fully understood (Davis et al. 2008). 
Treatment with abatacept has also been shown to have broad effects on cytokines in RA patients. Abatacept shows an 
impact within 24 hours in human in vitro mixed-lymphocyte reactions (MLR) on IL-2, TNF-α, and IFN-γ (Davis, 
Nadler et al. 2008).  In vivo, abatacept reduces the levels of multiple cytokines in RA patients including TNF-α, sIL-
2R and IL-6 (Weisman et al. 2006).  In addition, abatacept suppresses multiple biomarkers (cytokines and chemokines) 
in the synovium from RA patients (Buch et al. 2009). What these studies don’t show is which cell type(s) was most 
impacted. 
The best evidence for abatacept’s direct effects on APCs comes from reports on both in vitro and in vivo effects on 
macrophages and B cells. Abatacept inhibits pro-inflammatory cytokine (TNF-a, IL-12, INF-g) secretion by in vitro 
activated human macrophages (Wenink et al. 2012). Abatacept can also downregulate production of IL-6, TNFα, IL1-
β and TGFβ from activated synovial macrophages from RA patients (Cutolo et al. 2009).  B-cell populations are 


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notably decreased in RA synovium of abatacept-treated patients (Buch et al. 2009). Direct effects of abatacept on 
plasmablasts has also been proposed (Carvajal Alegria et al. 2016).  Together, all of this data suggests that abatacept’s 
impact on the immune system is not limited to T cells. Activations of macrophages and B cells are also likely impacted 
by abatacept therapy. 
Background 
Abatacept is a recombinant fusion protein (MW 92 kDa) consisting of the extracellular domain of human CTLA4 and 
a fragment (hinge - CH2 - CH3 domains) of the Fc domain of human immunoglobulin (Ig) GI that has been modified 
to prevent complement fixation and antibody-dependent cellular cytotoxicity. Abatacept is a selective costimulation 
modulator that inhibits T-cell activation by binding to CD80 and CD86 on antigen presenting cells, thereby blocking 
the interaction with CD28 on T-cells that provides a costimulatory signal necessary for full activation of T-cells. By 
inhibiting CD28 mediated T-cell activation upstream of inflammatory cytokines, such as TNF, abatacept utilizes a 
unique mechanism of action that offers significant therapeutic benefit to patients with a variety autoimmune-mediated 
diseases (Linsley and Nadler 2009). Abatacept, 250 mg for intravenous (IV) infusion, is indicated to treat participants 
with rheumatoid arthritis (RA) age 18 and older and participants with polyarticular juvenile idiopathic arthritis (pJIA) 
age 6 to 17.  
IV-administered abatacept was first approved in the US for the treatment of moderate-to-severe RA in adults in 
December 2005. Since then, IV abatacept has received marketing approval for the treatment of adult RA in many other 
countries, including the EU, Canada, Australia, and Japan. IV abatacept was also approved in the US for the treatment 
of moderately-to-severely active juvenile idiopathic arthritis (JIA) in pediatric patients 6 years of age or older in April 
2008. In addition, IV abatacept has received marketing approval for the treatment of JIA in several other countries, 
including the EU, Canada, and Australia. In 2017, abatacept was approved for adult use in psoriatic arthritis (PsA) in 
the US and has also received marketing approval for the treatment of PsA in several other countries, including the EU, 
Canada, and Australia. A subcutaneous (SC) formulation of abatacept in a prefilled syringe and autoinjector has been 
approved for adult RA and PsA patients in the US, EU, and several other countries; it is also approved in the US and 
EU for use in JIA. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of abatacept is provided in the 
Investigator’s Brochure (IB) (Company, B.M.S. 2020a; Company, B.M.S. 2020b). 
Clinical Evidence for Abatacept Suppression of Cytokine Release Syndrome 
There is some clinical data to inform the impact on cytokine release syndrome (CRS). Patients with active systemic 
JIA, some with current macrophage activation syndrome (MAS), who were heavily treated with multiple agents, 
including high dose corticosteroids and anakinra, responded to the addition of abatacept. The time course for the 
benefit of abatacept is not well described but the ability to decrease doses or suspend some concomitant therapy is 
reported.  
A subject with active immune checkpoint inhibitor-associated myocarditis did demonstrate clinical and biochemical 
improvement within a day of initiating abatacept therapy (Salem et al. 2019).  This clinical course has been seen in 
other similar patients treated with abatacept (personal communication of unpublished data). 
The strongest evidence for rapid onset of abatacept and its effect on CRS is from prevention, not treatment. Use of 
peripheral blood stem cell (PBSC) graft for post-transplantation cyclophosphamide (PTCy)-based haploidentical 
hematopoietic cell transplantation (HCT) is associated with early CRS in over 92% of patients (14% severe CRS) 
(Jaiswal and Chakrabarti 2020). Treatment with abatacept 1 day before the infusion of the PBSC graft (followed 
dosing on day +5, +20, +35 and every four weeks after) decreased the rate of CRS to 6% (none severe). The continued 
use of abatacept is because of ongoing donor lymphocyte infusions, which are therapeutic in this context and also 
believed to be the source of the CRS process.  
In a related clinical setting, abatacept has been studied for acute graft-versus-host disease (aGVHD) prevention during 
unrelated-donor hematopoietic cell transplantation (HCT), in both HLA matched (8/8) and unmatched (7/8) patients 


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(Koura et al. 2013; Watkins et al. 2017). Patients who receive unrelated-donor HCT are at elevated risk of severe 
aGVHD and death. Abatacept treatment at days -1, +5, +14, and +28 almost completely suppresses severe (Grade III-
IV) aGVHD without negative impact on relapse and without significant impact on patient safety. CMV reactivation, 
but not EBV, was seen more frequently (47% vs 33%, p=0.16) but uncontrolled infections were not a major problem. 
The relevance of these reports is that they illustrate the rapid effects of abatacept on feedforward mechanisms that 
produce CRS. They also suggest that the onset of abatacept’s therapeutic effects can be sufficiently rapid as to be 
clinically relevant in the setting of COVID-19. 
 
3. INTRODUCTION 
3.1. 
Risk/Benefit Assessment 
3.1.1. 
Abatacept  
3.1.1.1. Potential Risks of Abatacept 
The safety profile of abatacept is well established based on the safety data collected from a number of clinical studies 
and 14-year post-marketing experience during the treatment of autoimmune/inflammatory diseases; abatacept has 
been well-tolerated and shown a favorable benefit-risk profile in the approved disease population (i.e., RA, PsA, pJIA). 
Infections and infusion related reactions (for IV formulation) are identified risks for abatacept, the majority of these 
events are non-serious and do not impact benefit/risk profile of the product. For infections, during the double-blind, 
placebo-controlled period of RA studies (9 IV studies and 2 SC studies in the integrated safety database), the incidence 
rate of overall infections was comparable between abatacept group (total of 2,653 subjects with mean exposure 
duration of 10.8 months ) and placebo group (total of 1,485 subjects with mean exposure duration of 10.3 months): 
93.21 versus 93.02 per 100 patient-years; a small increase for IR of overall serious infections in the abatacept group 
compared to placebo group (3.0 vs 2.25 per 100 patient-years). Majority of the infections were caused by common 
pathogens; the most commonly reported PTs of infections were upper respiratory tract infection (IR 14.3 per 100 
patient-years) and nasopharyngitis (IR 14.3 per 100 patient-years); the most frequently reported serious infection was 
pneumonia (IR 0.68 per 100 patient-years) in abatacept group, which was comparable to that in placebo group (IR 
0.72 per 100 patient-years). The IR of opportunistic infections appeared to be numerically lower in abatacept group 
compared to placebo (0.17 vs 0.56 per 100 patient years). For the infusion related reactions occurred in IV abatacept 
studies, most of the peri-infusional events that occurred within 24 hours following the start of infusion were non-
serious dizziness and nausea; serious events of hypersensitivity/anaphylactic reactions were rare. Safety experience 
from clinical studies in PsA and pJIA patients was similar to that in RA studies. Ten-year post-marketing epidemiology 
studies in RA population did not reveal any new safety finding relevant to these two identified risks.   
Malignancies and autoimmune disorders have been reported with abatacept use; however, the clinical and post-
marketing data do not show an increased risk of these events associated with abatacept use, therefore, the potential 
role of abatacept in the development of these diseases cannot be concluded based on the available evidence.  
The potential deleterious impact of abatacept on viral clearance is certainly a concern that we recognize. The 
previously discussed murine model of influenza infection-induced immunopathology clearly demonstrates the risk of 
blunting anti-viral responses in abatacept-treated mice prior to viral exposure (Teijaro et al. 2009). These concerns are 
not new. Throughout the abatacept clinical development program, concerns over the impact of therapy on infectious 
agents has been paramount.  
During pre-clinical abatacept development, host resistance models of infection were explored (Linsley and Nadler 
2009). Of note, negative impacts on immune responses were only noted for herpes simplex infections. The observation 
that abatacept partially inhibits the generation of CD8 cytotoxic T cell (CTL) responses but does not inhibit CD8 T 
cell cytotoxic activity has been reported, which could also predict deleterious impact on viral responses (Van Gool et 
al. 1996; Whitmire and Ahmed 2000).  


