Clinical trial NCT05894577
Conditions: Covid19
Keywords: SARS-CoV-2 COVID-19 Placebo Duke University Health System Outcomes Duke Clinical Research Institute ACTIV 6 ACTIV montelukast
Sponsor: Susanna Naggie, MD
Start date: 2023-01-27; Completion date: 2024-01-01
Enrollment: 1453 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the effectiveness of repurposed medications (study drug(s) in reducing symptoms of non-hospitalized participants with mild to moderate COVID-19. Participants will receive either study drug or placebo. They will self-report any new or worsening symptoms or medical events they may experience while taking study drug or placebo. This study is intended to be all remote with no in person visits, unless the study team feels it is in the best interest of a participant to see them in person.

Prior and current drug arms are listed on clinicaltrials.gov and will be updated with the activation of any new drug arms. Each study arm will also have its own clinicaltrials.gov entry and will include "Pro00107921" in the Unique Protocol ID.

Detailed description:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel betacoronavirus that first emerged in December 2019 and has since caused a global pandemic unseen in almost a century with respect to the number of cases and overall mortality. The clinical disease related to SARS-CoV-2 is referred to as Coronavirus Disease 2019 (COVID-19). Over 2020, advances were made for treatment of COVID-19 and several vaccinations have received emergency use authorization for prevention of SARS-CoV-2 infections. However, the pandemic continues to evolve with new variants and surges of infections in different regions of the world, requiring an ongoing evidence-generating platform, in particular for the treatment of COVID-19 infection in the outpatient setting.

This proposed platform protocol can serve as an evidence generating system for prioritized drugs repurposed from other indications with an established safety record and preliminary evidence of clinical efficacy for the treatment of COVID-19. The ultimate goal is to evaluate if repurposed medications can make participants feel better faster and reduce death and hospitalization.

This platform protocol is designed to be flexible so that it is suitable for a wide range of settings within healthcare systems and in community settings where it can be integrated into routine COVID-19 testing programs and subsequent treatment plans. This platform protocol will enroll participants in an outpatient setting with a confirmed polymerase chain reaction (PCR) or antigen test for SARS-CoV-2.

Participants will be randomized to study drugs or placebo based on the arms that are actively enrolling at the time of randomization. Study drugs may be added or removed according to adaptive design and/or emerging evidence. When there are multiple study drugs available, randomization will occur based on appropriateness of each drug for the participant as determined by the study protocol and investigator and participant equipoise. Each participant will be required to randomize to at least one study drug versus placebo. The probability of placebo to treatment will remain the same regardless of eligibility decisions.

Eligible participants will be randomized (1:1), in a blinded fashion, to either the study drug arm or placebo arm in addition to standard of care. As additional study drugs are added, the randomization will be altered to leverage placebo data across arms. Participants will receive a complete supply study drug or placebo with the quantity depending on the study drug/placebo to which they are randomized.

All study visits are designed to be remote. However, screening and enrollment may occur in-person at sites and unplanned study visits may occur in-person or remotely, as deemed appropriate by the site investigator for safety purposes. Participants will be asked to complete questionnaires and report safety events during the study. Participants will be prompted by the online system to report safety events and these will be reviewed and confirmed via medical records and site staff, as necessary.

Arms: arm 1: Montelukast will be self-administered orally by each participant at a dose of 10 mg once a day for 14 days. arm 2: Placebo - appearance and size matched to active study drug.

Placebo will be self-administered orally by each participant, with number of tablets matched to active study drug dosing.
Interventions: intervention 1: Placebo intervention 2: Montelukast
Intervention descriptions: intervention 1: Each study arm will contain a placebo comparator. Placebo will look similar to study drug and will be administered via the same route of administration and dose. However, placebo will be an inactive substance, containing no study drug. intervention 2: Montelukast sodium is a white to off-white powder. The 10 mg montelukast tablets are beige, rounded square-shaped, biconvex, film-coated tablets. Each tablet contains 10.4 mg of montelukast sodium, which is equivalent to 10 mg montelukast. All packaging will be labeled to indicate that the product is for investigational use.

Protocol documents:
ICF_000.pdf: 
 
ACTIV-6: COVID-19 Study of Repurposed Medications - Arm F (Montelukast) 
NCT05894577 
ICF version date Dec 22, 2022 
 


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TITLE: 
ACTIV-6: COVID-19 Outpatient Randomized Trial to Evaluate 
Efficacy of Repurposed Medications 
 
PROTOCOL NO.: 
None 
 
WCG IRB Protocol #20211467 
 
SPONSOR: 
Duke Clinical Research Institute 
 
<<CF-Main Header Block - Investigator>> 
STUDY-RELATED 
PHONE NUMBER(S): 
<<CF-Main User Defined #1>> 
 
[24 hour number is required] 
 
SPONSOR VERSION:  
9.0 
 
You are being invited to participate in ACTIV-6: COVID-19 Outpatient Randomized Trial to 
Evaluate Efficacy of Repurposed Medications. About 15,000 participants from around 280 
sites across the United States will be involved. The study is funded by The National Center for 
Advancing Translational Sciences (NCATS), a division of The National Institutes of Health (NIH). 
Duke Clinical Research Institute (DCRI) is the clinical coordinating center and Vanderbilt 
University Medical Center (VUMC) is the data coordinating center for this study. Please 
consider the following information in making your decision.  
 
STUDY SUMMARY 
You are being asked to participate in this study because you have been diagnosed with the 
SARS-CoV-2 virus, you currently have some symptoms of COVID-19, the disease caused by the 
virus, and you are at least 30 years old.  As part of this study, you will be given either a study 
medication or a placebo to see what types of effects the study medication or the placebo may 
have on your ability to get better and recover from the infection. You may benefit, but there is 
no guarantee. Others may benefit from the information learned.  
 
There are now multiple therapies that have been authorized or approved by FDA for the 
treatment of mild-to-moderate COVID-19 in the outpatient setting. Resources like 


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https://combatcovid.hhs.gov/possible-treatment-options-covid-19 may provide information 
about recommended treatments. These include monoclonal antibodies and antiviral 
medications, and more options may be approved in the future. Some of these therapies are 
given as an infusion and some are pills. These therapies have all been shown to help your body 
fight off COVID-19 and reduce the risk of severe disease and hospitalization. Monoclonal 
antibodies and antiviral medications are recommended for treatment of mild to moderate 
COVID-19 for people that have risk factors for more severe symptoms and complications. If you 
are interested in receiving monoclonal antibodies or antiviral medications you should discuss 
this with your healthcare provider. You and your doctor will decide which treatment options 
are right for you. You may receive any of these therapies and still participate in the study. This 
is your choice. 
 
Your participation in the study will last about 6 months (180 days).  All study visits can be 
remote (not in person). You will complete some surveys online or by phone if you do not have 
access to a computer/tablet/smart phone or internet. You may be asked to come in for an in-
person visit if the research study team feels this is in your best interest.  The surveys will ask 
you about your symptoms, general health, any medications you are currently taking and about 
any new or worsening medical problems you may be experiencing.   
 
This study will compare multiple study medications and placebo. Placebo is a product that will 
look like the study medication, but it is inactive (does not contain any study medication). 
Researchers use placebo so they can find out if the study medication does anything for a 
participant’s health. The study medication or placebo you will receive depends on when you 
enter the study and which study medications the study doctor determines are appropriate for 
you, based on your other medications and medical conditions.  At your first visit, you will be 
assigned to receive study medication or placebo. The assignment is done by randomization (a 
process like pulling numbers from a hat).  Neither you nor the study team will know if you are 
receiving study medication or placebo. 
 
While participating in this research, you will continue to receive standard of care (care you 
would have received even if you were not participating in this study) as directed by your regular 
health care provider. 
 


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The potential side effects and risks are dependent on the drug chosen, but can include aches, 
rash, and serious allergic reactions. 
 
More information about the ACTIV-6 study is provided below. If you are interested, please 
continue to read. If there is anything in this form you do not understand, please ask questions. 
 
INTRODUCTION 
Why am I being asked to take part in this study? 
You are being asked to participate in this study because you have had a recent COVID-19 test 
that is positive for the COVID-19 virus, you are exhibiting some mild to moderate symptoms of 
COVID-19, and you are at least 30 years of age.   
 
Why is this study being done? 
Researchers would like to evaluate whether medications that are already approved by the FDA 
for other diseases might also work for COVID-19.  This study is testing this in people with mild 
to moderate COVID-19 who do not require hospitalization. Use of these drugs for this study is 
considered “investigational.”  Investigational means these study medications or placebo are 
being researched for their effect on COVID-19. They are not approved by the FDA as treatment 
for COVID-19, but they are approved by the FDA for some other conditions.   
 
VOLUNTARY PARTICIPATION/ POTENTIAL BENEFITS 
 
Can I say no if I don’t want to participate? 
Yes, you do not have to take part. Your participation is voluntary. You can continue 
to get your usual health care even if you are not in this study.  
 
Will there be any benefit to others or me? 
We do not know if you will benefit from taking part in this study. Your participation may help 
doctors learn more about possible medications that could help treat COVID-19.  The 
information learned from this study may benefit others in the future. 


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WHAT YOU CAN EXPECT IF YOU DECIDE TO PARTICIPATE 
 
How long will I be in this study? 
Your participation will last about 180 days (6 months).  
 
Who will be my doctor on this study?  
Once you are enrolled in the study, you will continue under the care of your 
local (regular) health care provider. This healthcare provider should be your contact for all 
medical decisions and health-related questions. We may need to contact your health care 
provider during the time you are on study and afterwards.   
 
While participating in this research, you will continue to receive standard of care (care you 
would have received even if you were not participating in this study) as directed by your regular 
health care provider. Your regular health care provider will inform you of any changes to your 
care, based on your participation in this study. 
 
What is involved in this study? 
A member of the research study team will tell you about the study and ask you questions about 
your health and medications.  Because this study does not have in-person visits, you will 
communicate with the study team online or by phone.  Once you receive and start taking the 
study medication or placebo, you will be asked to complete a survey, either online or by 
telephone if you are not able to use the internet. The survey will ask you about your general 
health and well-being, any new symptoms you have, or changes to your health. The survey will 
let us know how you are doing. If you do not fill out the online survey, we will follow up with 
you to check on how you are doing. If you need help completing the surveys, the study team 
can assist you. If you report you are hospitalized during the study, go to an urgent care center, 
or visit an emergency department, we may review your medical record to get information 
about your health status and the hospitalization or emergency visit. You will be asked to sign a 
medical record release for this purpose.  The signed medical record release form is required for 
your participation in this study.  
 


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If you decide to participate and you are a good fit for the study, the information below 
describes in more detail what will happen during the study. 
 
Personal Information 
As part of this study, we will ask you to provide the following information: 
 
• Your date of birth so we can confirm your age. 
• Your phone number, email address, and cell phone so we can contact 
you to see how you are doing and to be sure you are doing all of the 
things needed for the study. Tell your study team if your contact 
information changes while you are participating. It’s important that we 
know the address where you are staying so we can send you your study 
medication to the correct place. 
• We will ask you to sign a medical release form to access your medical 
records so we can review your positive COVID-19 test result and any 
hospitalizations that occurred while you are participating in the study.  
• Contact information for a trusted person that you know (family member 
or friend) so we can contact them if we cannot reach you. These people 
may give us some information about your health if you are unable to do 
so. 
• A list of all your medicines (prescription and non-prescription). 
 
BASELINE (SCREENING) VISIT  
When you are first thinking about being in the study, you will either complete an online form or 
talk to someone from the study team, typically on the telephone.  The purpose of this visit is to 
check your interest in participating and to confirm that you can participate in the study.  We 
will tell you about the study, how we will follow you, and you will be asked to provide your 
consent to participate.  At this visit, we will also:  
 
• 
Ask you to provide a clear photograph of your positive COVID-19 test result  
• 
Ask you to provide identifying personal information such as home address, email, phone 
number, and a trusted person that you know (family or friend)  


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• 
Ask questions about your health, including potential for pregnancy and contraceptive 
use, and about any medications you are currently taking  
• 
Complete online surveys about your health, mood, and COVID-19 symptoms you may be 
experiencing  
• 
Confirm that you can get the study medication or placebo shipped to your home. It is 
not possible to ship study medication or placebo to a post office box. 
• 
Assign you to the study medication or placebo  
 
After the study team speaks with you and evaluates your health and medical information, there 
may be reasons you are unable to participate in this study.  These reasons will be explained to 
you.  
 
Study Medication Assignment 
You will be randomized to receive study medication or placebo.  Randomization means you will 
receive either study medication or placebo. Randomization will be determined by chance (like 
pulling numbers from a hat). As the number of drugs being tested increases, so does the chance 
you will be randomized to an active drug instead of placebo dependent upon which study 
arm(s) you choose. Neither you, your study doctor, nor the staff at the study site will know to 
which group you have been assigned, but we can quickly find out if there is ever a need to know 
for your safety and/or well-being.   
 