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In spite of these pre-clinical observations, clinical observations, both from controlled trials and post marketing 
surveillance, have been of less concern. A review of safety data of viral infections from an integrated safety database 
of RA clinical studies (includes 7044 participants receiving IV or SC abatacept for a total exposure of 21994.84 patient 
years during the cumulative period (controlled plus long-term open label)), reveals the following:  
1. During the randomized placebo-controlled double-blind short-term period of the studies, the most frequently 
(>1.0%) reported PTs of viral infections and infections that could be caused by virus in the ABA group vs. 
placebo group, respectively, were upper respiratory tract infection (11.9% vs 12.1%), nasopharyngitis (11.8% 
vs 10%), bronchitis (6.5% vs 5.8%), influenza (5.8% vs 5.9%), pharyngitis (3.5% vs 3.3%), rhinitis (2.4% vs 
1.3%), conjunctivitis (2.1% vs 1.5%), gastroenteritis (2.0% vs 3.0%), oral herpes (1.8% vs 1.3%), herpes 
zoster (1.5% vs 1.4%), pneumonia (1.8% vs 1.1%). Majority of these events were mild or moderate in severity 
and abatacept use did not cause increased severity of infections compared to placebo. 
2. During the DB ST period of the studies, the most frequently reported PTs (≥ 2 cases) of serious viral 
infections and infections that could be caused by virus in ABA group and placebo group were pneumonia 
(0.6% vs 0.6%), bronchitis (0.2% vs 0), gastroenteritis (0.1% vs 0.1%), herpes zoster (0.1% vs 0). Among 
these events, death outcomes were reported for pneumonia and the IRs for fatal pneumonia were 0.08 vs 0.16 
per 100 patient-years for abatacept and placebo, respectively. 
3. There were no increases for the incident rates of serious infections reported during cumulative period 
compared to those reported in short-term period. 
Of note is the absence of an imbalance in viral pneumonias, specifically influenza. Also, the median event duration 
for influenza was similar between abatacept treated patients and placebo group. Antibody responses to the 
conventional seasonal influenza vaccine in abatacept treated RA patients were also studied (Alten et al. 2016). The 
study demonstrated that most participants on abatacept were able to mount an appropriate immune response. While 
this study did not demonstrate impact on actual influenza rates, it does support the extensive clinical observation that 
abatacept therapy may not influence anti-influenza responses in a clinically meaningful way. 
Review of the post-marketing safety experience (estimated exposure at 763,109 p-y as of 30-Sep-2019 in > 13 years) 
identified 21 cases of coronavirus infection by 13-Apr-2020, events of confirmed COVID-19 or suspected COVID-
19 were reported in 13 of these cases. The majority of these cases contained minimal information and robust 
assessment of the impact of abatacept on COVID-19 is not possible. One literature report from Japan reported possible 
COVID-19 in a 70-year-old male received abatacept and tacrolimus to treat RA and interstitial lung disease (ILD). 
The patient developed respiratory compromise and ultimately required ventilatory support. Testing of sputum but no 
other sources was positive for SAR-CoV-2. A recent published letter describes 8 patients being treated with targeted 
therapies for chronic arthritis in Italy. Among them were 2 patients receiving therapy with abatacept, 1 with confirmed 
and one with suspected SARS-CoV-2 infection. Only 1 of the patients required hospitalization, and then only briefly 
for oxygen therapy and all recovered without incident (Monti et al. 2020).  Belatacept is a related drug to abatacept 
with a similar mechanism of action. In a recent report (Marx et al. 2020), a 58 year old kidney transplant patient on 
belatacept and MMF became infected with SARS-CoV-2 and had a mild clinical course with rapid recovery. The 
authors hypothesized that ongoing immunotherapy with belatacept may protect from severe clinical course of COVID-
19 by limiting cytokines/chemokines production. 
The abatacept label has a warning for risk of serious infections, including fatal sepsis and pneumonia. The clear risk 
for abatacept use is in bacterial infections, mostly of the respiratory and urinary tract. This includes a higher rate of 
complications in patients with COPD. The abatacept label also warns about treatment initiation in patients with an 
active infection until the infection is controlled. Of note, extensive experience in the use of abatacept to treat RA in 
elderly patients with co-morbidities has been reported (Monti et al. 2017). This suggests that among biologic DMARD 
therapies, abatacept may have less risk of infections (Curtis et al. 2014; Kang et al. 2019; Chen et al. 2020). 
Based on the review of safety data relevant to viral infections from clinical studies and post marketing experience, 
there is no evidence suggesting increased risk of severe respiratory illnesses associated with abatacept use. Current 
evidence suggests that once COVID-19 patients develop symptoms of respiratory compromise, their anti-viral 
responses, including adaptive immune responses, are well underway but the pathological process leading to CRS-like 
scenario has only just begun. It is proposed that abatacept may interrupt this process without greatly interfering with 
the viral clearance and that any study to be attempted should be aware of these goals and concerns. 


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3.1.1.2. Potential Benefits of Abatacept 
It is hypothesized that abatacept therapy can modulate the ongoing/emerging dysregulated immune response 
considered to be driving the progression of disease severity in the setting of SARS-CoV-2 infection.  Abatacept is not 
a therapy for neutralizing cytokines but for preventing further cellular activation (e.g. CD4+ T cells, B cells, 
macrophages) and production of cytokines and interrupting the feedforward pathological process.  The sponsor’s 
hypothesis is that once patients with COVID-19 develop symptoms of respiratory compromise, their anti-viral 
responses, including adaptive immune responses, are well underway but the pathological process leading to the CRS-
like scenario has not yet fully developed. We hypothesize that abatacept may interrupt this process without negatively 
impacting viral clearance. 
Abatacept has demonstrated the ability to modulate the maladaptive immune response in multiple clinical models of 
Cytokine Release Syndrome (CRS) and in clinical conditions characterized by CRS. The most relevant data for the 
use of abatacept in the setting of COVID-19 comes from a mouse model of influenza pneumonitis. In this model, 
treatment with CTLA4-Ig decoupled the protective and immunopathological memory T cell responses following 
secondary infection without effecting viral clearance and reduced the development of the immunopathology and 
enhanced recovery. The use of CTLA4-IG in mouse models of both Toxic Shock and Staph B induced cytokine storm 
resulted in significant reductions in morbidity (including lung damage and edema) and mortality, and lower levels of 
both Il-6 and Ifn-ϒ (Whitfield et al. 2017). 
3.1.1.3. Assessment of Potential Risks and Benefits of Abatacept  
Current evidence indicates that once COVID-19 patients develop symptoms of respiratory compromise, their anti-
viral responses, including adaptive immune responses, are well underway but the pathological process leading to a 
CRS-like scenario has only just begun. The sponsor proposes that abatacept may interrupt this process without greatly 
interfering with the viral clearance. 
Preclinical work indicates that abatacept can suppress or control cytokine production, including clinical scenarios 
consistent with CRS. Clinical work in multiple complex disease states also suggests abatacept therapy can suppress 
or help manage excessive cytokine production. 
Abatacept has been studied in human clinical trials and marketed for over 15 years. Most patients treated have chronic, 
immune-mediated diseases with use of concomitant immunosuppressant therapies and co-morbid conditions. The 
most notable risk for abatacept use is an increase in the rate of bacterial infections, particularly of the respiratory and 
urinary tract. Based on the review of safety data relevant to viral infections from clinical studies and post-marketing 
experience, there is no evidence suggesting an increased risk of viral respiratory illnesses, severe or otherwise, 
associated with abatacept use. 
The study of the therapeutic potential of abatacept in symptomatic patients with COVID-19 at high risk for progression 
to respiratory failure is warranted. Concerns over the negative impact on viral clearance or secondary bacterial 
infections are appropriate. These concerns are mitigated by the relatively short course of treatment in the setting of 
hospitalized monitoring and care, monitoring of super-infections during the study and an oversight study committee. 
More detailed information about the known and expected benefits and risks and reasonably anticipated adverse events 
of abatacept may be found in the Investigator’s Brochure (Company, B.M.S. 2020a; Company, B.M.S. 2020b). 
 
4. 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.  All the endpoints for the 
overall trial are defined in the body of the main ACTIV-1 IM protocol. 
 


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5. STUDY DESIGN 
5.1. 
Justification for Dose 
5.1.1. 
Justification for Dose of Abatacept 
Abatacept is available in 2 formulations, lyophilized for intravenous infusion and pre-filled syringe for subcutaneous 
injection. Pharmacokinetic evaluation over 2 decades of clinical development has shown that the most relevant PK 
parameter is trough (Cmin) levels which are best at predicting maximal efficacy and are driven by weight-based 
dosing. Superior efficacy is observed with 10 mg/kg dosing in RA patients. Dosing frequency of Day 1, 15, 28 and 
every 28 days afterwards was established as an efficacious dosing regimen for reaching target Cmin levels. 
Evidence based on pharmacokinetic, pharmacodynamic and clinical efficacy data suggest that higher doses of 
abatacept would not be more effective in RA patients. Higher doses of abatacept at 30 mg/kg have been tested in 
BMS sponsored trials. In patients with PsA, higher doses did not produce better efficacy but also did not result in 
any increase in safety signal. In inflammatory bowel disease, no clinical efficacy was seen. In lupus nephritis, higher 
doses were thought needed due to urinary losses of abatacept due to the severe proteinuria unique to this disease. 
None of these studies suggested higher abatacept doses were associated with increased safety concerns.  Based on 
the experiences in other systemic inflammatory diseases, which we believe are somewhat informative as to what we 
will see in COVID-19 related disease, we believe a one time IV dose of abatacept would be sufficient to provide 
continuous exposure above the target Cmin and have no reason to believe a higher dose or higher frequency would 
be needed. 
 
6. STUDY POPULATION 
The study population will adhere to the master protocol population, except for the noted additional exclusions and 
considerations below. 
6.1. 
Inclusion Criteria 
The same as the master protocol. 
6.2. 
Sub-Study Specific Exclusion Criteria 
The same as the master protocol. 
6.3. 
Exclusion of Specific Populations 
Children and adolescents will not be included in this trial. Abatacept has been used extensively in pediatric patients.  
The data with abatacept use in pregnant women are insufficient to inform on drug-associated risk. In reproductive 
toxicology studies in rats and rabbits, no fetal malformations were observed with intravenous administration of 
abatacept during organogenesis at doses that produced exposures approximately 29 times the exposure at the 
maximum recommended human dose (MRHD) of 10 mg/kg/month on an AUC basis. However, in a pre- and postnatal 
development study in rats, ORENCIA altered immune function in female rats at 11 times the MRHD on an AUC 
basis.  There are no adequate and well-controlled studies of abatacept use in pregnant women. The data with abatacept 
use in pregnant women are insufficient to inform on drug-associated risk. 
Intravenous administration of abatacept during organogenesis to mice (10, 55, or 300 mg/kg/day), rats (10, 45, or 200 
mg/kg/day), and rabbits (10, 45, or 200 mg/kg every 3 days) produced exposures in rats and rabbits that were 
approximately 29 times the MRHD on an AUC basis (at maternal doses of 200 mg/kg/day in rats and rabbits), and no 
embryotoxicity or fetal malformations were observed in any species 
In a study of pre- and postnatal development in rats (10, 45, or 200 mg/kg every 3 days from gestation day 6 through 
lactation day 21), alterations in immune function in female offspring, consisting of a 9-fold increase in T-cell-
dependent antibody response relative to controls on postnatal day (PND) 56 and thyroiditis in a single female pup on 
PND 112, occurred at approximately 11 times the MRHD on an AUC basis (at a maternal dose of 200 mg/kg). No 
adverse effects were observed at approximately 3 times the MRHD (a maternal dose of 45 mg/kg). It is not known if 


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immunologic perturbations in rats relevant indicators of a risk for development of autoimmune diseases in humans 
are exposed in utero to abatacept. Exposure to abatacept in the juvenile rat, which may be more representative of the 
fetal immune system state in the human, resulted in immune system abnormalities including inflammation of the 
thyroid and pancreas [see Nonclinical Toxicology. 
There is no information regarding the presence of abatacept in human milk, the effects on the breastfed infant, or the 
effects on milk production. However, abatacept was present in the milk of lactating rats dosed with abatacept. 
 
7. STUDY PRODUCT 
7.1. 
Study Product(s) and Administration  
Participants will be randomized according to the procedure described in the master protocol. 
If there are supply limitations on any product, the arms containing that product will be temporarily closed to 
enrollment and the corresponding placebo is not needed.  
7.1.1. 
Study Product Description  
Abatacept for Injection is a lyophilized powder for intravenous infusion. ORENCIA for Injection is supplied as a 
sterile, white, preservative-free, lyophilized powder for reconstitution and dilution prior to intravenous 
administration. Following reconstitution of the lyophilized powder with 10 mL of Sterile Water for Injection, USP, 
the solution of abatacept is clear, colorless to pale yellow, with a pH range of 7.2 to 7.8. Each single-use vial of 
abatacept for Injection provides 250 mg abatacept, maltose (500 mg), monobasic sodium phosphate (17.2 mg), and 
sodium chloride (14.6 mg) for administration. 
7.1.2. 
Dosing and Administration 
The dose of abatacept will be 10 mg/kg with a maximum dose of 1000 mg. Study medication will be administered in 
a fixed volume of 100 mL at a constant infusion rate over approximately 30 minutes. The IV line must be flushed 
with 25 mL of NS solution at the end of the infusion.  The administration window will be within 24 hours of 
randomization. 
Infusion of abatacept and remdesivir should not be given concurrently in order not to confound attribution of 
possible infusion reactions or hypersensitivity events. 
Duration of therapy: 
• 
Abatacept IV component –  single infusion on Day 1. 
7.1.3. 
Dose Escalation 
Not Applicable 
7.1.4. 
Dose Modifications 
In the absence of adverse events, participants will complete their scheduled infusion as prescribed by protocol.  If 
there is evidence of toxicity (e.g., infusion reaction) that, in the judgment of the Investigator, could place the 
participant at increased risk, study drug administration should be discontinued. 
Management of Possible Acute Hypersensitivity Reactions to Abatacept 
Hypersensitivity or acute allergic reactions may occur as a result of the protein nature of abatacept. Should any of 
these reactions occur during the course of the study, they need to be reported as specified in 8.3.6 (Adverse 
Events). In this study, participants’ vital signs will be monitored before and following study drug administration. 
Appropriate emergency equipment and qualified personnel should be available where the participants are treated in 
the event of a serious anaphylactic reaction. 


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The following information is provided to assist in the recognition of hypersensitivity reactions and in the management 
of those reactions should they occur during or after the administration of abatacept. Care should be taken to treat 
any acute toxicities expeditiously, should they occur. When IV dosing of abatacept is conducted, equipment such as 
a portable tank or wall-source of oxygen, endotracheal intubation set, oral airway, mask, ambu-bag, syringes, 
injectable epinephrine, injectable antihistamine, and injectable corticosteroids should be kept in the vicinity where 
the participant is treated. 
Signs and management of potential acute hypersensitivity reactions include: 
a) Symptomatic Hypotension should be managed by discontinuing the infusion of study medication, placing the 
participant in the Trendelenburg position and administering intravenous fluid. Additional medical intervention 
may also include the use of epinephrine, corticosteroids, antihistamines and pressor agents. 
b) Dyspnea should be managed by discontinuing the infusion of study medication and observing the participant for 
worsening of the event and for the appearance of additional signs and symptoms of anaphylaxis. Antihistamines, 
epinephrine and corticosteroids may be administered as indicated. 
c) Acute pain in the chest, back or extremities may also be a sign of anaphylaxis and may be treated as described 
above for dyspnea 
d) Chills, fever, urticaria or generalized erythema may all be signs of an allergic reaction to protein products. 
Such signs and symptoms may be treated with acetaminophen and antihistamines. 
The decision of whether to complete the infusion of study medication if symptoms improve or have resolved will 
be left to the medical judgment of the Investigator. 
7.1.5. 
Overdosage 
Doses of Abatacept up to 50 mg/kg have been administered intravenously without apparent toxic effect. In the case 
of overdosage, it is recommended that patients should be monitored for any signs or symptoms of adverse reactions 
and have the appropriate symptomatic treatment instituted immediately. 
7.1.6. 
Preparation/Handling/Storage/Accountability 
7.1.6.1. Acquisition and Accountability 
Investigational products (IP) will be shipped to the site either directly from participating companies, from the 
Sponsor, or from other regional or local drug repositories. All other supplies should be provided by the site. Multiple 
lots of each IP may be supplied. 
Study products received at the sites will be open label and not kit specific, unless specified in the protocol-specific 
Manual of Procedures (MOP) or pharmacy manual. Drug preparation will be performed by the participating site’s 
unblinded research pharmacist on the same day of administration to the participant. 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 participant 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.  


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Unused product at the end of the study should be saved until instructed by the Sponsor. 
7.1.6.2. Formulation, Appearance, Packaging, and Labeling  
Abatacept component: 
Abatacept for Injection is a lyophilized powder for intravenous infusion. ORENCIA for Injection is supplied as a 
sterile, white, preservative-free, lyophilized powder for reconstitution and dilution prior to intravenous 
administration. Following reconstitution of the lyophilized powder with 10 mL of Sterile Water for Injection, USP, 
the solution of abatacept is clear, colorless to pale yellow, with a pH range of 7.2 to 7.8. Each single-use vial of 
abatacept for Injection provides 250 mg abatacept, maltose (500 mg), monobasic sodium phosphate (17.2 mg), and 
sodium chloride (14.6 mg) for administration. It is supplied as an individually packaged, single-use vial with a 
silicone-free disposable syringe, providing 250 mg of abatacept in a 15-mL vial. 
Injectable placebo component: 
Injectable placebo will be normal IV saline (0.9% NaCl) made up unblinded by the resident pharmacist and blinded 
to the study team.  Note that the type of infusion bag used for placebo should be identical to that used for the 
preparation of the abatacept infusion in order to ensure the blind in the study. 
7.1.6.3. Product Storage and Stability 
Abatacept should be stored at 2oC-8oC and protected from light. 
7.1.6.4. Preparation 
Refer to the protocol-specific MOP for details about preparation.  
 
Use aseptic technique.  
abatacept for Injection is provided as a lyophilized powder in preservative-free, single-use vials. Each ORENCIA 
vial provides 250 mg of abatacept for administration. The abatacept powder in each vial must be reconstituted with 
10 mL of Sterile Water for Injection, USP, using only the silicone-free disposable syringe provided with each vial 
and an 18- to 21-gauge needle. After reconstitution, the concentration of abatacept in the vial will be 25 mg/mL. If 
the abatacept powder is accidentally reconstituted using a siliconized syringe, the solution may develop a few 
translucent particles. Discard any solutions prepared using siliconized syringes.  
If the silicone-free disposable syringe is dropped or becomes contaminated, use a new silicone-free disposable 
syringe from inventory. 
 
1) Use 10 mL of Sterile Water for Injection, USP to reconstitute the abatacept powder. To reconstitute the 
abatacept powder, remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the 
syringe needle into the vial through the center of the rubber stopper and direct the stream of Sterile Water 
for Injection, USP, to the glass wall of the vial. Do not use the vial if the vacuum is not present. Rotate the 
vial with gentle swirling to minimize foam formation, until the contents are completely dissolved. Do not 
shake. Avoid prolonged or vigorous agitation. 
2) Upon complete dissolution of the lyophilized powder, the vial should be vented with a needle to dissipate 
any foam that may be present. After reconstitution, each milliliter will contain 25 mg (250 mg/10 mL). The 
solution should be clear and colorless to pale yellow. Do not use if opaque particles, discoloration, or other 
foreign particles are present.  
3) The reconstituted abatacept solution must be further diluted to 100 mL as follows. From a 100 mL infusion 
bag or bottle, withdraw a volume of 0.9% Sodium Chloride Injection, USP, equal to the volume of the 
reconstituted abatacept solution required for the patient’s dose. Slowly add the reconstituted abatacept 
solution into the infusion bag or bottle using the same silicone-free disposable syringe provided with each 
vial. Gently mix. Do not shake the bag or bottle. The final concentration of abatacept in the bag or bottle 
will depend upon the amount of drug added but will be no more than 10 mg/mL. Any unused portions in 
the abatacept vial must be immediately discarded.  
4) Prior to administration, the abatacept solution should be inspected visually for particulate matter and 
discoloration. Discard the solution if any particulate matter or discoloration is observed.  