Depending on when you join the study, some of the study medications listed in this consent 
form will not be available.   
 
Study medication or placebo will be shipped directly to your home. To ensure study medication 
arrives on schedule, it is important to the let the study team know if your address changes.  You 
must provide a street address so we can make sure the study medication or placebo gets to 
you. It is not possible to ship to a PO Box.  
 
You will be provided instructions about how to take the medication.  To ensure study 
medication or placebo is taken as directed, and at the required intervals, you will be provided 
additional information about how to record taking study medication or placebo each day. 
 


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INTERVENTION PERIOD (DAYS 1-14)  
There may be a brief period between your consent to be in the study and the study medication 
or placebo arriving at your address. Once the study medication or placebo arrives at your 
address, the following events will occur: 
 
Day 1: 
• 
Receipt of study medication or placebo  
• 
Study medication self-administration (you take study medication or placebo as directed)  
• 
Provide information about your general health and well-being, including potential for 
pregnancy and contraceptive use  
• 
Provide information about any new or worsening symptoms 
• 
Provide information about any medical care you have received or any new medications 
you are taking 
 
Days 2-14: 
• 
Take study medication as directed 
• 
Complete a daily survey to confirm you took your study medication or placebo and to 
tell us about your health and well-being, including potential for pregnancy and 
contraceptive use, any medical care you have received, and any new medications you 
are taking. 
• 
We ask that you report symptoms each day until each symptom resolves (must be 
resolved at least 3 days in a row).  Symptom reporting will begin once you start taking 
the study medication and ending 28 days later.   
• 
On Days 3, 7, and 14 only: Collect reading from the oxygen monitor you received from 
the study  
• 
On Days 7 and 14 only: Provide information about your mood and quality of life, and 
your ability to perform normal tasks at home and your overall health  
• 
You will stop taking study medication or placebo, per prescribing instructions  
• 
On Day 14, a member of the study team will call to check in and evaluate your current 
health and ask you about any new medications you may be taking. We ask that you 
please make every effort to keep this remote visit appointment. It is important for the 
study team to evaluate you throughout the study. 
 


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FOLLOW-UP PERIOD (DAYS 15 - 28) 
The following events will occur during the Follow-Up Period, after you have finished taking the 
study medication or placebo.  
 
Days 15-28: 
• 
If you are still experiencing symptoms, then we will continue to ask you about your 
health each day. We will stop asking you these questions when you have had no 
symptoms for at least three days.  
 
Day 21: 
• 
You will continue to report your symptoms and we will continue to ask you about your 
health each day. We will stop asking you these questions when you have had no 
symptoms for at least three days (in a row) 
 
Day 28:  
• 
Remote assessment/visit (Day 28) – A member of the study team will call to check in 
and evaluate your current health and ask you about any new medications you may be 
taking. We ask that you please make every effort to keep this remote visit 
appointment. It is important for the study team to evaluate you throughout the study. 
• 
You will also be asked to complete surveys about your Quality of Life, overall health and 
well-being, and your ability to perform normal tasks at home. 
• 
You can stop reporting your symptoms if they have resolved for at least three days (in a 
row). 
 
DAY 90, DAY 120, AND DAY 180  
The following events will occur around Day 90, Day 120, and Day 180.  At these visits, the 
following events will occur:  
 
• 
You will provide information about any medications you are currently taking 
• 
Provide information about your general health, including pregnancy, and well-being  
• 
Provide information about any new or worsening symptoms, including symptoms that 
persist after infection otherwise known as post-acute sequelae of COVID-19 (PASC) or 
long COVID  


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• 
Fill out Quality of Life Survey, providing information about your mood, your ability to 
perform routine tasks and your overall health  
 
Day 180 will be considered your final visit and your participation will end. There may be 
circumstances that could require us to continue to follow-up with you after this last visit.  A 
member of the study team will provide you with this information.   
 
UNPLANNED STUDY VISIT 
If you have any bad side effects while taking study medication or placebo, we may want to 
follow-up with you to get more information about the event. To do this, we may contact you for 
additional information and/or you may be asked to come in for a clinic visit. Your study doctor 
will provide information about what is needed and how you should proceed. 
 
ONLINE SURVEYS AND PHONE CALLS 
After your initial (Baseline) visit with the study team, we will ask you to complete brief surveys 
online or by phone to find out about your health, mood, medications and if you are taking your 
study medication. We will ask you to do these surveys throughout the study.  
 
We ask that you provide your name and phone number so that the study organizers or your site 
may contact you. We will also ask you for the name and phone number of a person that you 
know and trust that can answer health questions about you if we are unable to reach you or 
you are unable to tell us yourself. This contact information is confidential and will only be 
available to representatives of the groups who are helping to organize this study - Duke Clinical 
Research Institute (DCRI) and Vanderbilt University Medical Center. Your site or DCRI may also 
contact your physician’s office to obtain medical records to collect information about any care 
you have received if you have not been able to be contacted by phone. 
 
If you miss any of your remote visits and/or are unable to complete your online surveys, the 
following will occur:  
 
• 
Your site, or the DCRI Participant Research Operations (PRO), may contact you by phone 
or other methods.  


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• 
These staff from your site, or the DCRI PRO, will ask you questions that are on the online 
surveys. 
• 
This phone interview should take about 15 minutes to complete. 
• 
If we cannot reach you, or if you are unable to answer questions, we will contact your 
trusted friend or family member to answer questions on your behalf.  
• 
Once enrollment is completed at your research study site, the site may close.  If so, then 
all study questions can be answered by the DCRI PRO. If you have any questions 
concerning the study during this time, you should call 833-385-1880. All your healthcare 
will continue to be performed by your personal healthcare provider. 
 
CAN I STOP PARTICIPATING BEFORE THE STUDY IS COMPLETE? 
You can choose to not participate or stop participating at any time without penalty or loss of 
benefits or access to standard medical care (care you would have received if you were not 
participating in this research). If possible, we would like for you to stay in the study until it is 
complete to make sure the final study results are helpful to you and others who may get 
COVID-19.   
 
If you are thinking about stopping, please let your study doctor know as soon as possible.  Your 
study doctor can talk about options that might work for you to continue.  
 
We will tell you if we learn anything new that might change your mind about being in the study. 
If you decide to stop participating, your usual medical care will not be affected.  
 
If you decide to stop taking the surveys and study calls, we will follow you by reviewing your 
medical record.  
 
If we lose contact with you, we will keep collecting information from your medical record to see 
how you are doing until the study is done. 
 
Your participation in the study may be stopped by your study doctor at any time without your 
consent. 


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HOW WILL MY CONFIDENTIALITY BE PROTECTED? 
In all research, there is a possible risk of the loss of confidentiality, but we will do our best to 
keep your information secure. 
 
This study will have a Certificate of Confidentiality issued by the National Institutes of Health 
(NIH). This certificate is to protect the identity of research participants. It means that doctors, 
researchers, and other staff involved in this study cannot be forced to provide identities of any 
participants in any legal proceeding. The certificate protects against the involuntary release of 
information about subjects collected during this research.  However, you may choose to 
voluntarily disclose the protected information and this certificate does not prohibit such 
voluntary disclosure.  Furthermore, the parties listed in the “Use of Health Information” section 
of this consent form may review our records under limited circumstances and this certificate 
does not prohibit such disclosure. 
 
We will keep your personal information secure in the data system. You will be assigned a 
unique code that will be the link between you and your study information. This process keeps 
your health information and study results separate from your other personal information. Your 
personal information will be kept securely and will not be made available to anyone except for 
reasons described in this consent form, such as for shipping the study medication to you.  
 
Receiving Information from Your Medical Record 
We will review your medical record while you are in the study. This information may include 
any medical visits or hospital, or emergency room visits you had during the study. We may also 
collect information about medicines, lab results, and other information that we determine may 
be useful to the study. Reviewing your medical, pharmacy, and laboratory records will help us 
understand your health status while you are participating in this study.  
 
ALTERNATIVES 
What other choices are there? 
Two types of treatments have been authorized or approved by FDA for the treatment of mild-
to-moderate COVID-19 in the outpatient setting: monoclonal antibodies and antiviral drugs.  


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Monoclonal antibodies are man-made proteins that can help your body fight off COVID-19 and 
reduce the risk of severe disease and hospitalization. Antiviral drugs stop specific viruses from 
multiplying in the body.  These medications are recommended for treatment of mild to 
moderate COVID-19 for people that have risk factors for more severe symptoms and 
complications.  New treatments may become available or be recommended in the future.  
Resources like https://combatcovid.hhs.gov/possible-treatment-options-covid-19 may provide 
information about recommended treatments. 
 
If you are interested in receiving monoclonal antibodies or antiviral drugs, you should discuss 
with your healthcare provider which treatment options are recommended for you.   
 
You may receive these medications for COVID-19 and still participate in the study. This is your 
choice.  
 
Your other choice is not to participate in the study. Your usual medical care will continue 
whether or not you participate in this study. 
 
RESULTS AND STUDY PROGRESS 
Will I be told the results of the research? 
You will be notified if we find any new information that may affect your willingness to continue 
participating in this study.  
 
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. 
 
The set of information used to decide the results may be made available to other researchers. 
This includes survey results and other health information collected from all study participants. 
Identifying information like your name, date of birth, home address, phone number, or email 
address will not be included in this information set. You will be assigned a unique code that will 
be the link between you and your study information.  
 


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Results of the research may also be published.  If results are published, they will not contain any 
information that is specific to you.  Once the study is complete, there may be an opportunity to 
share the results of this research.  If this occurs, you will be notified about how to access these 
results.   
 
POSSIBLE RISKS AND DISCOMFORTS 
A team of health experts called the Independent Data Monitoring Committee will regularly 
monitor the safety of study participants and the progress of the study overall. The committee 
can stop and hold a study if they have concerns about safety.  
 
What risks can I expect from taking part in this study? 
Possible side effects associated with the study medication or placebo are listed at the end of 
this document and are dependent on which study medication you get. You will indicate your 
willingness to participate in each study arm (arm means which study medication you will 
receive).   Each arm will contain study medication or placebo and you will be randomized to 
receive either study medication or placebo.   
 
It is important to notify the study team of any new or worsening problems you may experience 
while on this study. There may be unknown risks from participation.  
 
There is also the slight risk of loss of confidentiality.  Every effort will be made to protect your 
information, as described later in this form.  
 
PAYMENT AND COSTS 
Will I be paid for being in this study? 
You will receive one payment for your participation in the study. You will receive up to a $125 
gift card upon completion of the study through Day 120. The study team will determine when 
your participation is complete and will provide details regarding this payment, based on your 
participation through the Day 120 visit for the study. Your email and protected health 
information (PHI) may be shared with individuals and/or companies involved in processing 
payments. <<CF-Main Payment for Part. Paragraph>> 
<<CF-Main Financial Disclosure>> 


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Are there costs to me for being in this study? 
The study medication or placebo will be provided to you free of charge.  Study medication or 
placebo will only be provided according to the schedule described in this consent. Study 
medication or placebo will not be provided past your final study visit.  You may keep the oxygen 
monitor provided by the study. You or your insurance provider will be billed for any medical 
care that you would receive whether or not you are part of this study.  
 
USE OF HEALTH INFORMATION FOR RESEARCH 
 
What is Protected Health Information (PHI)?  
The PHI collected for this research study includes your name, address, phone 
number, email address, date of birth, and relevant health information like 
your medications and medical conditions.  
 
Will my PHI remain private? 
We will make every effort to keep your PHI safe. We will store records in a locked cabinet or 
office or on a password-protected computer. Your identity and your PHI will not be shared 
outside of this study unless it is required to protect your safety, the safety of others, or if you 
give us approval to share it. 
 
Who will have access to or receive my PHI? 
Your PHI may be given to others only if needed for reasons that are part of carrying out the 
study, such as determining the results of the study, making sure the study is being done 
correctly, and providing required reports.  
 
Some of those that may receive, use, or disclose your PHI are: 
• 
ACTIV-6 researchers and staff including the NIH and Duke Clinical Research Institute 
(DCRI) and the Vanderbilt University Medical Center 
• 
Researchers and staff at sites who are helping with the study 
• 
Healthcare professionals affiliated with the study  
• 
Healthcare providers who have provided your health services or treatment 
• 
Pharmacy staff and representatives who will package and ship study medication 


Consent to Participate 
In a Research Study 
 
 
 
 
 
IRB Approved Template 
 
MUST BE APPROVED  
 
FOR SITES BEFORE USE  
 
AS MODIFIED 
 
Dec 22, 2022 
 
 
 
15 of 28 
Participant Initials: _________ 
• 
Representatives of the institutional review board (IRB) sometimes called the “ethics 
board” <<CF-Main SMO Company 1>> <<CF-Main Affiliated IN Language 1>> 
• 
Government health and regulatory agencies such as the FDA 
• 
A team of health experts call the Independent Data Monitoring Committee who will 
regularly monitor the safety of study participants and the progress of the study overall 
 
Your information may be shared with groups who are not listed above. The federal privacy rules 
may not apply to these groups; however, they have their own rules and codes to assure that all 
efforts, within reason, will be made to keep your PHI private. 
 
How long will you keep my PHI? 
We will keep your health information and the consent form for as long 
as we need it, which will be for at least six (6) years. <<CF-Main User 
Defined #6>>This approval does not expire. Any research information 
entered into your medical record will be kept for as long as records are 
kept by the place where you receive your health care. 
 
Do I have to share my PHI with you? 
If you do not agree to use of your PHI, you will not be able to enroll or continue in this study. 
We will stop collecting information about you, but information we have already collected will 
still be used. You can tell your study doctor by sending a letter to his/her address that you want 
to take away your approval to use your PHI. You can find his/her address below. If you decide 
to stop your participation in the study, you can send a request through the web portal. 
 
CONTACT INFORMATION 
You will be provided a copy of your consent.  Please refer to this consent if you have questions 
at any time during your participation on this study.  The study team contact information is 
provided here:  
 
Study Site Name:  
[Site] 
Study Doctor Name:  
[Name/Credentials of Responsible PI at Site] 
Study Doctor Contact:  
[Number(s)] (24 hours) 
Study Doctor Address:  
[Address] 
 
[City, State, Zip] 


Consent to Participate 
In a Research Study 
 
 
 
 
 
IRB Approved Template 
 
MUST BE APPROVED  
 
FOR SITES BEFORE USE  
 
AS MODIFIED 
 
Dec 22, 2022 
 
 
 
16 of 28 
Participant Initials: _________ 
 
Study Coordinator Name  
(if applicable): 
[Name/Credentials of Alternate Point of Contact for the Study] 
Study Coordinator  
Contact (if applicable): 
[Number(s)] <<CF-Main Emerg. Phone Number>> 
 
Is there anyone I can call if I have questions or problems? 
If you have questions, concerns, or complaints about your participation, or suffered an injury or 
physical issue caused by the study, please call your study doctor at the number listed above. 
 
If you have questions, concerns, or complaints about study participation, you may contact the 
ACTIV-6 study hotline at (833)-385-1880.  
 
Immediate necessary medical care is available at [Site]<<CF-Main User Defined #2>> if you are 
injured because of your participation in this study. However, there is no commitment by 
[Site]<<CF-Main User Defined #2, your physicians, Duke University (Duke Clinical Research 
Institute), or the NIH to provide monetary compensation or free medical care to you in the 
event of a study-related injury.  
 
PREP 
Study related subject injury compensation will not be provided by Duke. 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 the Study medication.  Subjects using the 
Study medication may have limits on their right to sue the manufacturers, the Study sponsor, 
healthcare providers and others for significant injuries and adverse reactions.  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. 
 
If you have questions, concerns or complaints about the research, or information about your 
rights as a research subject, you should contact the WCG Institutional Review Board (IRB). The 


Consent to Participate 
In a Research Study 
 
 
 
 
 
IRB Approved Template 
 
MUST BE APPROVED  
 
FOR SITES BEFORE USE  
 
AS MODIFIED 
 
Dec 22, 2022 
 
 
 
17 of 28 
Participant Initials: _________ 
IRB is a group of people who review the research to protect your rights as a study participant. 
You can call the WCG IRB at toll free at 855-818-2289, or email at 
researchquestions@wcgirb.com.  
 
STUDY MEDICATIONS  
Depending on when you join the study, some of the study medications listed in this consent 
form will not be available for you.  Any drug may have side effects.  Because of this, it is 
important to notify the study team of any new or worsening conditions you may experience 
while taking study medication or placebo and after you finish taking the required dose of study 
medication or placebo.  It is also important to tell the study team about any new or current 
medications you are taking. 
 
RISK OF PREGNANCY WHILE TAKING STUDY MEDICATIONS   
• For people capable of getting pregnant:  
The effects of the ACTIV-6 study medications on a developing pregnancy or breastfeeding infant 
are unknown.  If you are pregnant or planning to become pregnant during the next 90 days and 
or are breast feeding, please inform the study team. You will be asked to complete a Pregnancy 
Reasonably Excluded Checklist. 
 
If you are someone who could become pregnant (you have not had a hysterectomy and/or both 
tubes and/or both ovaries removed and/or you are not postmenopausal and over the age of 
45) and you have a sexual partner who is able to conceive children (has not had a vasectomy 
with a negative post-surgery semen analysis), it will be important for you to practice effective 
birth control methods while taking study medication or placebo.  Please ask the study team 
about acceptable methods. 
 
Because no birth control method is 100% effective, you should notify your study doctor 
immediately if you think there is any chance you could be pregnant, even if you have had a 
recent negative pregnancy test. If you become pregnant, we may want to review your medical 
history before and after you give birth.  


Consent to Participate 
In a Research Study 
 
 
 
 
 
IRB Approved Template 
 
MUST BE APPROVED  
 
FOR SITES BEFORE USE  
 
AS MODIFIED 
 
Dec 22, 2022 
 
 
 
18 of 28 
Participant Initials: _________ 
 
• 
For people who can get someone pregnant:  
If you can conceive children and your partner is someone who could possibly become pregnant 
(they have not completed menopause and are over the age of 45 or have not had a 
hysterectomy and/or both tubes and/or both ovaries removed) you should practice effective 
birth control methods while taking study medication or placebo.  If you have questions about 
what is considered effective birth control, please ask the study team.  
 
You should not donate sperm for the duration of the study and for 30 days after the last dose of 
study medication. 
 
If your partner becomes pregnant while you are taking study drug, it is important to notify the 
study team right away.  They may want to review your partner’s medical history during and 
after the birth. 
 
RISKS ASSOCIATED WITH FLUVOXAMINE MALEATE AND PLACEBO 
Any drug may have side effects.  Because of this, it is important to notify the study team of any 
new or worsening conditions you may experience while taking fluvoxamine or placebo and 
after you finish taking the required dose of fluvoxamine or placebo.   
 
Because some drugs should not be taken with fluvoxamine or placebo, it is also important to 
tell the study team about any new or current medications (prescription and non-prescription) 
that you are taking before you start taking fluvoxamine or placebo. Taking fluvoxamine may 
make it more difficult for your body to break down caffeine; 1 cup of coffee has the effects of 4 
cups while taking fluvoxamine.   
 
Below are some possible, known risks associated with fluvoxamine and placebo. There may also 
be unknown risks from participation. If you experience side effects such as difficulty breathing, 
wheezing, change in heart rate, nausea, vomiting and diarrhea, rash or hives shortly after 
taking fluvoxamine, you should seek medical attention right away, as these could be signs of 
a severe or life-threatening allergic reaction.  


Consent to Participate 
In a Research Study 
 
 
 
 
 
IRB Approved Template 
 
MUST BE APPROVED  
 
FOR SITES BEFORE USE  
 
AS MODIFIED 
 
Dec 22, 2022 
 
 
 
19 of 28 
Participant Initials: _________ 
 
The most common (more likely) side effects of fluvoxamine or placebo are:  
 
• Nausea 
• Somnolence (feeling drowsy, sleepy)  
• Insomnia (hard to fall asleep and stay asleep) 
• Asthenia (physical weakness, lack of energy)  
• Nervousness 
• Headache 
• Dry mouth  
• Dyspepsia (indigestion) 
• Constipation 
• Abnormal ejaculation  
• Sweating  
• Anorexia (loss of appetite, not eating) 
• Tremor (uncontrolled quivering or trembling) 
• Vomiting 
 
Rare (less likely) side effects of fluvoxamine or placebo are: 
 
• 
Hematemesis (vomiting blood) 
• 
Purpura (rash of purple spots under the skin caused by internal bleeding from small 
blood vessels)  
• Hemoptysis (coughing up blood)  
• Laryngismus (spasm of the larynx which can cause heavy or labored breathing)  
• 
Hematospermia (blood in semen) 
• 
Withdrawal syndrome (physical and mental symptoms that occur after stopping or 
reducing intake of a drug)  
• 
Suicidal thoughts in people under 24 years old 
Because of possible side effects, you will not be able to receive fluvoxamine maleate as part of 
this study if you have any of the following conditions or are taking any of these drugs: 
• 
bipolar disorder 


Consent to Participate 
In a Research Study 
 
 
 
 
 
IRB Approved Template 
 
MUST BE APPROVED  
 
FOR SITES BEFORE USE  
 
AS MODIFIED 
 
Dec 22, 2022 
 
 
 
20 of 28 
Participant Initials: _________ 
• 
use of selective serotonin (or norepinephrine) reuptake inhibitors (SSRIs/SNRIs) or 
monoamine oxidase inhibitors (MAOIs) within two weeks,  
• 
use of fluoxetine (Prozac) within 45 days  
• 
current use of tizanidine (a muscle relaxant), thioridazine (a medicine for schizophrenia), 
alosetron (IBS drug), pimozide (to treat verbal tics), diazepam (to treat anxiety), 
ramelteon (to treat insomnia), linezolid (an antibiotic).  
• 
Are pregnant or nursing 
You should ask your doctor if it is safe to take fluvoxamine maleate if you have any of the 
following conditions or are taking any of the following medications: 
• 
liver dysfunction 
• 
warfarin (a blood thinner),  
• 
diltiazem, propranolol, and metoprolol (to control blood pressure or heart rate),  
• 
tramadol or fentanyl (painkillers),  
• 
buspirone (for anxiety),  
• 
lithium (for bipolar disorder),  
• 
amphetamines (for ADHD),  
• 
St. John’s Wort (an herbal supplement)  
• 
carbamazepine (for seizures) 
• 
tricyclic antidepressants 
• 
antipsychotic drugs, such as clozapine 
• 
benzodiazepines, such as alprazolam 
• 
Methadone 
• 
Mexiletine 
• 
Theophylline 
• 
NSAIDS or aspirin   
 
□ Study participant agrees to participate in the fluvoxamine and placebo arm of this 
study  
 
□ Study participant does not agree to participate in the fluvoxamine and placebo arm of 
this study  
 


Consent to Participate 
In a Research Study 
 
 
 
 
 
IRB Approved Template 
 
MUST BE APPROVED  
 
FOR SITES BEFORE USE  
 
AS MODIFIED 
 
Dec 22, 2022 
 
 
 
21 of 28 
Participant Initials: _________ 
RISKS ASSOCIATED WITH MONTELUKAST AND PLACEBO  
Below are some possible, known risks associated with montelukast and placebo. There may 
also be unknown risks from participation. 
 
The most common (more likely) side effects of montelukast or placebo are:  
• 
Upper respiratory infection 
• 
Fever 
• 
Headache 
• 
Sore throat 
• 
Cough 
• 
Abdominal pain 
• 
Diarrhea 
• 
Ear infection 
• 
Influenza 
• 
Runny nose 
• 
Sinus infection 
 
Rare (less likely) side effects of montelukast or placebo are: 
• 
Dizziness 
• 
Nasal congestion 
• 
Rash  
• 
Elevated liver enzymes  
• 
Neuropsychiatric events including agitation, hostility, anxiousness, depression, 
sleepwalking, suicidal thinking/behavior, and tremors 
 
Because of potential side effects, you will not be able to receive montelukast as part of this 
study if you have any of the following conditions or are taking any of these drugs: 
• 
Aspirin or other non-steroidal anti-inflammatory agents (NSAIDs) like ibuprofen  
 
□ Study participant agrees to participate in the montelukast and placebo arm of this 
study  
 
□ Study participant does not agree to participate in the montelukast and placebo arm of 
this study  


Consent to Participate 
In a Research Study 
 
 
 
 
 
IRB Approved Template 
 
MUST BE APPROVED  
 
FOR SITES BEFORE USE  
 
AS MODIFIED 
 
Dec 22, 2022 
 
 
 
22 of 28 
Participant Initials: _________ 
STATEMENT OF CONSENT 
My signature below indicates that I have read and understood this consent form. I have had 
enough time and opportunity to think about the information, ask questions, and get my 
questions answered to my satisfaction. I understand that I am under no obligation to 
participate in this study, but I am willing to participate, and I am freely giving my consent to 
participate in the ACTIV-6 study.  
 
A copy of this form will be given to you<<CF-Main California Bill of Rights>>. 
 