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5) The entire, fully diluted abatacept solution should be administered over a period of 30 minutes and must be 
administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (pore size of 0.2 
μm to 1.2 μm). 
6) The infusion of the fully diluted abatacept solution must be completed within 24 hours of reconstitution of 
the ORENCIA vials. The fully diluted abatacept solution may be stored at room temperature or refrigerated 
at 2ºC to 8ºC (36ºF to 46ºF) before use. Discard the fully diluted solution if not administered within 24 
hours.  
7) Abatacept should not be infused concomitantly in the same intravenous line with other agents. No physical 
or biochemical compatibility studies have been conducted to evaluate the coadministration of abatacept 
with other agents. 
7.2. 
Measures to Minimize Bias: Randomization and Blinding 
Randomization will be conducted as specified in the Master Protocol. 
7.3. 
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). 
7.4. 
Concomitant Therapy 
7.4.1. 
Permitted Concomitant Therapy and Procedures 
All concomitant therapies permitted in the master protocol will be allowed for this sub-study. 
Of specific note to cotreatment with corticosteroids, Orencia is routinely co-administered with low dose 
corticosteroids (CS, prednisone or equivalent ≤ 10 mg/day) in its labeled indications for the treatment of 
Rheumatoid Arthritis, Psoriatic Arthritis and Juvenile Idiopathic Arthritis and is not associated with increased risk of 
adverse outcomes. Concomitant use of abatacept with higher doses of CS has been studied in other disease areas, 
e.g. lupus nephritis.  Based on clinical trial data, use of high dose CS with sustained abatacept treatment may be 
associated with some increased risk for serious bacterial infections. 
7.4.2. 
Prohibited Concomitant Therapy 
All concomitant therapies prohibited in the master protocol will also be prohibited for this sub-study.   
7.4.3. 
Rescue Medicine 
Not Applicable. 
7.4.4. 
Non-Research Standard of Care 
Not Applicable. 
 
 
8. STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
8.1. 
Halting Criteria and Discontinuation of Study Intervention 
8.1.1. 
Individual Study Product Halting  
Individual study product halting will be managed according to the Master Protocol. 
Abatacept Halting 
If there is evidence of toxicity (e.g., infusion reaction) that, in the judgment of the Investigator, could place the 
participant at increased risk, study drug administration should be discontinued. 


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8.1.2. 
Study Halting 
Study halting will be managed as specified by the Master Protocol. 
8.2. 
Withdrawal from the Study 
Sub-study will have the same requirements as the main study. 
8.3. 
Lost to Follow-Up 
Sub-study will have the same requirements as the main study. 
8.4. 
Readmission  
Sub-study will have the same requirements as the main study. 
 
 
9. STUDY ASSESSMENTS AND PROCEDURES 
Sub-study will have the same assessments and procedures as the main protocol. 
10. STATISTICAL CONSIDERATIONS 
Statistical analysis will be performed as described within the main body of the ACTIV-1 IM master protocol. 
 
 


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APPENDIX 3 – SUB-STUDY 3 – CENICRIVIROC (CVC) 
1. SUB-STUDY SUMMARY 
1.1. 
Sub-study overview 
The sub-study population corresponds to moderately and severely ill patients infected with the COVID-19 virus. 
Recruitment will target patients already hospitalized for treatment of COVID-19 infection as well as patients being 
treated for COVID-19 infection in Emergency Departments while waiting to be admitted to the hospital. Patients 
both in and out of the ICU are included in the study population. 
Enrollment will begin as soon as all elements are met for the sub-study to activate. 
The time on drug period is 28 days (i.e., up to Day 28 of the study), with assessments on each day of the hospital 
stay. Patients will be followed after hospital discharge and after last dose of drug, with periodic follow-up 
assessments through Day 60 (i.e., approximately 30 days after last dose of drug).  
1.2. 
Enrollment Period  
Enrollment began in October 2020. It is anticipated that enrollment will be completed in 4-6 months. 
1.3. 
General 
This sub-study is designed to evaluate cenicriviroc (CVC) for the treatment of moderately or severely ill 
hospitalized patients infected with COVID-19. Sub-study will have the same assessments and procedures as the 
main protocol. 
The effectiveness of CVC as add-on therapy to SoC will be evaluated based on the primary endpoint of time to 
recovery after 28 days. The sample size requirements are based on the ability to detect a moderate improvement in 
time to recovery (3-4 fewer days). 
1.4. 
Study Population 
Hospitalized adults (≥18 years old) with COVID-19, including patients both in and out of the ICU. Patients seeking 
care for COVID-19 in an Emergency Department (ED) and waiting to be admitted to the hospital are included. 
1.5. 
Inclusion Criteria 
Inclusion criteria are outlined in the main body of the ACTIV-1 IM protocol. 
1.6. 
Agent Specific Exclusion Criteria 
Use of medications that are contraindicated with CVC and that could not be replaced or stopped during the study 
period (See Appendix 3 Table 3 for Disallowed Medications).  
1.7. 
Study Intervention 
Therapeutic agents will be evaluated as an add-on therapy to SoC. The study intervention is as outlined in the main 
body of the ACTIV-1 IM protocol. 
For the cenicriviroc (CVC) component, CVC will be administered with food as a 450 mg oral loading dose on Day 
1, followed by a 300 mg (150 mg BID) maintenance dose for the duration of the study (through Day 28).  The 
administration window of the loading dose will be within 24 hours of randomization. 
 
Duration of therapy: 
• 
Cenicriviroc Oral component – 28 days, including while hospitalized and post-discharge. 
 


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1.8. 
 Schedule of Assessments 
Assessments will be performed according to Table 1-1 in 1.1.8 in the main body of the ACTIV master protocol. 
   
 
2. JUSTIFICATION FOR SELECTION 
Severe pneumonia and respiratory-tree infection caused by coronaviruses such as SARS-CoV and MERS-CoV are 
often associated with massive inflammatory cell infiltration and elevated pro-inflammatory cytokine and chemokine 
responses -- resulting in injury to the respiratory tree and an acute respiratory distress syndrome (ARDS). Patients 
with this cytokine storm have been observed to have high levels of CCL2 (MCP1) and CCL5 (RANTES), likely 
caused by feedback from SARS-CoV upregulating CCR2 and CCR5 (Law et al. 2009). Elevated CCL5 may lead to 
severe lung inflammation, ARDS, and death in patients with SARS (Ng et al. 2007) demonstrated that the 
RANTES-28 G allele, which is associated with high levels of CCL5, was a risk factor for poor outcomes and death 
in Hong Kong and Beijing Chinese SARS patients. This study noted that these chemokines, released from activated 
immune cells, not only take part in the anti-viral immune response but are causative of cell damage and organ 
dysfunction. Further demonstrated was the significant induction of CCR-1, CCR-3 and CCR-5 mRNA expression in 
SARS-CoV infected dendritic cells (DCs), suggesting the possibility of an autocrine loop facilitating DC trafficking. 
Moreover, presence of the CCL2 G-2518A allele, which leads to high CCL2 levels, made patients more susceptible 
to infection with SARS-CoV (Tu et al. 2015). Thus, clinical data demonstrate that both CCL5 and CCL2 play key 
roles in the inflammatory sequelae and poor clinical outcomes of SARS-CoV infection. 
In patients with ARDS, CCL2 is upregulated, inducing the migration of circulating CCR2+ inflammatory cells into 
alveoli (Zemans and Matthay 2017). Patients with ARDS have elevated levels of CCL2 in BAL fluid compared with 
controls and greater neutrophil recruitment (Williams et al. 2017). 
Rationale for dual targeting of CCR2 and CCR5 
Both CCR2 and CCR5 play roles in ARDS and the consequences of SARS-CoV. Rationale of dual inhibition 
includes:  redundancy among these pathways and dual inhibition preventing a spill over that may occur with 
blocking only one; and, these two routes have complementary roles in infection-associated inflammation and tissue 
damage. For example, CCR2 targeted action is more critical for inhibition of circulating immune cells (e.g., 
monocytes, memory T cells), their trafficking, and migration into tissue; CCR5 action is more related to inhibiting 
tissue-based immune cells, and therefore a somewhat later time window (e.g., macrophages, activated T effector 
cells, dendritic cells).  Both CCR2/5 paths have been shown to be operative, and effects off-set by attenuation of 
CCR2/5 has been shown to be operative in: CoV infection; ARDS; and influenza-caused lung inflammation, tissue 
destruction, and fibrosis. Moreover, specifically with CVC, dual CCR2/5 has been shown to be an effective 
mechanism in pre-clinical models of liver inflammation/fibrosis and viral encephalitis.  
Importantly, shown in a murine model of SARS-CoV infection, there are 2 time windows: 1) before the onset or 
worsening of pneumonitis when the administration of a CCR2 inhibitor has the highest likelihood of being 
beneficial to patients with COVID-19 and 2) during the pneumonitis when both CCR2 and CCR5 inhibition may be 
beneficial, reinforcing the potential role for dual targeting of CCR2/5 (Appendix 3 Figure 1) (Chen et al. 2010). 
 


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Appendix 3 Figure 1: Pathogenesis of SARS-CoV Infection in Senescent Mice 
 
Cenicriviroc (CVC) is a novel small-molecule, orally active, well-tolerated, potent and selective antagonist of CCR2 
and CCR5 with anti-inflammatory and anti-fibrotic activity. Data from animal and clinical studies support a 
favorable action of CVC in inflammation associated with severe infection. In a mouse model of acute liver injury, 
administration of CVC significantly decreased the numbers of monocyte-derived macrophages and associated 
inflammation and tissue damage. CVC also reduced the numbers of Kupffer cells or tissue-based macrophages with 
a KC-like phenotype peri-injury. Other immune cell populations such as neutrophils or lymphoid cells were not 
affected (Puengel, Krenkel et al. 2017). In a 2nd mouse model of liver injury, CCR2 inhibition with CVC reduced 
the influx of proinflammatory monocytes into the liver, which significantly attenuated the early phase of tissue 
injury and later necrosis (Mossanen et al. 2016). Of note, lung disease models demonstrating infiltrating monocyte-
derived interstitial macrophages have a similar inflammatory phenotype, including CCR2/5 based processes, as in 
the liver disease models, and alveolar macrophages share multiple features with Kupffer cells in the liver. Moreover, 
immunomodulatory action from CVC has been shown to result in reductions of inflammation and in tissue 
preservation in murine models of viral encephalitis. 
In an ex-vivo study of monocytes derived from HIV-infected patients, dual CCR2/5 inhibition with CVC was more 
effective in decreasing trans-endothelial migration of monocytes than single CCR2 or CCR5 blockade. Moreover, 
CVC was also associated with decreased expression of E-selectin on endothelial cells, a major receptor for 
monocyte recruitment (D'Antoni et al. 2018). 


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Appendix 3 Figure 2: Mechanism of Action for Cenicriviroc (CVC) 
  
We hypothesize that CVC, by blocking CCR2 and CCR5, will decrease recruitment of infiltrating monocyte-derived 
interstitial macrophages and other immune cells, known to be operative in respiratory tissues in coronavirus 
infections, thus preventing the cytokine storm, respiratory injury, and ARDS with COVID-19 (Mossanen et al. 2016; 
Puengel et al. 2017). Also, we hypothesize that the reduction of trans-endothelial vascular migration of monocytes 
could play a role in attenuating vascular-based injury. Therefore, we believe that treatment with CVC could prevent 
the cytokine storm that cause the lung injury and is the cause of acute respiratory distress syndrome (ARDS) in 
patients with COVID-19. 
We propose the investigation of administration of CVC in patients hospitalized due to COVID-19, in those who 
have not yet developed severe respiratory disease or are early in a course of respiratory compromise, and in those 
with substantial respiratory compromise, with the objective of reducing the risk of evolution to severe lung injury. 
The documented safety profile allows the potentially broad treatment of patients, e.g. at several stages of COVID-
19. 
 
3. INTRODUCTION 
3.1. 
Risk/Benefit Assessment 
3.1.1. 
Cenicriviroc  
3.1.1.1. Potential Risks of Cenicriviroc 
Cenicriviroc (CVC) is contraindicated in participants with clinically significant hypersensitivity to any components 
of its formulation. 
Warnings and Precautions 
Treatment-emergent elevations in liver transaminases have been observed in participants receiving CVC treatment. 
Most elevations were transient, mild to moderate in severity, and resolved upon continued treatment with CVC. 
Some elevations were severe in intensity and resulted in dose interruption or permanent discontinuation of CVC. 
CVC has been administered to >2000 patients, including patients with non-alcoholic fatty liver disease (NASH) and 
a separately to those with HIV, in clinical trials.  In NASH patients with pre-existing liver disease, 2 cases of 
possible autoimmune hepatitis (1 participant in the CVC arm and 1 participant in the placebo arm) have been 
observed.  
Hepatic and Renal Impairment 


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Based on clinical data (studies 652-1-121 and 3152-102-002), CVC exposures did not increase in participants with 
mild hepatic impairment (Child-Pugh A), increased in participants with moderate (Child-Pugh B) (AUC0-tau 55%), 
and significantly increased in severe (Child-Pugh C) (AUC0-t 40%) hepatic impairment relative to corresponding 
matched healthy participants. These clinical studies allowed inclusion for ALT or AST abnormalities up to 5x ULN.  
Of note: based on the PK and safety results for these studies, no CVC dose adjustment will be required in patients 
with hepatic impairment. Based on results from the human ADME study (Study 3152-103-002), renal excretion of 
CVC and its metabolites was negligible (< 2% of dose). Consistent with this observation, the renal excretion of CVC 
(non-radiolabel study) was observed to be < 0.00011% (Study 01-03-TL-652-001). The impact of end stage renal 
disease on the PK of CVC is under evaluation (Study 3152-104-002). 
Drug Interactions 
CVC is a substrate of CYP3A4, CYP2C8 and P-gp. CVC is also a weak inhibitor of CYP3A4 and an inhibitor of 
BCRP and P-gp. The following classes of medications are disallowed at any time during CVC treatment: 
• 
Potent CYP3A4 inhibitors and CYP3A4 inducers will be excluded 
• 
Potent CYP2C8 inhibitors will be excluded 
• 
Drugs with narrow therapeutic windows that are sensitive CYP3A4 substrates will be excluded (i.e., drugs 
which should not be co-administered with weak CYP3A4 inhibitors such as CVC) 
• 
Appropriate dose adjustments of BCRP substrates are recommended 
Co-administration of CVC and remdesivir is allowed. 
Co-administration of CVC and glucocorticoids is allowed. 
When required, acid-reducing agents should be administered at least 2 hours after the CVC (4 hours for fast-acting 
antacids). It is recommended to use an H2 receptor antagonist (except cimetidine) or antacids rather than a proton 
pump inhibitor. It is recommended to start with the lowest dose of these agents and titrate according to clinical 
response. If lipid lowering medications are used, clinical monitoring and dose titration are recommended to achieve 
the desired clinical response. 
See Appendix 3 Table 3 and Appendix 3 Table 4 for fuller instructions regarding allowed concomitant drugs. 
In summary, the risks of CVC are low and similar to placebo. 
3.1.1.2. Potential Benefits of Cenicriviroc 
CVC may or may not improve clinical outcome of an individual trial participant with COVID-19. However, there is 
potential benefit to society from their participation in this study resulting from insights gained about the CVC under 
study as well as the natural history of the disease. While there may not be benefits for an individual participant, there 
may be benefits to society if a safe, efficacious therapeutic agent can be identified during this global COVID-19 
outbreak. 
3.1.1.3. Assessment of Potential Risks and Benefits of Cenicriviroc 
CVC is generally a well-tolerated medication, which has been administered to participants up to 2 years at different 
doses. It is well tolerated in a wide dose range. There are no significant toxicities that have been observed in prior 
studies. An increase of nasopharyngitis in the second year of administration without an increase in upper respiratory 
tract infections has been reported from a long-term exposure trial (2 years). Since the drug is administered for only 
28 days we do not expect any of those side effects. The loading dose of 450 mg on day one will be split into two 
doses (300 mg (AM) and 150 mg (PM)); note: participants enrolled in the study in the latter portion of the day may 
receive only the 300 mg component of the Day 1 loading dose (see Appendix 3 Table 2 for specific dosing 
scenarios). Additional side effects are not expected. Clinical and pharmacologic assessments support this dose, and 
supportive data exist for significantly higher doses. 
 


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4. 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.  All the endpoints for the 
overall trial are defined in the body of the main ACTIV-1 IM protocol. 
 
5. STUDY DESIGN 
5.1. 
Justification for Dose 
5.1.1. 
Justification for Dose of Cenicriviroc 
To ensure rapid onset of action of CVC, a loading dose of 450 mg will be administered on Day 1 (300 mg first dose 
in the morning and 150 mg 12 hours later); patients enrolled in the trial in the latter portion of the day may receive 
only the 300 mg component of the Day 1 loading dose (see Appendix 3 Table 2 for details on dosing scenarios). 
Starting Day 2, patients will receive 150 mg of CVC twice per day (total dose of 300 mg per day) through Day 28. 
Prior clinical data, clinical pharmacological data, and PK/PD modelling have indicated that CVC inhibited CCR2 
(measured as MCP-1 increase) and CCR5 (measured as MIP-1b increase) with an IC50 of 25 ng/mL and 43 ng/mL, 
respectively (3152-102-002: ACCP poster, 2019). This model predicts maximal increase in MCP-1 (~6-fold) and 
MIP-1b (~2-fold) achieved at steady state by once daily dosing of 150 mg CVC, which reflects complete receptor 
occupancy. In order to achieve complete receptor occupancy at an earlier time, a loading dose of 300 mg CVC in the 
morning and 150 mg CVC after 12 hours will be administered: patients enrolled in the trial in the latter portion of 
the day may receive only the 300 mg component of the Day 1 loading dose (see Appendix 3 Table 2 for details on 
dosing scenarios). This dosing regimen predicts achievement of ~90% receptor occupancy by end of Day 1. 
Thereafter, continued dosing of 150 mg CVC twice daily is expected to maintain effective receptor occupancy for 
the duration of the treatment. 
Moreover, the total dose of 450 mg CVC on Day 1 (split into 300 mg and 150 mg; see Appendix 3 Table 2 for 
details on dosing scenarios) is justified based on clinical trials in which multiple doses of CVC up to 900 mg QD for 
7 days were administered to healthy volunteers with no safety findings observed. Furthermore, other safety margin 
data also give support for this dosing regimen. In GLP toxicology studies, the NOAEL was determined to be 2000 
mg/kg/day in mice, 100 mg/kg/day in rats, and 1000 mg/kg/day in monkeys. Based on the most sensitive NOAEL 
dose of 100 mg/kg/day in rats, a HED of 960 mg was estimated. The most commonly observed AEs (≥ 2%) with 
CVC in multiple-dose studies evaluating daily doses up to 900 mg for ≥ 7 days were headache and constipation. 
Furthermore, CVC has been shown to be safe and well-tolerated following multiple-dose administration of 450 mg 
and 900 mg once daily for 7 days (Study 3152-107-002). In study 3152-107-002, steady state Cmax of CVC at doses 
of 450 mg and 900 mg was 2977 ng/mL and 4025 ng/mL, respectively, and the corresponding AUC0-τ values were 
37724 and 72905 ng.h/mL, respectively. Since the Day 1 dose of 450 mg in the current study is being split (as 300 
mg in the morning and 150 mg to be administered after 12 hours), and from day 2 onwards the dose of 300 mg is 
split (as 150 mg BID), the maximal CVC concentrations (Cmax)  as well as steady state AUC (AUCt) in this study 
are expected to be less than those observed in earlier clinical studies (3152-107-002 and 3152-106-002). Note: 
patients enrolled in the trial in the latter portion of the day may receive only the 300 mg component of the Day 1 
loading dose (see Appendix 3 Table 2 for details on dosing scenarios). 
Since food has been shown to have significant effect on CVC exposure, all doses are recommended to be 
administered within 30 minutes of consumption of a meal (or feeds), which is also how CVC has been administered 
in other clinical trials. 
Pharmacokinetic Modelling Assessments for Dose Rationale 
CVC is a dual antagonist of CCR2 and CCR5 receptors. Increase in serum concentrations of ligands of CCR2 
(MCP-1) and CCR5 (MIP-1β) is used as a surrogate marker (biomarker response) to determine CVC receptor 
occupancy in clinical studies. In an earlier Phase 1 clinical study (Study 3152-105-002), exposure response 
relationship between plasma CVC concentrations and biomarker response (MCP-1 or MIP-1β) were explored using 