Participant: 
 
 
Print name: 
__________________________________________________________________ 
 
 
Signature: 
__________________________________________________________________ 
 
 
Date: 
____________________________________ 
Time (24 hour clock)  _________ 
 
 
Study Doctor or Designee Who Obtained Consent: 
 
 
Print name: 
__________________________________________________________________ 
 
 
Signature: 
__________________________________________________________________ 
 
 
Date: 
____________________________________ 
Time (24 hour clock)  _________ 
 


Consent to Participate 
In a Research Study 
 
 
 
 
 
IRB Approved Template 
 
MUST BE APPROVED  
 
FOR SITES BEFORE USE  
 
AS MODIFIED 
 
Dec 22, 2022 
 
 
 
23 of 28 
Participant Initials: _________ 
ACTIV-6 MEDICAL RECORDS RELEASE FORM 
AUTHORIZATION FOR RELEASE OF PROTECTED HEALTH INFORMATION 
 
 
I, _______________________________, birthdate __ __ __ /__ __ /__ __ __ __, have signed a consent  
 
FIRST & LAST NAME, PRINTED 
 
 
       
          month               day                 yea 
form to participate in the ACTIV- 6 study. For the purposes of the study, I give permission to the 
site study team, including personnel at the Duke Clinical Research Institute (DCRI), to collect 
medical information and billing information from any medical or healthcare facility I visit or at 
which I’m seen during my participation in the research.  
 
The information I agree to have disclosed for the research includes:  
 
• 
Medical bills (UB04 and/or Abstract Coding Summary) 
• 
Hospital discharge summaries 
• 
Reports from procedures, surgeries, laboratory tests, biopsies, radiologic images 
• 
Results of autopsy  
• 
Hospital patient discharge instructions 
• 
Clinic notes/visits 
 
This list represents the most information my site or DCRI could collect, but my site or DCRI will ask for 
the minimum necessary for research purposes and limited to specified dates of service. 
 
By signing this form, I authorize the patient accounts and medical records departments at any medical 
or healthcare facility at which I am treated or evaluated to disclose medical information and billing 
information to the ACTIV-6 study team at my site or DCRI. 
 
I understand that, if I sign this form, I am still able to receive medical treatment that is not related to the 
study. I understand that I can revoke this authorization, at any time, by writing to the ACTIV-6 study 
team at one of the addresses below. If I revoke the authorization, I understand information that was 
already shared will still be used for research purposes. Unless I revoke it earlier, this authorization will 
expire at the end of the research study. I understand that information used or disclosed by means of this 
authorization could be redisclosed and would no longer be protected under federal law. I will receive a 
copy of this authorization. 
 
 
_________________________________________________       DATE SIGNED ______/______/_________ 
                                                 SIGNATURE 
 
 
 
 
 
           MONTH          DAY               YEAR 


Consent to Participate 
In a Research Study 
 
 
 
 
 
IRB Approved Template 
 
MUST BE APPROVED  
 
FOR SITES BEFORE USE  
 
AS MODIFIED 
 
Dec 22, 2022 
 
 
 
24 of 28 
Participant Initials: _________ 
 
************************************************************************************* 
 
SITE OR DCRI PERSONNEL WILL COMPLETE THIS SECTION:  
For this research subject, please supply the information [indicated by a checked box below or, as 
indicated on the fax cover sheet]:
 
 Medical bills (UB04 and/or Abstract 
Coding Summary) 
 Hospital discharge summaries 
 Reports from procedures, surgeries, 
laboratory tests, biopsies, radiologic images 
 Results of autopsy  
 Hospital patient discharge instructions 
 Clinic notes/visits 
 History and physical form 
 
FOR DATE(S) OF SERVICE [Or, as indicated on the fax cover sheet] ___________________________ 
Please mail or fax the information requested to: 
 
Site: 
By Mail: [insert address) 
FAX Number: [insert Fax number] 
 
DCRI: 
By Mail: Duke Clinical Research Institute, ATTN: ACTIV-6 Coordinating Center 
300 West Morgan Street, Suite 800 
Durham, NC 27701 
FAX Number: TBD 
 
<<CF-Main California HIPAA>> 


Consent to Participate 
In a Research Study 
 
 
 
 
 
IRB Approved Template 
 
MUST BE APPROVED  
 
FOR SITES BEFORE USE  
 
AS MODIFIED 
 
Dec 22, 2022 
 
 
 
25 of 28 
Participant Initials: _________ 
 
**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)  


Consent to Participate 
In a Research Study 
 
 
 
 
 
IRB Approved Template 
 
MUST BE APPROVED  
 
FOR SITES BEFORE USE  
 
AS MODIFIED 
 
Dec 22, 2022 
 
 
 
26 of 28 
Participant Initials: _________ 
 
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. 


Consent to Participate 
In a Research Study 
 
 
 
 
 
IRB Approved Template 
 
MUST BE APPROVED  
 
FOR SITES BEFORE USE  
 
AS MODIFIED 
 
Dec 22, 2022 
 
 
 
27 of 28 
Participant Initials: _________ 
 
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 
 

SAP_002.pdf: 
ACTIV-6: COVID-19 Study of Repurposed Medications - Arm F (Montelukast)  
NCT05894577 
Statistical Analysis Plan v5.0 date Apr 01, 2022 
 


ACTIV-6 
COVID-19 Outpatient Randomized Trial to  
Evaluate Efficacy of Repurposed Medications 
 
 
STATISTICAL ANALYSIS PLAN (SAP) 
 
 
 
Funding Agency 
National Center for Advancing Translational Sciences 
Date 
2022-04-01 
Version 
5.0 
Principal Investigator 
Adrian Hernandez, MD, MHS 
Duke Clinical Research Institute 
200 Morris St. 
Durham, NC 27701 
Phone: 919-668-7515 
Email: adrian.hernandez@duke.edu 
Co-Principal 
Investigator/IND Sponsor:  
Susanna Naggie, MD, MHS 
Duke Clinical Research Institute 
200 Morris St. 
Durham, NC 27701 
Phone: 919-684-2584 
Email: susanna.naggie@duke.edu 
Data Coordinating Center 
Chris Lindsell, PhD 
Vanderbilt University School of Medicine 
2525 West End Avenue 
Suite 1100, Rm 11129 
Nashville, TN 37203 
Phone: 615-343-9867 
Email: chris.lindsell@vumc.org 
Statisticians 
Thomas G. Stewart, PhD (DCC) 
Frank Harrell, PhD (DCC) 
 
 
 


ACTIV-6 Statistical Analysis Plan
2 
CONFIDENTIAL
v5.0 01-Apr-2022
Approval Signatures
By signing below, I indicate that I have reviewed this document in its entirety and approve its contents.
Statistician: 
Thomas G. Stewart, PhD
Approval Date
Principle Investigator: 
Adrian Hernandez, MD, MHS
Approval Date
Co-Principal Investigator/IND Sponsor:
Susanna Naggie, MD, MHS
Approval Date
Principle Investigator
i
:
Adrian Hernandez MD MHS
4/8/2022
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April 15 2022
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2022-04-01


ACTIV-6 Statistical Analysis Plan 
 
3 
CONFIDENTIAL  
 
v5.0 01-Apr-2022  
Contents 
 
1 
Summary ................................................................................................................................................ 5 
2 
Schedule of planned analyses ................................................................................................................. 6 
3 
Analysis plan for the primary endpoint .................................................................................................. 6 
3.1 
Time to recovery (within 28 days) ................................................................................................ 6 
3.1.1 
Definition .......................................................................................................................... 6 
3.1.2 
Estimand ........................................................................................................................... 6 
3.1.3 
Model ................................................................................................................................ 6 
3.1.4 
Priors ................................................................................................................................. 7 
3.2 
All cause hospitalization or death (within 28 days) ...................................................................... 7 
3.2.1 
Definition .......................................................................................................................... 7 
3.2.2 
Estimand ........................................................................................................................... 7 
3.2.3 
Model ................................................................................................................................ 7 
3.3 
Missing data .................................................................................................................................. 7 
3.4 
Heterogeneity of treatment effect ................................................................................................. 7 
4 
Analysis of screening endpoint .............................................................................................................. 8 
4.1 
Concordance-, discordance-, equivalence- probabilities............................................................... 8 
4.2 
Days Benefit .................................................................................................................................. 8 
4.3 
Model ............................................................................................................................................ 9 
4.3.1 
Effect of previous state and time ..................................................................................... 10 
4.3.2 
Constraints and number of parameters ............................................................................ 12 
4.4 
Method of inference .................................................................................................................... 12 
4.5 
Likelihood ................................................................................................................................... 12 
4.6 
Priors ........................................................................................................................................... 13 
4.7 
Decision thresholds ..................................................................................................................... 13 
4.7.1 
Guidance to proceed to evaluation of primary endpoint ................................................. 13 
4.7.2 
Futility ............................................................................................................................. 13 
4.8 
Missing outcome data ................................................................................................................. 14 
4.9 
Covariate adjustment................................................................................................................... 14 
5 
Model diagnostics and sensitivity analyses .......................................................................................... 14 
6 
Analysis plan for secondary endpoints ................................................................................................. 15 
6.1 
Schedule of planned analyses ..................................................................................................... 15 
6.2 
Definitions and analysis details ................................................................................................... 15 


ACTIV-6 Statistical Analysis Plan 
 
4 
CONFIDENTIAL  
 
v5.0 01-Apr-2022  
6.2.1 
Mean time unwell ............................................................................................................ 15 
6.2.2 
Hospitalization or death (Day 14 and Day 28) ................................................................ 16 
6.2.3 
Mortality (Day 28) .......................................................................................................... 16 
6.2.4 
Hospitalization, urgent care, emergency room visit, or death (Day 28) ......................... 16 
6.2.5 
Symptom Count (Day 14) ............................................................................................... 16 
6.2.6 
COVID Clinical Progression Scale (Day 7, Day 14, and Day 28) .................................. 16 
6.2.7 
Modified Patient-Reported Outcomes Measurement Information System (PROMIS)-29 
(Day 7, Day 14, Day 28, and Day 90) ........................................................................................... 17 
7 
Trial characteristics .............................................................................................................................. 17 
7.1 
Simulation Study ......................................................................................................................... 17 
7.1.1 
Constructing a data generation model for time to event ................................................. 17 
7.1.2 
Summary of design choices and decision thresholds ...................................................... 18 
7.2 
Type I error control and power ................................................................................................... 18 
7.3 
Supplementary details of simulation ........................................................................................... 19 
7.3.1 
The primary estimand ..................................................................................................... 19 
7.3.2 
The estimation procedure ................................................................................................ 19 
7.3.3 
Posterior distribution of the treatment effect .................................................................. 19 
7.3.4 
The second approximation .............................................................................................. 20 
7.3.5 
How good is the approximation? .................................................................................... 20 
7.3.6 
Calibration of type I error ............................................................................................... 24 
7.3.7 
Power .............................................................................................................................. 25 
 
 
 


ACTIV-6 Statistical Analysis Plan 
 
5 
CONFIDENTIAL  
 
v5.0 01-Apr-2022  
1 Summary 
The key features of the trial are summarized in detail in the study protocol.  The following table restates 
some of the key study features from the protocol. 
Feature  
Description  
Study Design 
Multicenter, blinded, placebo-controlled randomized clinical trial 
Sample Size 
A maximum of 1200 
Primary Aim 
To evaluate the effectiveness of repurposed medications [study drug(s)] 
in reducing symptoms of non-hospitalized participants with mild to 
moderate COVID-19 
Primary Outcome 
Appendix specific.  Either (a) time to recovery or the composite endpoint 
of (b) hospitalization or death 
Primary Estimand 
Appendix specific. 
Secondary Outcomes 
x 
Mean time unwell 
x 
Hospitalization or death (Day 14 and Day 28), if not primary 
x 
Time to recovery (within 28 days), if not primary 
x 
Mortality (Day 28) 
x 
Hospitalization, urgent care, emergency room visit, or death 
(Day 28) 
x 
COVID Clinical Progression Scale (Day 7, Day 14, and Day 28) 
x 
Modified Patient-Reported Outcomes Measurement Information 
System (PROMIS)-29 (Day 7, Day 14, Day 28, and Day 90) 
Inference approach 
Bayesian posterior probabilities, point estimates, and credible intervals 
Planned screening analyses  N = 300 and possibly 600 
Screening endpoint 
guidance quantity 
ܲ(ݏܿݎ݁݁݊݅݊݃ ݁݊݀݌݋݅݊ݐ ܽݐ ܰ= 1200 > 0) 
Planned interim analyses 
If screening endpoint met, primary endpoint interim analysis at possibly 
N=300, 600, 900 
Planned interim rules 
Futility: posterior predictive ܲ(primary endpoint efficacy at N =
1200) < 0.05 
Efficacy: posterior P(primary endpoint efficacy) > 0.95 
Type I error control 
The combination of the screening endpoint, primary endpoint efficacy 
and futility rules, schedule of interim analyses, and choice of priors 
result in a simulated type I error rate of 0.05 
Power 
The minimal detectable effect at 80% power is a time to recovery hazard 
ratio of 1.2. 