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a sequential PK/PD model (Appendix 3 Figure 3).  The structural PK model was a two-compartment model with 
first-order absorption and with a lag time. The exposure response for each biomarker was modelled by an indirect 
pharmacodynamic response model. The kinetic parameter estimates from the indirect response model are 
summarized in Appendix 3 Table 1. 
Appendix 3 Figure 3: Sequential approach of population PK and Indirect response model utilized to determine 
exposure response 
 
 
 
 
 
 
 
 
 
 
Appendix 3 Table 1: 
Parameter Estimates for Indirect 
Response Model 
 
RSE – relative standard error for estimated typical value; IIV – inter-individual variability; n.e. – not estimated; 
Kin=Baseline*kout; %inhibition of kout = Cp*Imax/(Cp+IC50); “fixed” - to aid a stable estimation, some parameter 
values were fixed in final model based on values obtained in iterative model runs and evaluated through numerical 
and visual goodness-of-fit. 
Based on these parameters, the biomarker response (% change from baseline of MCP-1 or MIP-1β) was predicted 
following once daily dosing of 150 mg CVC (Appendix 3 Figure 4). These simulations suggest maximal change in 
MCP-1 levels (~5.5-fold increase) and MIP-1β (~2-fold) upon once daily dosing of CVC for at least 5 days and 10 
days, respectively. 


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Appendix 3 Figure 4: Predicted biomarker response following once daily dosing of 150 mg CVC 
 
Since treatment of fibrosis in NASH patients require chronic administration of CVC (AURORA study duration: 5 
years of once daily treatment of 150 mg CVC) and the earliest change in endpoint (reduction in fibrosis) is expected 
after once daily treatment for 1 year, achieving maximal biomarker change after 5 to 10 days of once daily treatment 
is acceptable in NASH indication. However, COVID-19 is a severe acute infectious disease that requires rapid onset 
of action and relatively short duration of treatment (planned duration of treatment 28 days). Therefore, dosing 
regimen containing a total loading dose of 450 mg CVC (divided as 300 mg in the morning + 150 mg in the 
evening) was proposed on Day 1 of this study followed by dose of 300 mg/day (divided as 150 mg in the morning 
plus 150 mg in the evening). For the proposed dosing regimen, the biomarker response (% change from baseline of 
MCP-1 or MIP-1β) was predicted as shown (Appendix 3 Figure 5). As per simulations, loading dose is expected to 
increase MCP-1 levels by 6-fold and MIP-1β levels by 1.5-fold on Day 1. Following twice-daily administration of 
150 mg CVC, maximal increase in MCP-1 (~7-fold) and MIP-1β (~2-fold) were sustained during the duration of 
treatment beginning Day 2. These simulations suggest effective blockade of activation of CCR2 and CCR5 receptors 
by respective ligands could be achieved rapidly and sustained by following the proposed dosing regimen. 
Appendix 3 Figure 5: 
Predicted biomarker response following proposed dosing regimen of CVC (Day 1: 300 
mg in the morning + 150 mg in the evening, Day 2 to Day 29: 150 mg twice daily) 
 
As of January 2020, approximately 2000 participants have been exposed to either single or multiple doses of CVC in 
completed and ongoing clinical studies. CVC doses explored in these clinical studies range from 25 mg to 900 mg 


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across all CVC studies. There was no apparent dose- or exposure-relationship for safety observed. Furthermore, 
splitting the daily dose is expected to limit the plasma peak concentrations of CVC corresponding to 300 mg dose on 
Day 1 and 150 mg dose from Day 2 onwards. In addition, food effect on the bioavailability of CVC formulation is 
significant (up to 5.2-fold increase with standard breakfast). The CVC dose can be administered to an intubated and 
severely ill COVID-19 patient via G-tube and with liquid food. In such a case, if there were to be reduced enteral 
absorption, then any lowered plasma concentrations/exposure of CVC may be partially offset by the twice-daily 
dosing of CVC.  
In summary, these data provide support and rationale for the proposed dosing being well within appropriate 
parameters and safety.  The sponsor believes the proposed loading dose (450 mg on Day 1) and twice daily 
administration of 150 mg CVC are clearly justified based on the following: safe use of CVC doses up to 900 mg in 
prior clinical studies; immediate need for optimal plasma exposure of CVC in patients with COVID-19 infection, 
ensure full antagonistic activity against CCR2 and CCR5 receptors in target tissues; and maintenance of such 
exposure throughout the duration of treatment without compromising patient safety. 
 
6. STUDY POPULATION 
The study population will adhere to the master protocol population, except for the noted additional exclusions and 
considerations below. 
6.1. 
Inclusion Criteria 
The same as the master protocol. 
6.2. 
Sub-Study Specific Exclusion Criteria 
Use of medications that are contraindicated with CVC and that could not be replaced or stopped during the study 
period (See Appendix 3 Table 3 for Disallowed Medications).  
6.3. 
Exclusion of Specific Populations 
Children and adolescents will not be included in this trial.   
No data currently exist for the effects of CVC on reproduction and development in humans. Pregnancy should be 
avoided in women receiving this compound. Women of childbearing potential should undergo pregnancy testing 
prior to initiation of CVC and periodically during treatment. In addition, adequate contraceptive methods should be 
consistently used by males and females during and for 1 month after treatment with CVC. Pregnancies in both 
female participants and in partners of male participants should be reported to the PI. 
CVC is contraindicated in nursing mothers. CVC and its metabolites were detected in milk secreted from rats 
administered CVC. CVC milk to plasma ratios ranged from 0.7 to 0.8 in dams indicating that milk represents a 
potential route of exposure to CVC in rat pups. The extent to which CVC or any of its metabolites are excreted in 
human breast milk is not known. 
 
7. STUDY PRODUCT 
7.1. 
Study Product(s) and Administration  
Participants will be randomized according to the procedure described in the master protocol. 
If there are supply limitations on any product, the arms containing that product will be temporarily closed to 
enrollment and the corresponding placebo is not needed.  


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7.1.1. 
Study Product Description  
The CVC drug product is a solid oral dosage (tablet form) containing 150 mg of the active ingredient as a free base 
equivalent. The CVC 150 mg tablets are capsule-shaped, 15.7 × 7.9 mm in diameter and plain on both sides. The 
inactive ingredients of CVC tablets include fumaric acid, microcrystalline cellulose, croscarmellose sodium, 
colloidal silicon dioxide and magnesium stearate, which is film coated with an Opadry II yellow, a polyethylene 
glycol (PEG) and partially hydrolyzed polyvinyl alcohol (PVA) non-functional film coat. 
7.1.2. 
Dosing and Administration 
For the CVC component, treatment will be administered to participants while hospitalized as in-patients and will 
continue whether or not the patient is discharged from the hospital for a total 28-day course. CVC should be 
administered twice daily at approximately 12-hour intervals in fed condition and at approximately the same time 
each day (±2 hours). Patients may receive a larger dose (450 mg total) for their first day of treatment as a loading 
dose administered as a morning dose of 300 mg and an evening dose of 150 mg. The administration window will be 
within 24 hours of randomization. See Appendix 3 Table 2 for further details. 
Doses should be administered with food (or tube-feeds). For participants requiring mechanical ventilation, 
Investigators will need to determine the most appropriate means for providing the drug product with food (i.e., 
crushed tablet by feeding tube with adequate flush); preparation instructions for administration of CVC using a G-
tube or other enteral feeding tube are in the Pharmacy Manual. If a feeding tube is not available for >24 hours, the 
participant will discontinue study drug intervention, but will remain in the study for endpoints and safety 
observations.  
Appendix 3 Table 2: Dosing of CVC Depending on Time of Day of Randomization (Scenarios) 
 
Scenario 1 
Scenario 2 
Scenario 3 
 
Participant is 
randomized and entered 
into the system for first-
dose of Day 1 with 
breakfast 
Participant is 
randomized and entered 
into the system for first-
dose of Day 1 with 
lunch or early afternoon 
snack/meal 
Participant is 
randomized and entered 
into the system for first-
dose of Day 1 with 
dinner; 2nd dose of Day 
1 is N/A 
BID Dose 
Dose 1 
Dose 2 
Dose 1 
Dose 2 
Dose 1 
Dose 2 
Day 1 (Loading 
Dose, mg) 
300 
150 
300 
150 
300 
N/A 
Time of dosing 
8:00 AM 
8:00 PM 
11:30 AM 
11:30 PM 
6:00 PM 
N/A 
Acceptable Time 
Range 
6 – 10 AM 
6 – 10 PM 
9:30 AM – 
1:30 PM 
9:30 PM – 
1:30 AM 
4 – 8 PM 
N/A 
Days 2-28 
(Dose, mg) 
150 
150 
150 
150 
150 
150 
Time of dosing 
8:00 AM 
8:00 PM 
8:00 AM 
8:00 PM 
8:00 AM 
8:00 PM 
Acceptable Time Range 
6 – 10 AM 
6 – 10 PM 
6 – 10 AM 
6 – 10 PM 
6 – 10 AM 
6 – 10 PM 
 
 


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Any dose that is delayed may be given later that calendar day. Any dose that is missed (not given that calendar day) 
is not made up. The treatment course continues as described above even if the participant becomes PCR negative.  
 
Duration of therapy: 
• 
Cenicriviroc (Oral) – 28 days (i.e., up to Day 28 of study), including while hospitalized and post-discharge. 
 
7.1.3. 
Dose Escalation 
Not Applicable 
7.1.4. 
Dose Modifications 
See Table in section 7.4.2, Allowed Medications Requiring Dose Adjustments.  
 
7.1.4.1. Dose Modifications for Adverse Events 
If there is evidence of toxicity that, in the judgment of the Investigator, could place the participant at increased risk, 
study drug administration should be interrupted. Resumption of dosing should be discussed with the Sponsor. 
Any potential dose modifications of CVC need to be discussed with the Sponsor. 
Liver Assessment: Suggested Actions and Follow-up  
 
Close monitoring should be initiated for the following participants: 
• 
Participants enrolled with a normal baseline serum aminotransferases (AT) who develop an increase of 
serum AT ≥3 × ULN, or 
• 
Participants enrolled with elevated baseline AT who develop an increase of serum AT >2 × the baseline 
value  
The participant should be evaluated for liver biochemistry elevation potentially meeting Hy’s law criteria (see 
below) as soon as possible, preferably within 24 to 48 hours from the time the investigator becomes aware of the 
abnormal results. Evaluation should typically include repeat testing of all 4 of the usual serum biochemical measures 
(ALT, AST, ALP, and TBL) to confirm the abnormalities and to determine if they are increasing or decreasing. 
Testing should be repeated until the levels decrease or stabilize.  
If it is difficult for the participant to return to the study site promptly, the participant should be retested locally, but 
normal laboratory ranges should be recorded, results should be made available to sponsor’s study physician and the 
investigator immediately, and the data should be included in the eCRF. If repeat testing within this time frame is not 
possible, the study intervention should be discontinued. 
It is critical to initiate close monitoring immediately upon detection and confirmation of signals of liver 
biochemistry elevation potentially meeting Hy’s law criteria as early as possible and not to wait until the next 
scheduled visit or monitoring interval. Close monitoring of the participant should be initiated in conjunction with the 
sponsor and consideration given to the following: 
• 
Obtain a more detailed history of symptoms and prior or concurrent diseases.  
• 
Obtain a history of concomitant drug use, including nonprescription medications, herbal products and 
dietary supplements, alcohol and recreational drug use, and special diets.  
• 
Obtain a history of exposure to environmental chemical agents.  
• 
Initiation of appropriate evaluations including applicable laboratory tests (e.g., direct bilirubin, INR), 
physical assessments, and other assessments (e.g., imaging) 


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o 
Rule out other potential causes of biochemical abnormalities, e.g., acute viral hepatitis types A, B, 
C, D, and E; autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic hepatopathy; and 
biliary tract disease.  
• 
Consider gastroenterology or hepatology consultations. 
If any of the following criteria are met, discontinuation of study intervention should be considered (if indicated, 
prior to receipt of confirming retest biochemistry laboratory test results) and the sponsor notified of the 
discontinuation: 
• 
ALT or AST ≥3 × ULN and the participant is symptomatic with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia (>5%) 
• 
ALT or AST ≥3 × ULN and total bilirubin >2 × ULN or INR >1.5  
• 
ALT or AST ≥5 × ULN for more than 2 weeks 
• 
ALT or AST ≥8 × ULN 
All participants showing liver biochemistry elevation meeting potential Hy’s law criteria should be followed until all 
abnormalities return to normal or to the baseline state. 
Reporting of Potential Hy’s Law Cases 
Potential Hy’s law cases are defined by biochemical test results of hepatocellular injury and impaired hepatic 
function. They should be evaluated and followed further (i.e., close monitoring initiated) to determine whether these 
laboratory abnormalities are indicative of liver biochemistry elevation meeting potential Hy’s law criteria. As 
indicated above, discontinuation of study intervention should also be considered. Criteria that identify a potential 
Hy’s law case are as follows: 
• 
ALT or AST ≥3 × ULN AND 
• 
Total bilirubin ≥2 × ULN AND 
• 
Alkaline phosphatase <2 × ULN 
Sites must report every participant who meets the Hy’s law criteria if this occurs within the time the participant signs 
the ICF until 30 days after the last dose of study intervention. 
A laboratory alert for a liver biochemistry elevation potentially meeting Hy’s law criteria case will be sent 
immediately to the sponsor and investigators when the above criteria have been met, even if no clinical symptoms 
have been experienced. An Adverse Event of Interest Abnormal Liver Function Reporting Form should be 
completed as soon as possible (within 24 hours of notification) for liver biochemistry elevations potentially meeting 
Hy’s law criteria cases and submitted to the Sponsor. The eCRF pages associated with the potential Hy’s law cases 
must be completed within 7 calendar days. Potential Hy’s law cases will be evaluated by a hepatologist with 
expertise in drug-induced liver injury (DILI) and reviewed by the DSMB. 
7.1.5. 
Overdosage 
No specific information is available on the treatment of overdose of CVC. In the event of overdose, the participant 
should be observed closely for signs of toxicity. Appropriate supportive treatment should be provided if clinically 
indicated. 
An overdose of CVC, regardless of the presence of an associated SAE, is considered an ECI and must be 
documented and reported.   
Additionally, an SAE associated with an overdose of CVC must be documented and reported according to the 
requirements for SAEs.  


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7.1.6. 
Preparation/Handling/Storage/Accountability 
7.1.6.1. Acquisition and Accountability 
Investigational products (IP) will be shipped to the site either directly from participating companies, from the 
Sponsor, or from other regional or local drug repositories. All other supplies should be provided by the site. Multiple 
lots of each IP may be supplied. 
Study products received at the sites will be open label and not kit specific, unless specified in the protocol-specific 
Manual of Procedures (MOP) or pharmacy manual. Drug preparation will be performed by the participating site’s 
unblinded research pharmacist on the same day of administration to the participant. 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 participant 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. 
7.1.6.2. Formulation, Appearance, Packaging, and Labeling 
CVC Component: 
The Cenicriviroc mesylate drug product formulation used for clinical trials is DP-7A, it is supplied as an immediate-
release tablet for oral administration containing 150 mg of Cenicriviroc as Cenicriviroc mesylate (CVC) drug 
substance. The 150 mg tablets are yellow-coated. The formulated tablet contains the following excipients: fumaric 
acid (solubility enhancer), microcrystalline cellulose (filler), croscarmellose sodium (disintegrant), colloidal silicon 
dioxide (glidant), magnesium stearate (lubricant), and Opadry® II yellow (film coating). 
Study drug will be provided in a HDPE bottle containing desiccant, and induction sealed. 
Oral placebo component: 
Placebo tablets match the active product in appearance. Placebo tablets contain excipients of microcrystalline 
cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, Opadry® II yellow, lactose 
monohydrate, and FD&C Yellow #5 Aluminum Lake. 
7.1.6.3. Product Storage and Stability 
CVC study drug is to be stored at 15°C to 30°C (59°F to 86°F) with transient excursions permitted to -20°C (-4°F) 
to 60°C (140°F). 
7.1.6.4. Preparation 
Refer to the protocol-specific MOP for details about preparation.  


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No agent preparation is required for CVC oral dosing. Preparation instructions for use of CVC with a feeding tube 
can be found in the Pharmacy Manual.  
7.2. 
Measures to Minimize Bias: Randomization and Blinding 
Randomization will as specified in the Master Protocol. 
7.3. 
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). 
7.4. 
Concomitant Therapy 
7.4.1. 
Permitted Concomitant Therapy and Procedures 
All concomitant therapies permitted in the master protocol will be allowed for this sub-study, except 
lopinavir/ritonavir, as indicated below. 
7.4.2. 
Prohibited Concomitant Therapy 
All concomitant therapies prohibited in the master protocol will also be prohibited for this sub-study.  Additional 
prohibited therapies are detailed below. 
CVC Component: 
Caution should always be exercised when administering concomitant medications based on the individual 
medication profile and clinical risk-benefit assessment. A complete list of prohibited medications is provided in 
Appendix 3 Table 3. Concomitant therapies of particular note include: 
• 
Antiretroviral agents (See the table below [Appendix 3 Table 3] for other antiretroviral agents) 
o CVC can be used in combination with remdesivir. 
o Dolutegravir, Tenofovir each has no significant impact on CVC exposure and would be acceptable to 
co-administer with study intervention in this study. 
o Ritonavir or any combination of a protease inhibitor with ritonavir should not be co-administered with 
drug product in this study due to a significant drug interaction between ritonavir and CVC. 
 
Appendix 3 Table 3:  For CVC, Disallowed Medications 
Disallowed Medications 
 
Antibacterials 
rifampin, nafcillin, clarithromycin, erythromycin, telithromycin 
Anticonvulsants 
carbamazepin, phenytoin 
Antidepressants 
Nefazodone 
Antifungals 
voriconazole, itraconazole, ketoconazole, posaconazole 
Antihistamines 
Astemizole 
Anti-inflammatory drugs 
Sulfasalazine 
Antimetabolite drugs 
Methotrexate 
Antipsychotics 
Pimozide 
Antivirals 
Efavirenz, etravirine, boceprevir, dasabuvir/ombitasvir/paritaprevir/ritonavir, indinavir, 
lopinavir/ritonavir, nelfinavir, ombitasvir/paritaprevir/ritonavir, ritonavir, saquinavir, 
telaprevir, glecaprevir/pibrentasvir 
Ade Ergot Alkaloids 
dihydroergotamine, ergonovine, ergotamine, methylergonovine 


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Lipid-lowering agents 
Gemfibrozil 
Other 
Cisapride 
 
 
Appendix 3 Table 4: Allowed Medications Requiring Dose Adjustments 
Allowed Medications Requiring Dose Adjustments 
Opioids:  
Fentanyl, Alfentanil 
The preference for opioid use for analgesia is to employ a non-fentanyl-based 
strategy (e.g., dilaudid). Note: fentanyl and alfentanil are CYP3A4 substrates, 
thus use of either with CVC may increase fentanyl and alfentanil exposure. 
 