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Study populations 
x 
Modified Intention to Treat (mITT) defined as all participants 
who receive study drug/placebo. 
x 
Safety population defined as all participants in the mITT 
population who report taking at least one dose of study drug or 
matching placebo 
 
2 Schedule of planned analyses 
Fixed enrollment triggers will be used for interim analyses. A screening analysis will occur after 
enrollment and completion of 14 day follow up of approximately 300 participants in a study arm (150 in 
study drug arm and 150 in placebo arm).  If deemed appropriate based on the screening endpoint, a 
primary endpoint interim may occur immediately at N=300.  Subsequent interim analyses may occur at 
N=600 or 900.  If the study (appendix) has not terminated early for futility or efficacy at previous interim 
analyses, a final analysis will occur at N=1200.  Individual study drugs may require different sample 
sizes, and the sample sizes may be adjusted based on the results of interim analyses. 
3 Analysis plan for the primary endpoint 
The primary endpoint is appendix specific.  Possible endpoints include (a) time to recovery (within 28 
days) or (b) hospitalization or death (within 28 days). 
3.1 Time to recovery (within 28 days) 
3.1.1 Definition 
Time to recovery is defined in accordance with the sustained clinical recovery endpoint described in FDA 
guidance document for COVID-19 clinical trials (https://www.fda.gov/media/137926/download).  
Specifically, day of recovery is the first day on which the participant reports three consecutive days 
without COVID-19 symptoms.  
3.1.2 Estimand 
The Fine-Gray approach will be used to compare each intervention to placebo with respect to the 
cumulative incidence of recovery, accounting for the semi-competing risk of mortality (Fine and Gray 
1999). The treatment effect parameter is estimated from a piece-wise proportional hazards regression 
model of the recovery endpoint in which subjects who die are retained in the risk set. 
3.1.3 Model 
The proportional hazards regression model will be constructed using a smooth, flexible parametric 
baseline hazard function.  The model will be estimated within the Bayesian framework.  The following 
covariates will be included in the regression component of the model: 
1. Randomization assignment 
2. Age as a restricted cubic spline with 3 knots 
3. Gender 
4. Duration of symptoms prior to treatment 
5. Calendar time as restricted cubic spline with 4 knots 
6. Vaccination status 
7. Geographic region (Northeast, Midwest, South, West) 
8. Call center indicator 
9. Additional appendix-specific covariates relevant to baseline disease severity and patient risk. 


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3.1.4 Priors 
The regression parameter for randomization assignment will be assigned a normal prior distribution with 
mean zero and standard deviation 0.1, selected so that type I error is bounded within 0.05.  All other 
regression parameters will have a non-informative prior. 
3.2 All cause hospitalization or death (within 28 days) 
3.2.1 Definition 
If a participant is hospitalized for any reason or dies from any cause within 28 days of receipt of study 
drug, then the participant will have experienced the all cause hospitalization or death endpoint. 
3.2.2 Estimand 
The difference in hospitalization or death rates will be summarized as an odds ratio estimated from a 
Bayesian logistic regression model.  
3.2.3 Model 
The Bayesian logistic regression model will include the following covariates: 
1. Randomization assignment 
2. Age as a restricted cubic spline with 3 knots 
3. Gender 
4. Duration of symptoms prior to treatment 
5. Calendar time as restricted cubic spline with 4 knots 
6. Vaccination status 
7. Geographic region (Northeast, Midwest, South, West) 
8. Call center indicator 
9. Additional appendix-specific covariates relevant to baseline disease severity and patient risk. 
3.3 Missing data 
Despite efforts to accurately collect all baseline and outcome data, some missingness may occur.  For 
time to recovery, participants who are lost to follow-up will by censored at the time of last follow-up.   
Missing data in the covariates will be handled with imputation and posterior stacking.  If the percentage 
of observations with missing covariates exceeds 5%, then multiple imputation (predictive mean 
matching) will be used.  Otherwise, single imputation (conditional mean of the complete cases) will be 
used. 
3.4 Heterogeneity of treatment effect 
Heterogeneity of treatment effect will be evaluated for the following variables: 
1. Vaccination status 
2. Calendar time (pandemic epoch) as a restricted cubic spline with 3 knots 
3. Duration of symptoms (time from symptom onset) as a restricted cubic spline with 3 knots 
4. Age as a restricted cubic spline with 3 knots 
5. BMI as a restricted cubic spline with 3 knots 
6. Patient reported symptom severity (none, mild, moderate, severe) 
Heterogeneity of treatment effect will be assessed by estimating model posterior probabilities for a full 
model including interaction term(s) with randomization assignment and a reduced model without the 
interaction term(s).  The reduced model, ܯ௥, is the primary endpoint regression model with the addition 


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of a variable in question (if not already in the model).  For example, for vaccination status, two models 
are: 
ܯ௥: 
Ⱦଵtrt + Ⱦଶݔଶ+ ڮ + Ⱦ௞ݔ௞+ ɀଵvaccinated 
ܯ௙: 
Ⱦଵtrt + ڮ + Ⱦ௞ݔ௞+ ɀଵvaccinated + ɀଶtrt × vaccinated 
Model posterior probabilities, ܲ൫ܯ௙หݕ൯ and ܲ(ܯ௥|ݕ), will be estimated using non-skeptical, non-
informative priors.  Because the analyses for heterogeneity of treatment effect are exploratory, there are 
no decision thresholds for reportable findings.  
4 Analysis of screening endpoint 
4.1 Concordance-, discordance-, equivalence- probabilities 
The OR and Wilcoxon test are translations of the treatment effect quantities known as concordance- and 
discordance- probabilities, which is why the Wilcoxon test can be performed by estimating a common OR 
fit with an ordinal regression model without covariates.  In the setting of a treatment assignment variable, 
the concordance-, discordance-, and equivalence- probabilities are defined as a comparison of outcomes 
from a randomly selected subject in the intervention arm (denoted by A) and a similarly selected subject 
in the non-intervention arm (denoted by B): 
concordance = ܲ(intervention outcome better) = ܲ(ܻ஺< ܻ஻) 
discordance = ܲ(non-intervention outcome better) = ܲ(ܻ஺> ܻ஻) 
equivalence = ܲ(outcomes identical) = ܲ(ܻ஺= ܻ஻). 
4.2 Days Benefit  
Days benefit is a summary measure of the treatment effect built on the concordance and discordance 
probabilities.  As such, it is related to the common OR (and the Wilcoxon test), but it does not require the 
proportional odds assumption.  It is a summary of treatment effect measured in days, which is an absolute 
and clinically relevant scale.  The measure captures any degree of reduction in symptom burden or 
decreases in clinical event rates. 
Days benefit is the cumulative difference of concordance and discordance probabilities over the course of 
follow-up.  It is interpreted as a difference in days.  Specifically, consider the outcome trajectory of study 
subjects assigned intervention to subjects assigned placebo, calculating (a) the expected number of days 
that a subject on treatment has a better outcome than placebo and (b) the expected number of days that the 
subject on placebo has a better outcome than intervention.  The difference between the two counts is the 
days benefit.   
To illustrate the definition, consider an hypothetical 14-day profile of outcome probabilities displayed in 
panels A and B in the figure below.  For the sake of illustration, the outcome probabilities are different 
between the intervention and non-intervention arms.  The colors in the profile plot denote distinct 
symptom and outcome scale values.  At the bottom of the plot (in blue) is “no symptoms”.  At the top (in 
red) is “death”.  The intermediate scale values are ordered in between the extremes.  The height of each 
box represents the probability of the corresponding outcome score.  For example, on day 1, there is an 
approximate 0.18 probability that a patient in the intervention arm will report no symptoms. 
The probabilities in panels A and B can be translated into concordance-, discordance-, and equivalence-
probabilities, which are shown in panel C.  Consider the comparison of a randomly selected patient in the 
intervention arm and a randomly selected patient in the non-intervention arm.  Concordance occurs when 


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the outcome for the intervention arm patient is better than the outcome of the patient in the non-
intervention.  Discordance is the opposite event, and equivalence occurs when the outcome scores are 
equivalent between the two.   
Days benefit, restated in terms of concordance and discordance probabilities, is the difference between (a)
the probability that the intervention is better and (b) the probability that the non-intervention is better, 
summed over all the days of follow-up.  In panel C, it is the area of the purple region minus the area of 
the orange region.  Mathematically, it is expressed as
days benefit = ෍ܲ(intervention better|ݐ)
ଵସ
௧ୀଵ
െܲ(non-intervention better|ݐ),
or equivalently,
days benefit = follow-up time × [ܲ(intervention better)– ܲ(non-intervention better)].
This quantity has the benefit of being measured in days, a scale that is readily understood and directly 
related to the practical impact of the treatment. An estimate of 3 days of benefit corresponds to a surplus 
of 3 days with better outcomes than the alternative treatment as captured by the primary endpoint.
The measure can also be modified to estimate how the treatment effect changes over time or over baseline 
symptom status. Estimates of expected benefit conditional on baseline covariate values can also be 
calculated, and the change in expected days benefit as a function of covariate values can be displayed in a 
partial effect plot.
4.3
Model
Consider a ܭcategory ordinal outcome assessed at ܶtime points. Let ܻdenote the vector of random 
outcomes ܻଵ, … , ்ܻ.  The lower-case notation ݕand ݕଵ, … , ݕ்denotes the observed values.  Let trt
indicate treatment assignment of intervention or placebo and let ݕ଴be the baseline symptom and outcome 
scale.  The probability model for the outcome can be decomposed into conditional components:
ܲ(ܻ= ݕଵ, ݕଶ, … , ݕ்|ݕ଴, trt) = ܲ(்ܻ= ݕ்|ݕ்ିଵ, ݕ்ିଶ, … , ݕଵ, ݕ଴, trt)
× ܲ(்ܻିଵ= ݕ்ିଵ|ݕ்ିଶ, … , ݕଵ, ݕ଴, trt) ڮ ܲ(ܻଷ= ݕଷ|ݕଶ, ݕଵ, ݕ଴, trt)
× ܲ(ܻଶ= ݕଶ|ݕଵ, ݕ଴, trt)ܲ(ܻଵ= ݕଵ|ݕ଴, trt)
Figure 1. Illustration of Days Benefit


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The model for analysis builds on three assumptions/modeling choices: 
1. Markov Property.  The Markov Property assumes that the conditional probability of today’s 
outcome only depends on yesterday’s outcome and not the entire trajectory of outcomes.  
Mathematically, this is expressed as ܲ(ܻ௧= ݕ௧|ݕ௧ିଵ, ݕ௧ିଶ, … , ݕଵ, ݕ଴, trt) = ܲ(ܻ௧= ݕ௧|ݕ௧ିଵ, trt) 
2. Smoothness in time and state. The effect of treatment over time and the effect of the previous 
outcome (including the interaction of time and previous outcome) can be described adequately 
well with continuous functions like restricted cubic splines or polynomials in the cumulative log 
odds scale. 
3. Non-proportionality.  The model does not assume proportionality; however, it does contain non-
proportionality parameters with skeptical priors. 
We discuss each of these modeling choices in turn.  First, the Markov assumption simplifies the 
expression of the probability model.  The conditional probability components are only a function of the 
previous outcome and treatment assignment. 
ܲ(ܻ= ݕଵ, ݕଶ, … , ݕ்|ݕ଴, trt) = ܲ(்ܻ= ݕ்|ݕ்ିଵ, trt)ܲ(்ܻିଵ= ݕ்ିଵ|ݕ்ିଶ, trt) ڮ ܲ(ܻଵ= ݕଵ|ݕ଴, trt) 
This is a common modeling choice when analyzing transition state outcomes, as it reduces the complexity 
of the model by reducing the number of model parameters. 
Like the Markov assumption, the choice to impose smoothness on the effects of time and previous 
outcome state reduces the number of parameters to estimate.  It allows the effect estimates to borrow 
information from adjacent time points and previous outcomes.  This choice also has implications for 
missing outcomes, which is likely to be important in this trial as a substantial proportion of patients are 
unlikely to report an outcome for every day of follow-up. 
The conditional probability components are modeled on the cumulative log odds scale, specifically 
log
ܲ(ܻ௧൒݇|ݕ௧ିଵ,trt)
1 െܲ(ܻ௧൒݇|ݕ௧ିଵ,trt) = regression function 
Ignoring the longitudinal nature of the data for a moment, the simplest form of the model is 
forԛkԛ = ԛʹ, … , ԛK: ԛԛԛ log
ܲ(ܻ௧൒݇|trt)
1 െܲ(ܻ௧൒݇|trt) = ൜Ƚ௞ԛifԛtrtԛ = ԛͲ
Ⱦ௞ԛifԛtrtԛ = ԛͳ 
where Ƚଶ൒Ƚଷ൒ڮ ൒Ƚ௄ 
and  Ⱦଶ൒Ⱦଷ൒ڮ ൒Ⱦ௄ 
The Ƚ parameters relate to the estimated probabilities of the outcome states among subjects in the placebo 
arm (trt=0), and the Ⱦ parameters capture the same for subjects in the intervention arm (trt =1).  It is 
common to assume that ȽଶെȾଶ= ȽଷെȾଷ= ڮ Ƚ௄െȾ௄ as a way to estimate a single common 
treatment effect.  This assumption is known as the proportional odds assumption.   
4.3.1 Effect of previous state and time 
The above model, as currently written, does not include a term for either the previous state or time on 
treatment.  The most flexible approach would be to specify a set of model parameters for each previous 
state and time point.   


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forԛkԛ = ԛʹ, … , ԛK: ԛԛԛ log
ܲ(ܻ௧൒݇|trt)
1 െܲ(ܻ௧൒݇|trt) = ቊ
Ƚ௧,௬೟షభ,௞ԛifԛtrtԛ = ԛͲ
Ⱦ௧,௬೟షభ,௞ԛifԛtrtԛ = ԛͳ 
where௖Ƚ௧,௬೟షభ,ଶ൒Ƚ௧,௬೟షభ,ଷ൒ڮ ൒Ƚ௧,௬೟షభ,௄ 
Ⱦ௧,௬೟షభ,ଶ൒Ⱦ௧,௬೟షభ,ଷ൒ڮ ൒Ⱦ௧,௬೟షభ,௄ 
 
If the number of possible outcome states is small, such a model may be appropriate.  However, each 
additional outcome state increases the number of model parameters.  When the number of states is 
moderate to large, modeling the log odds as a flexible function of the previous state, ݕ௧ିଵ, will cap the 
number of parameters and constrain the log odds to vary smoothly over the range of previous state values. 
To capture the effect of the previous state in the model, smooth functions like polynomials or restricted 
cubic splines replace the constant terms.  For the sake of notational ease, we used the notation 
ݏ(ݐ, ݕ௧ିଵ, ݀) to denote a smooth function of ݀ parameters capturing the effect of time and previous state.  
Note that because outcome state K is death, the transition probabilities are known when ݕ௧ିଵ= ܭ. 
forԛ݇ԛ = ԛʹ, … , ԛܭ  and   ݕ௧ିଵ< ܭ: 
 
        ԛԛԛ log
ܲ(ܻ௧൒݇|ݕ௧ିଵ,trt)
1 െܲ(ܻ௧൒݇|ݕ௧ିଵ,trt) = ቊ
ݏఈೖ(ݐ, ݕ௧ିଵ, ݀) ݂݅ ݐݎݐ =  0
ݏఉೖ(ݐ, ݕ௧ିଵ, ݀) ݂݅ ݐݎݐ =  1 
 
where  ݏఈమ(ݐ, ݕ௧ିଵ, ݀) ൒ݏఈయ(ݐ, ݕ௧ିଵ, ݀) ൒ڮ ൒ݏఈ಼(ݐ, ݕ௧ିଵ, ݀)   
and       ݏఉమ(ݐ, ݕ௧ିଵ, ݀) ൒ݏఉయ(ݐ, ݕ௧ିଵ, ݀) ൒ڮ ൒ݏఉ಼(ݐ, ݕ௧ିଵ, ݀)  
 
Were it not for the constraints imposed by the ordinal model, regression-type surfaces capturing the 
effects of time and previous state could be used directly for ݏఈೖor ݏఉೖ.  In was follows, we describe 
functions of time and previous state which include regression-like components which also conform to the 
constraints.  Specifically, the regression components are constructed from the cross product of smooth 
basis functions.  The quantity ݀ represents the total number of parameters that define the surface.  Note 
that ݀= ݀௬× ݀௧, where ݀௬ is the number or basis functions along the previous state dimension and ݀௧ is 
the number along the time dimension.  The quantities ݀௬ and ݀௧ need not be the same, as one dimension 
may warrant additional basis functions to capture more complex, nonlinear effects.  If the individual basis 
functions are of the form 
ݏ(ݔ) = ߠଵ+ ߠଶݏଶ(ݔ) + ߠଷݏଷ(ݔ) + ڮ + ߠௗݏௗ(ݔ), 
then the cross product of the basis functions, say ݏt for time and ݏp for previous state, is  
෍෍߶௜,௝
ௗ೟
௝ୀଵ
ௗ೤
௜ୀଵ
ݏ௜
௣(ݕ௧ିଵ)ݏ௝
௧(ݐ). 
Each surface is defined sequentially, starting with ݏఈమ(or ݏஒమ). 


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ݏ஑మ(ݐ, ݕ௧ିଵ, ݀) = ෍෍Ԅ௜,௝
஑మݏ௜
௣(ݕ௧ିଵ)ݏ௝
௧(ݐ) 
ݏ஑య(ݐ, ݕ௧ିଵ, ݀) = ݏ஑మ(ݐ, ݕ௧ିଵ, ݀) െ݁ݔ݌෍෍Ԅ௜,௝
஑యݏ௜
௣(ݕ௧ିଵ)ݏ௝
௧(ݐ) 
ݏ஑ర(ݐ, ݕ௧ିଵ, ݀) = ݏ஑య(ݐ, ݕ௧ିଵ, ݀) െexp ෍෍Ԅ௜,௝
஑రݏ௜
௣(ݕ௧ିଵ)ݏ௝
௧(ݐ) 
and, in general for ݏ஑಼, k>2, 
ݏ஑ೖ(ݐ, ݕ௧ିଵ, ݀) = ݏ஑ೖషభ(ݐ, ݕ௧ିଵ, ݀) െexp ෍෍Ԅ௜,௝
஑ೖݏ௜
௣(ݕ௧ିଵ)ݏ௝
௧(ݐ). 
Defining the surfaces in this way ensure that  ݏ஑ೖషభ(ݐ, ݕ௧ିଵ, ݀) ൒ݏ஑ೖ(ݐ, ݕ௧ିଵ, ݀).  The same construction 
holds for ݏஒೖ. 
4.3.2 Constraints and number of parameters 
Without the smooth functional relationship over time and previous state, there would be 2ܶ(ܭെ1)ଶ 
parameters. 
2ณ
trt groups
×
ܶณ
time points
×
ܭെ1
ᇣᇤᇥ
previous states
× ܭെ1
ᇣᇤᇥ
intercepts
= 2ܶ(ܭെ1)ଶ 
With the smooth functional relationships described above, there are 2݀(ܭെ1) parameters.   
2ณ
trt groups
×
݀ณ
time and 
previous state surface
× ܭെ1
ᇣᇤᇥ
intercepts
= 2݀(ܭെ1) 
The smallest possible model is with ݀= 3, though to allow for more flexible effect surfaces, ݀ will be 
larger.  Note that the parameters are highly constrained, and the degrees of freedom in the parameter 
space will be noticeably less.   
4.4 Method of inference 
Model parameters and subsequent summaries of treatment effect will be estimated with the Bayesian 
posterior distribution.  The posterior distribution is the normalized product of the likelihood model 
implied by the model described above and a set of prior distributions (which will be specified in the next 
section).  Point estimates will be generated as the mean of the marginal posterior distribution and interval 
estimates will be calculated from 95% highest posterior density limits. 
4.5 Likelihood 
The vector of model parameters ߶= (߶ఈ, ߶ఉ) is a combination of parameters that define the smooth 
surfaces of the cumulative log odds intercepts for the non-intervention and intervention arms.  Denoting 
ɀ௧,௬೟షభ,௬೟,trt = Ƚ௧,௬೟షభ,௬೟ or Ⱦ௧,௬೟షభ,௬೟ as the generic intercept term, then the likelihood can be expressed as 
ܲ(ܻ= ݕଵ, ݕଶ, … , ݕ்|ݕ଴,trt) = ෑܲ(ܻ௧= ݕ௧|ݕ௧ିଵ, ݐ,trt)
்
௧ୀଵ
 


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= ෑ
ە
ۖ
۔
ۖ
ۓ
1
1 + ݁ିஓ೟,೤೟షభ,಼,೟ೝ೟      ݂݅ ݕ௧= ܭ 
1 െ
1
1 + ݁ିஓ೟,೤೟షభ,మ,೟ೝ೟      ݂݅ ݕ௧= 1
1
1 + ݁ିஓ೟,೤೟షభ,೤೟,೟ೝ೟െ
1
1 + ݁ିஓ೟శభ,೤೟షభ,೤೟శభ,೟ೝ೟      ݋ݐ݄݁ݎݓ݅ݏ݁
்
௧ୀଵ
 
 
The overall log likelihood is the log of the product, resulting in a summation of the logged likelihood 
contribution of all subjects. 
4.6 Priors 
The quantities of inferential interest are not the raw parameters that characterize the smooth surfaces that 
capture the effects of time and previous state on the cumulative log odds intercepts.  Rather, the quantities 
of interest are parameters derived from the raw parameters, such as the transition probabilities and the 
degree of non-proportionality in the treatment effect for any specific combination of time and previous 
state.  As such, informative priors will be primarily placed on derived quantities to reflect prior beliefs 
about non-proportionality.  
Specifically, the informative model priors are: 
non proportionality ׽ ܧݔ݌(2) for each time and previous state 
The non-proportionality quantities are defined for each combination of time and previous state. 
Let ȟ୲,୷౪షభ,୩= Ƚ௧,௬೟షభ,௞െȾ௧,௬೟షభ,௞, 
then non proportionality, ݊݌௧,௬೟షభ= ݒܽݎ൫ȟ௧,௬೟షభ,ଶ, ȟ௧,௬೟షభ,ଷ, ڮ , ȟ௧,௬೟షభ,௄൯. 
The non-informative priors: 
Ԅ௜,௝
ஓೖ׽ ܰ(0,10), the regression parameters 
days benefit ׽ ܰ(0,4) 
4.7 Decision thresholds 
Decisions regarding screening are based on the posterior predictive distribution of expected days benefit.  
There is no formal decision threshold for inefficacy or harm because those findings are superseded by the 
futility rule.   
4.7.1 Guidance to proceed to evaluation of primary endpoint 
The ݌݋ݏݐ݁ݎ݅݋ݎ ݌ݎ݁݀݅ܿݐ݅ݒ݁ ܲ(days benefit at N=1200 > 0|interim data) will be calculated as a 
guidance quantity.  The trial has been calibrated so that the trial maintains the 0.05 bound on type I error 
regardless of how decision-makers choose to interpret the screening endpoint analysis.   
4.7.2 Futility 
A futility probability will be calculated at each interim analysis from the posterior predictive distribution.  
If the ݌݋ݏݐ݁ݎ݅݋ݎ ݌ݎ݁݀݅ܿݐ݅ݒ݁ P(concluding efficacy at N=1200|interim data) is sufficiently small, then 
decision-makers may terminate the trial early because it is unlikely that the study will demonstrate a 
positive benefit of treatment.  Even if the futility information is disregarded, the type I error is still 
bounded above by 0.05. 


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4.8 Missing outcome data 
All available symptom scale values within the 14 day follow-up period will be used in the analysis.  Each 
subject will contribute to the likelihood calculation for each observed outcome.  For example, if outcome 
values are observed for days 1, 3, and 12, then the likelihood contribution will be 
ܲ(ܻଵ= ݕଵ, ܻଷ= ݕଷ, ܻଵଶ= ݕଵଶ|ݕ଴,trt) = ܲ(ܻଵଶ= ݕଵଶ|ݕଷ,trt)ܲ(ܻଷ= ݕଷ|ݕଵ,trt)ܲ(ܻଵ= ݕଵ|ݕ଴,trt) 
where the probabilities conditional on outcomes from more than a day prior are calculated using the 
Chapman-Kolmogorov equation for n-step transition probabilities: 
ܲ(ܻ௧= ݕ௧|ݕ௧ି௥) 
= ෍෍ڮ ෍ܲ(ܻ௧= ݕ௧|ݕ௧ିଵ= ݅ଵ)ܲ(ܻ௧ିଵ= ݅ଵ|ݕ௧ିଶ= ݅ଶ)
௄
௜ೝషభୀଵ
ڮ ܲ൫ܻ௧ି(௥ିଵ) = ݅௥ିଵหݕ௧ି௥= ݕ௧ି௥൯
௄
௜మୀଵ
௄
௜భୀଵ
 
4.9 Covariate adjustment 
All the decision-making quantities are marginalized estimates from the covariate adjusted model.  
Specifically, for general covariates ݔଵ to ݔ௣, the model is  
forԛkԛ = ԛʹ, … , ԛK: ԛԛԛ log
ܲ(ܻ௧൒݇|trt)
1 െܲ(ܻ௧൒݇|trt) = ߠଵݔଵ+ ڮ + ߠଶݔ௣+ ቊ
Ƚ௧,௬೟షభ,௞ԛifԛtrtԛ = ԛͲ
Ⱦ௧,௬೟షభ,௞ԛifԛtrtԛ = ԛͳ 
where௖Ƚ௧,௬೟షభ,ଶ൒Ƚ௧,௬೟షభ,ଷ൒ڮ ൒Ƚ௧,௬೟షభ,௄ 
Ⱦ௧,௬೟షభ,ଶ൒Ⱦ௧,௬೟షభ,ଷ൒ڮ ൒Ⱦ௧,௬೟షభ,௄ 
For example, the covariates will include: 
1. Age 
2. Gender 
3. Duration of symptoms prior to treatment 
4. Additional appendix specific covariates relevant to baseline disease severity and patient risk. 
Note that the covariates are included in the model relying on a a proportional odds assumption.  
Summary measures, particularly of the screening endpoint treatment effect, will be calculated by 
marginalizing over the observed distribution of covariate values.  For example, expected days benefit 
would be calculated by averaging the conditional quantity over observed covariate combinations. 
Days benefit = 1
ܰ෍Days benefit | ݔ௜,ଵ, ڮ , ݔ௜,௣ 
ே
௜ୀଵ
 
5 Model diagnostics and sensitivity analyses 
The standard suite of model diagnostics for Bayesian models will be implemented, including graphical 
and analytical checks of the adequacy of the posterior samples, the model specification, and its 
predictions. 
Imputation, as an alternative to the complete data likelihood approach to missing data described in an 
earlier section, will be performed.  Further, a tipping point analysis will be provided which will estimate 
the degree to which differential missingness could change the conclusions of the analysis.  