If needed, fentanyl/alfentanil should be administered with close surveillance and a 
dose-titration strategy: 
• If feasible, it is recommended that the initial dose be decreased by 50% and 
up titrated to the desired effect.  
• If a customary starting-dose is needed in the Investigator’s judgment, should 
be down-titrated after initiation  
 
Sedative/hypnotics: midazolam, 
triazolam 
The preference for sedation is to employ a non-midazolam-based strategy (e.g., 
propofol). Note: the exposure of midazolam (a substrate of CYP3A4) can be 
increased 1.84-fold when co-administered with CVC. 
 
If needed, midazolam or triazolam should be administered with close surveillance 
and a dose-titration strategy: 
• If feasible, it is recommended that the initial dose be decreased by 50% and 
up titrated to the desired effect.  
• If a customary starting-dose is needed in the investigator’s judgement, 
should be down-titrated after initiation  
 
Immunosuppressants: cyclosporin, 
tacrolimus 
In patients actively receiving cyclosporine or tacrolimus, CVC should be given as 
150 mg QD instead of 150 mg BID.  
 
Gastric acid-reducing agents (H2 
receptor antagonists, antacids, 
proton-pump inhibitors [PPIs]) 
Gastric acid-reducing agents should be administered at least 2 hours after CVC 
dosing (4 hours after dosing is ideal for fast-acting antacids). When possible, an 
H2 receptor antagonist (except cimetidine) or antacid is preferred over a proton-
pump inhibitor (PPI). It is recommended to start with the lowest dose of these 
agents and titrate appropriately. 
• H2 receptor antagonists (e.g., famotidine or ranitidine) should not exceed a 
dose comparable to famotidine 40 mg daily.  
• Antacids (e.g., aluminum hydroxide, calcium carbonate, magnesium 
carbonate, magnesium hydroxide, or bismuth subsalicylate) should be given 
at least 4 hours after administration of study drug.  
• PPIs (e.g., omeprazole, lansoprazole, esomeprazole, pantoprazole, 
rabeprazole, dexlansoprazole) are not recommended, however if needed, 
administer approximately 3 hours after study drug at a dose that does not 
exceed doses comparable to omeprazole 20 mg daily. Note:  due to the 
prolonged acid-reducing effect of PPIs (~16-24 hours), it is advised to follow 
these recommendations to reduce their potential impact on absorption of the 
subsequent CVC dose.  
 


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Allowed Medications Requiring Dose Adjustments 
Lipid-lowering agents: 
atorvastatin, simvastatin, 
lovastatin, pravastatin, 
rosuvastatin 
The maximum recommended daily doses are as follows: 
• atorvastatin 40 mg,  
• simvastatin 20 mg,  
• lovastatin 40 mg,  
• pravastatin 40 mg, and  
• rosuvastatin 20 mg;  
• pitavastatin use is allowed without dose restriction 
 
The medical monitor or equivalent representative must be consulted prior to use of 
higher doses of statins than those recommended above. 
PDE5 enzyme inhibitors: 
sildenafil, tadalafil, vardenafil 
The recommended starting doses for these medications are as follows:  
• sildenafil 25 mg,  
• tadalafil 2.5 mg,  
• vardenafil 2.5 mg 
Anticoagulants 
The recommended instructions for these medications are as follows: 
• rivaroxaban - if required, do not exceed 10 mg 
• apixaban and edoxaban – may increase CVC exposure, use with reduced 
doses and close clinical monitoring 
 
7.4.3. 
Rescue Medicine 
Not Applicable. 
7.4.4. 
Non-Research Standard of Care 
Not Applicable. 
 
8. STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
8.1. 
Halting Criteria and Discontinuation of Study Intervention 
8.1.1. 
Individual Study Product Halting  
Individual study product halting will be managed as specified in the Master Protocol. 
Cenicriviroc Halting 
See Section 7.1.4.1 for information about dosing modifications and potential discontinuation of CVC due to 
laboratory abnormalities.  
8.1.2. 
Study Halting 
Study halting will be managed as specified in the Master Protocol. 
8.2. 
Withdrawal from the Study 
Sub-study will have the same requirements as the main study. 
8.3. 
Lost to Follow-Up 
Sub-study will have the same requirements as the main study. 


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8.4. 
Readmission  
Sub-study will have the same requirements as the main study. 
 
9. STUDY ASSESSMENTS AND PROCEDURES 
Sub-study will have the same assessments and procedures as the main protocol. 
 
10. STATISTICAL CONSIDERATIONS 
Statistical analysis will be performed as described within the main body of the ACTIV-1 IM master protocol. 
 
 


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APPENDIX 4 – ACTIV-1 IM PROTOCOL TEAM ROSTER 
Role 
Contact 
Study Chair 
William G. Powderly, MD 
J. William Campbell Professor of Medicine 
Larry J. Shapiro Director, Institute for Public Health 
Director, Institute of Clinical and Translational Sciences 
Co-Director, Division of Infectious Diseases 
Washington University School of Medicine in St. Louis 
wpowderly@wustl.edu  
NCATS Representatives 
Jane C. Atkinson, DDS 
Director, Trial Innovation Network  
jatkinso@mail.nih.gov  
 
Cynthia Boucher, MS 
Health Science Policy Analyst  
cynthia.boucher@nih.gov  
 
Soju Chang, MD, MPH 
Medical Officer 
soju.chang@nih.hhs.gov 
 
Sam Bozzette, MD, PhD 
Chief Medical Officer  
sam.bozzette@nih.gov  
OWS Representative 
Thomas Stock, DO 
Clinical Advisor, OWS Therapeutics  
Advanced Decision Vectors, Contractor Supporting OS/ASPR 
thomas.stock@hhs.gov 
BARDA Representative 
Anna O’Rourke, MS 
Senior Advisor, Division of Clinical Development 
Biomedical Advanced Research and Development Authority 
Anna.O'rourke@hhs.gov 
ACTIV Clinical TX WG/NIAID 
Representative 
Sarah Read, MD, MHS 
ACTIV Clinical Therapeutics Working Group Co-Chair 
Deputy Director, Division of AIDS, NIAID 
readsa@niaid.nih.gov 
Study Statisticians 
Blinded: 
Lisa LaVange, PhD 
Professor and Interim Co-Chair, Department of Biostatistics 
University of North Carolina Gillings School of Health 
lisa.lavange@unc.edu  
 
Unblinded: 
Michael Proschan, PhD 
Mathematical Statistician, Biometrics Research Branch, NIAID 
proscham@mail.nih.gov 


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Role 
Contact 
DSMB Statisticians 
Blinded: 
Kevin Anstrom, PhD 
Director of Biostatistics/Professor of Biostatistics and 
Bioinformatics 
Duke Clinical Research Institute 
kevin.anstrom@duke.edu 
 
Sean O’Brien, PhD 
Associate Professor of Biostatistics and Bioinformatics 
Duke Clinical Research Institute 
sean.m.obrien@duke.edu 
 
Unblinded: 
Hussein Al-Khalidi, PhD 
Professor of Biostatistics and Bioinformatics 
Duke Clinical Research Institute 
hussein.al-khalidi@duke.edu 
 
Susan Halabi, PhD 
Professor of Biostatistics and Bioinformatics 
Duke Clinical Research Institute 
susan.halabi@duke.edu 
Site Investigator 
Representatives 
Emily R. Ko, MD, PhD 
Assistant Professor, Department of Medicine 
Duke University 
emily.rayko@duke.edu 
Anne Lachiewicz, MD, MPH, FIDSA 
Associate Professor of Medicine 
Division of Infectious Diseases 
University of North Carolina 
anne_lachiewicz@med.unc.edu 
Jane O’Halloran, MD, PhD 
Assistant Professor of Medicine 
Washington University, St. Louis 
janeaohalloran@wustl.edu 
Site Coordinator 
Representative 
Michael Klebert, PhD 
Washington University 
mklebert@wustl.edu 
Community Representative – 
Chair of Community Advisory 
Board 
TBD 


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Role 
Contact 
Coordinating Center 
Representative(s) 
Theresa Jasion, MSIS 
Project Lead, Trial Innovation Center 
Duke Clinical Research Institute 
theresa.jasion@duke.edu  
 
Neta Nelson, MPH 
Associate Director, Clinical Operations 
Technical Resources International, Inc. 
nnelson@tech-res.com 
 
Sandra Mendez Giraldo, MD  
Project Manager I, General Medicine  
Syneos Health 
sandra.mendez@syneoshealth.com 
U.S. IND Sponsor 
Daniel K. Benjamin, MD, MPH, PhD 
Kiser-Arena Distinguished Professor 
Duke Clinical Research Institute 
danny.benjamin@duke.edu  
Ex-U.S. HA Sponsor 
Daniel Molina, PharmD, MBA 
VP, Strategic Planning 
Technical Resources International, Inc. 
dmolina@tech-res.com  
Industry Representatives 
Allergan/AbbVie: 
David B. Bharucha, MD, PhD, FACC 
Vice President, Clinical Development, R&D 
David.Bharucha@Allergan.com 
 
Bristol Myers Squibb: 
Brian J. Gavin, PhD  
Development Lead, Orencia & Nulojix 
Immunology & Fibrosis Development 
brian.gavin@bms.com  
 
Gilead Sciences: 
Huyen Cao, MD 
Sr. Director 
Huyen.Cao@gilead.com 
 
Janssen Pharmaceuticals/Johnson & Johnson: 
Maria Beumont-Mauviel, MD 
Senior Director, Hepatitis Franchise Medical Lead 
ID&V Medical Department  
mbmauvie@its.jnj.com 
FNIH Representative  
Stacey J. Adam, PhD 
Director, Cancer 
Foundation for the National Institutes of Health 
sadam@fnih.org 


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Role 
Contact 
Study Pharmacy 
Representative 
TBD 
 
 
 


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ACTIV-1 IM: Randomized Master Protocol for Immune Modulators for Treating COVID-19  
 
 
 
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