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6 Analysis plan for secondary endpoints 
The following table provides a summary of the planned secondary endpoints, the associated estimands, 
and an analysis approach. 
Endpoint 
Estimand 
Analysis method 
 
Mean time unwell 
Difference in means 
Screening endpoint model 
Hospitalization or death (Day 14 
and Day 28) 
 
Model based estimates of the 
treatment effect odds ratio 
 
If the number of events is less 
than 30, a descriptive analysis 
will be performed. 
Logistic regression  
Mortality (Day 28) 
 
Model based estimates of the 
treatment effect odds ratio 
 
If the number of events is less 
than 30, a descriptive analysis 
will be performed. 
Logistic regression 
Mortality (time to event) 
Model based estimates of the 
treatment effect hazard ratio 
 
If the number of events is less 
than 30, a descriptive analysis 
will be performed. 
Cox regression 
Hospitalization, urgent care, 
emergency room visit, or death 
(time to event within 28 days) 
 
Model based estimates of the 
treatment effect hazard ratio 
 
If the number of events is less 
than 30, a descriptive analysis 
will be performed. 
Cox regression 
COVID Clinical Progression 
Scale (Day 7, Day 14, and Day 
28) 
 
Treatment effect odds ratio 
 
 
Cumulative probability ordinal 
regression with logit link 
Modified Patient-Reported 
Outcomes Measurement 
Information System (PROMIS)-
29 (Day 7, Day 14, Day 28, and 
Day 90) 
 
Treatment effect odds ratio 
Cumulative probability ordinal 
regression with logit link 
 
6.1 Schedule of planned analyses 
Secondary endpoints will be analyzed as part of the final analysis. 
6.2 Definitions and analysis details 
6.2.1 Mean time unwell 
Mean time unwell is the expected number of days during 14 day follow-up that a patient is unwell, as 
defined by a dichotomization of the primary endpoint.  The summary measure will be reported for all 


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possible dichotomizations.  Mean time unwell for each individual treatment arm is estimated from the 
primary endpoint model, as is the difference in mean time unwell.  The resulting point estimate and 95% 
credible interval of the difference in means will be generated from the marginalized (over covariates) 
posterior distribution.  The posterior probability that the difference in means exceeds zero will also be 
reported. 
6.2.2 Hospitalization or death (Day 14 and Day 28) 
All cause hospitalization or death is hospitalization or death for any reason within the specified time 
window. 
A Bayesian logistic regression model with flat priors will model the time to hospitalization or death.  The 
regression model will include treatment assignment, age as a restricted cubic spline with 3 knots, and 
other covariates included in the primary endpoint model.  Model-based estimates of the odds of the 
outcome on or before day 14 and day 28 will be generated.  The resulting point estimate of the odds ratio 
comparing non-intervention and intervention arms, 95% credible interval, and the probability that the 
odds ratio is less than 1 will be generated from the posterior distribution marginalized over observed 
covariates. 
6.2.3 Mortality (Day 28) 
Like the hospitalization or death endpoint, time to death or loss-to-follow-up will be recorded for each 
subject.  A Cox proportional hazards regression with flat priors will model the time to death endpoint 
from which model-based estimates of the odds of death within 28 days will be calculated.  The baseline 
hazard will be degree 5 M-spline function.  The resulting point estimate of the odds ratio comparing cases 
to controls, 95% credible interval, and the posterior probability that the odds ratio is less than 1 will be 
reported. 
6.2.4 Hospitalization, urgent care, emergency room visit, or death (Day 28) 
Time to hospitalization, urgent care, or emergency room visit is the date of the first qualifying event.  
Subjects that do not experience the event are censored on the day of last follow-up.  This endpoint is 
analyzed like the mortality endpoint. 
6.2.5 Symptom Count (Day 14) 
Day 14 symptom count is the number of symptoms reported on day 14.  If symptom resolution occurred 
prior to day 14 and a symptom count is not available for day 14, then the value of this endpoint is 0.  If 
symptom count on day 14 is not available, then the nearest reported symptom count within 3 days may be 
used.   
6.2.6 COVID Clinical Progression Scale (Day 7, Day 14, and Day 28) 
The COVID clinical progression scale is the most severe of the following outcomes during the respective 
study day.   
1. No limitation of activities 
2. Limitation of activities 
3. Hospitalized, no oxygen therapy 
4. Hospitalized, on oxygen by mask or nasal prongs 
5. Hospitalized, on non-invasive ventilation or high-flow oxygen 
6. Hospitalized, on intubation and mechanical ventilation 
7. Hospitalized, on ventilation + additional organ support – pressors, RRT, ECMO 
8. Death 


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This endpoint will be analyzed with a cumulative probability ordinal regression with logit link (also 
called an ordered logistic model).  Flat priors will be used.  The regression model will include treatment 
assignment, age as a restricted cubic spline with 3 knots, and other relevant covariates.  The resulting 
point estimate of the odds ratio comparing cases to controls, 95% credible interval, and the probability 
that the odds ratio is less than 1 will be generated from the posterior distribution marginalized over 
observed covariates. 
Unless positively identified as dead or hospitalized, subjects are assumed to be 2 or lower on the scale.  
Subjects that are missing the endpoint are included in the analysis as a partially observed endpoint.  (The 
contribution to the likelihood is the sum of both probabilities.) 
6.2.7 Modified Patient-Reported Outcomes Measurement Information System (PROMIS)-29 
(Day 7, Day 14, Day 28, and Day 90) 
The PROMIS-29 is set of domain-specific subscales.  The overall score and individual subscale scores 
will be analyzed with a cumulative probability ordinal regression with logit link (also called an ordered 
logistic model).  Flat priors will be used.  The regression model will include treatment assignment, age as 
a restricted cubic spline with 3 knots, and other relevant covariates.  The resulting point estimate of the 
odds ratio comparing cases to controls, 95% credible interval, and the probability that the odds ratio is 
less than 1 will be generated from the posterior distribution marginalized over observed covariates.  
Subjects with missing responses will be excluded from the analysis. 
7 Trial characteristics 
7.1 Simulation Study 
Rather than mimic the analysis of the screening endpoint followed by the primary endpoint, the following 
simulation study considers the time to recovery endpoint as if it were evaluated at each possible interim 
analysis, N=300, 600, 900, and 1200.  This scenario represents the analysis sequence with largest type I 
error.  By bounding this scenario to a type I error rate of 0.05, the global type I error rate of the study will 
also be bounded by 0.05. 
In addition to the conservativeness introduced by bounding the worst-case scenario, this approach is also 
conservative because it does not account for the screening phase or futility rules, both of which put 
downward pressure on the type I error rate. 
7.1.1 Constructing a data generation model for time to event 
A model of time to event was constructed using an approach similar to method of moments with the 
Weibull distribution.  Specifically, the parameters of the Weibull distribution were selected so that the 
resulting mean recovery time was 15 days from symptom onset and the 75th percentile of recovery was 22 
days.  The resulting distribution matches commonly reported metrics for recovery and the recovery data 
already collected within ACTIV-6.  The Weibull distribution with shape 1.8 and scale 18.4 serves as the 
data generation model (the baseline model) for the simulations that follow.  The recovery outcomes for 
patients in the intervention arm were generated from the baseline model modified with an additional 
treatment effect parameter (log relative hazard) which altered the outcome profile relative to the non-
intervention arm.  By increasing or decreasing the treatment effect parameter (Ⱦ), the outcome profile of 
subjects in the intervention arm was improved or degraded.  The outcome profiles of the intervention and 
non-intervention arms were identical when the treatment effect parameter was set to zero.  For the sake of 


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simulation, the treatment effect assumes a proportional hazards treatment effect, and the treatment effect 
hazard ratio is ܪܴ= ݁ஒ. 
7.1.2
Summary of design choices and decision thresholds
There are a number of design choices and decision thresholds which can be adjusted to reduce the risk of 
type I error.  The following table summarizes the choices made for this trial.  
Design Choice
Schedule of analyses
At N=300, 600, 900, 1200
Treatment effect summary
Hazard ratio for the treatment assignment variable
Efficacy definition
Hazard ratio exceeds zero
Efficacy threshold
Posterior probability of efficacy exceeds 0.95
Futility threshold
(not incorporated into simulation) Posterior predictive probability of 
efficacy at N=1200 is not more than 0.05.
Treatment effect prior 
distribution
Normal distribution with mean 0 and standard deviation 0.1.
7.2
Type I error control and power
Suppose the treatment effect HR is 1.5.  In order to calculate the power in this setting, 5000 datasets were 
generated from the data generation model described above.  Each was analyzed with the Bayesian model 
described in section 3.1.3, starting with the first 300 subjects, then 600, and so on until 1200 subjects.  
The first triggering event (if there was one) plus the corresponding sample size was recorded for each 
dataset.  If no triggering event occurred by the final analysis, the dataset was said to have triggered the 
max sample size constraint.  Thus, each dataset generated one of two possible outcomes: efficacy or max 
sample size.  The value of the standard deviation of the prior for the treatment effect was selected so that 
type I error was capped at 0.05.  Power was calculated as the proportion of datasets that generated an 
efficacy outcome.  The following figure shows the power curve over a range of treatment effect sizes.  


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7.3 Supplementary details of simulation 
7.3.1 The primary estimand 
To summarize the differences between groups, we use the proportional hazards regression model. The 
transformed regression parameter exp(Ⱦଵ) is the hazard ratio and is the primary quantity for inference. 
log relative hazard = Ⱦଵtrt 
7.3.2 The estimation procedure 
As has been described here, here, and here, the Cox model can be estimated from a Poisson generalized 
linear model. The dataset can be restructured so that the Poisson model generates identical estimates of 
the treatment effect as those achieved with direct estimation using the Cox model. That is, the restructured 
data combined with the following regression (where Ƚ௧ denotes an estimate for each inter-event time 
interval) will generate identical estimates (and standard errors) of Ⱦଵ. 
log(ɉ) = Ƚ௧+ Ⱦଵݔ 
Because Ⱦଵ is the quantity of primary interest, the estimation of several intercepts (Ƚ௧) is a hassle, 
especially when our end goal is a Bayesian posterior distribution. However, additional manipulation of 
the dataset will admit a much simpler Poisson GLM which results in approximate but highly accurate 
estimates of Ⱦଵ. The intercept estimates are replaced with a single intercept (Ⱦ଴) and an offset term, 
(log(ݖ)). 
log(ɉ) = Ⱦ଴+ Ⱦଵݔ+ ݈݋݃(ݖ) 
For details about the connection between the Poisson GLM and the Cox model, see the documents linked 
above. For demonstration purposes, we show the estimates of Ⱦ1 from the Cox, Poisson GLM, and 
Poisson GLM with offset. 
7.3.3 Posterior distribution of the treatment effect 
The purpose of this document is to explain the derivation of the posterior distribution for Ⱦଵ in a Bayesian 
analysis. The jumping-off point is the Poisson GLM model with offset. 
ܻ௜׽ Poisson(ɉ௜) 
log(ɉ௜) = Ⱦ଴+ Ⱦଵݔ௜+ ݈݋݃(ݖ௜) 
The prior for the treatment effect is potentially informative, with variance Ʌ. The prior for the intercept is 
an improper flat prior. 
Ⱦ଴׽ flat prior 
Ⱦଵ׽ ܰ(0, Ʌ) 
The log posterior is of the form 
Ⱦ଴෍ݕ௜
௜
+ Ⱦଵ෍ݕ௜ݔ௜
௜
െ෍݁ஒబାஒభ௫೔ା୪୭୥(௭೔)
௜
െ1
2Ʌ Ⱦଵ
ଶ+ constant. 
To integrate out Ⱦ଴, note that the posterior can be expressed as 
݁஺ஒబ݁ି஻௘ಊబܥ 


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With 
ܣ= ෍ݕ௜
௜
 
ܤ= ෍݁ஒభ௫೔ା୪୭୥(௭೔)
௜
 
log ܥ= Ⱦଵ෍ݕ௜ݔ௜
௜
െ1
2Ʌ Ⱦଵ
ଶ+ constant 
and 
න
݁஺ஒబ
ஶ
ିஶ
݁ି஻௘ಊబܥԜ݀Ⱦ଴= ܤି஺Ȟ(ܣ)ܥ 
The log posterior of Ⱦଵ (denoted log ݂(Ⱦଵ|ݔ, ݕ)) is  
െ൥෍ݕ௜
௜
൩log ൥෍݁ஒభ௫೔ା୪୭୥(௭೔)
௜
൩+ Ⱦଵ෍ݕ௜ݔ௜
௜
െ1
2Ʌ Ⱦଵ
ଶ+ new constant 
7.3.4 The second approximation 
To approximate the posterior with a normal distribution, we use a Taylor series.  Specifically, 
Ɋො= rootԛ ݀
݀Ⱦଵ
log ݂(Ⱦଵ|ݔ, ݕ) 
Ʌ෠= െ൥݀ଶ
݀Ⱦଵ
ଶlog ݂(Ⱦଵ|ݔ, ݕ)ቤ
ஜෝ
൩
ିଵ
. 
Because the first and second derivatives of the log posterior are readily available, and the root is 
extremely easy to calculate, the computation time for estimating the posterior distribution is dramatically 
reduced compared to sampling approaches. 
7.3.5 How good is the approximation? 
First, we analyze a single dataset of increasing size.  On the left of each plot, we show the Kaplan-Meier 
curves for the survival data; on the right we show the posterior function overlaid by the normal 
approximation.  Because our expression for the posterior is only proportional to a distribution (that is, it 
isn't normalized to have unit area), we normalize the expression to have unit mode.  Likewise, the same 
type of normalization was implemented for the normal approximation.  In this example, a skeptical prior 
with variance 0.1 is used. 


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Second, we compare the approximate posterior solution to the brms (R-package) sampling solution.  
In the plot below, we have a QQ-type plot.  The quantiles from the normal approximation are paired with 
the empirical quantiles of the 4000 posterior draws.  The plot is generated for both N=300 and N=1200. 
 
The approximate normal posterior distribution matches extremely well with the posterior distribution 
generated from sampling. 
 


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Third, we compare the posterior probabilities from the approximate solution to that of the sampling 
method in 25 datasets.  Specifically, we calculate ܲ(Ⱦଵ> 0). 
 
7.3.6 Calibration of type I error 
In a trial with multiple looks, the variance of the treatment effect prior can be selected to achieve a desired 
type I error rate.   
Simulated outcome data were generated from a Weibull distribution.  Censoring occurred after 28 days.  
The resulting survival curve for the reference (placebo) arm is depicted in blue in the figure below.  In 
red, we show the survival curves when the hazard ratio is 3/2 or 2/3.  The reference survival curve was 
selected so that approximately 88% of subject experienced an event within 28 days. 
 


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In the figure below, we show the results of a simulation study which indicate that a prior variance of 
0.017 will achieve an error rate of 0.05.  Note that this simulation study does not reflect a futility rule, 
which if implemented, may reduce the type I error rate and allow for a less skeptical prior. 
 
7.3.7 Power 
Using the prior standard deviation identified in the calibration plot above, we perform a simulation study 
to get at the power of a trial with looks at 300, 600, 900, and 1200 subjects.  The minimal detectable 
difference at 80% power is HR=1.17 when the data follow the distribution used in this simulation. 


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Prot_001.pdf: 
ACTIV-6: COVID-19 Study of Repurposed Medications - Arm F (Montelukast)  
NCT05894577 
 
Protocol [v7.0] Dec 08, 2022 


CONFIDENTIAL 
ACTIV-6 Protocol [v7.0] 
 
 
1 
 
 
 
ACTIV-6: COVID-19 Outpatient Randomized Trial to Evaluate Efficacy of Repurposed 
Medications 
 
 
 
 
IND Number: 
 
155481 
Principal Investigator: 
Adrian Hernandez, MD, MHS 
Duke Clinical Research Institute 
200 Morris St. 
Durham, NC 27701 
Phone: 919-668-7515 
Email: adrian.hernandez@duke.edu 
Co-Principal 
Investigator/IND 
Sponsor: 
Susanna Naggie, MD, MHS 
Duke Clinical Research Institute 
200 Morris St. 
Durham, NC 27701 
Phone: 919-684-2584 
Email: susanna.naggie@duke.edu 
Data Coordinating 
Center Investigator 
Chris Lindsell, PhD 
Duke Clinical Research Institute 
200 Morris St. 
Durham, NC 27701 
Phone: 919-668-8700 
Email: chris.lindsell@duke.edu 
Lead 
 
Funding Agency: 
 
National Center for Advancing Translational Sciences  
Version: 
 
7.0 
Date: 
08DEC2022 
 
 
 


CONFIDENTIAL 
ACTIV-6 Protocol [v7.0] 
 
 
2 
Statement of Compliance 
 
This trial will be conducted in compliance with the International Council for Harmonisation 
(ICH) E6 (R2) guideline for Good Clinical Practice (GCP), and the applicable regulatory 
requirements from the United States (US) Code of Federal Regulations (CFR), including 45 CFR 
46 (Human Subjects Protection); 21 CFR 312 (Investigational New Drug); 21 CFR 50 (Informed 
Consent), and 21 CFR 56 (Institutional Review Board). 
All individuals who are responsible for the conduct, management, or oversight of this study have 
completed Human Subjects Protection and ICH GCP Training. 
 
 
 
 


CONFIDENTIAL 
ACTIV-6 Protocol [v7.0] 
 
 
3 
Site Principal Investigator Statement 
 
I have read the protocol, including all appendices, and the package insert(s)/product label(s), and 
I agree that the protocol contains all necessary details for my staff and me to conduct this study 
as described. I will personally oversee the conduct of this study as outlined herein and will make 
a reasonable effort to complete the study within the time designated. I agree to make all 
reasonable efforts to adhere to the attached protocol. 
I will provide all study personnel under my supervision with copies of the protocol and access to 
all information provided by the sponsor or the sponsor’s representative. I will discuss this 
material with study personnel to ensure that they are fully informed about the efficacy and safety 
parameters and the conduct of the study in general. I am aware that, before beginning this study, 
the IRB, or equivalent oversite entity must approve this protocol in the clinical facility where it 
will be conducted. 
I agree to obtain informed consent from participants, as required by the IRB of record and 
according to government regulations and ICH guidelines. I further agree to report to the sponsor 
or its representative any adverse events in accordance with the terms of this protocol and the US 
CFR, Title 21, part 312.64, ICH GCP 4.11. I further agree to ensure the study is conducted in 
accordance with the provisions as stated and will comply with the prevailing local laws and 
customs. 
 
 
 
 
 
Site Principal Investigator Name (Print) 
 
 
 
 
 
 
 
Site Principal Investigator Signature 
 
Date 


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ACTIV-6 Protocol [v7.0] 
 
 
4 
Table of Contents 
1. 
Protocol Summary ........................................................................................................12 
1.1. 
Synopsis ..........................................................................................................................12 
1.2. 
Schema ............................................................................................................................19 
2. 
Introduction ...................................................................................................................21 
2.1. 
Study Rationale ...............................................................................................................21 
2.2. 
Background .....................................................................................................................21 
2.3. 
Benefit/Risk Assessment ................................................................................................22 
2.3.1. 
Risk Assessment .............................................................................................................22 
2.3.2. 
Benefit Assessment .........................................................................................................22 
3. 
Objectives and Endpoints ............................................................................................23 
4. 
Study Design ..................................................................................................................25 
4.1. 
Overall Design ................................................................................................................25 
4.2. 
End of Study Definition ..................................................................................................26 
5. 
Study Population ...........................................................................................................27 
5.1. 
Inclusion Criteria ............................................................................................................27 
5.2. 
Exclusion Criteria ...........................................................................................................27 
5.3. 
Recruitment and Engagement .........................................................................................27 
5.3.1. 
Participant Recruitment ..................................................................................................27 
5.3.2. 
Participant Engagement ..................................................................................................27 
5.3.3. 
Participant Randomization Process .................................................................................28 
5.4. 
Screen Failures ................................................................................................................28 
5.5. 
Enrollment ......................................................................................................................29 
6. 
Study Drug(s) ................................................................................................................30 
6.1. 
Repurposed Medication Treatments ...............................................................................30 
6.2. 
Placebo ............................................................................................................................30 
6.3. 
Study Drug Accountability .............................................................................................30 
6.4. 
Concomitant Therapy .....................................................................................................30 
6.5. 
Intervention After the End of the Study ..........................................................................30 
7. 
Participant Withdrawal/Termination and Study Termination ................................31 
7.1. 
Participant Withdrawal/Termination ..............................................................................31 
7.2. 
Premature Termination or Suspension of the Study .......................................................31 
7.3. 
Lost to Follow-up............................................................................................................31 
8. 
Study Assessments and Procedures.............................................................................33 
8.1. 
Schedule of Events..........................................................................................................34 
8.1.1. 
Screening.........................................................................................................................35 
8.1.2. 
Intervention Period ..........................................................................................................35 
8.1.3. 
Follow-up Period ............................................................................................................36 
8.1.4. 
Final Visit........................................................................................................................37 
8.2. 
Clinical Assessments ......................................................................................................37 
8.3. 
Quality of Life Questionnaires .......................................................................................38 
9. 
Safety Assessments ........................................................................................................40 


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ACTIV-6 Protocol [v7.0] 
 
 
5 
9.1. 
Adverse Events and Serious Adverse Events .................................................................40 
9.1.1. 
Adverse Device Effect (ADE) and Unanticipated Adverse 
Device Effect (UADE) ....................................................................................................40 
9.1.2. 
Collection Period for AE and SAE Information .............................................................41 
9.1.3. 
Assessing Causality of a Serious Adverse Event ............................................................42 
9.1.4. 
Reporting and Monitoring of SAEs ................................................................................42 
9.1.5. 
Events of Special Interest................................................................................................43 
9.2. 
Unanticipated Problem (UP) and Terminations..............................................................44 
9.2.1. 
Definition of Unanticipated Problem ..............................................................................44 
9.2.2. 
Reporting of an Unanticipated Problem .........................................................................44 
10. 
Statistical Considerations .............................................................................................45 
10.1. 
Statistical Hypotheses .....................................................................................................45 
10.1.1.  Primary Hypothesis .........................................................................................................45 
10.2. 
Sample Size Determination ............................................................................................45 
10.3. 
Randomization ................................................................................................................45 
10.4. 
Blinding ..........................................................................................................................46 
10.5. 
Populations for Analyses ................................................................................................46 
10.6. 
Statistical Analyses .........................................................................................................46 
10.6.1.  General Considerations ...................................................................................................47 
10.6.2.  Statistical modeling .........................................................................................................47 
10.6.3.  Assessing Effectiveness (Primary Objective) .................................................................47 
10.6.4.  Interim Analyses (IA), Early Stopping, and Type-I Error Control .................................47 
10.6.5.  Sensitivity and Supplementary Analyses ........................................................................49 
10.6.6.  Differential Treatment Effects and Subgroup Analyses .................................................49 
10.6.7.  Secondary Clinical Endpoint ..........................................................................................50 
10.6.8.  Exploratory Analysis ......................................................................................................50 
10.6.9.  Adherence and Retention Analysis .................................................................................50 
10.7. 
Interim Reporting ............................................................................................................50 
10.8. 
Independent Data Monitoring Committee (IDMC) ........................................................51 
10.9. 
Adjudication Committee .................................................................................................51 
11. 
Ethical Standards ..........................................................................................................52 
11.1. 
Institutional Review Board (IRB) ...................................................................................52 
11.2. 
Informed Consent Process ..............................................................................................52 
11.3. 
Participant and Data Confidentiality...............................................................................52 
11.4. 
Site Management and Quality Assurance .......................................................................53 
11.5. 
Site Monitoring ...............................................................................................................53 
12. 
Data Handling and Record Keeping ...........................................................................55 
12.1. 
Data Collection and Management Responsibilities ........................................................55 
12.2. 
Study Records Retention ................................................................................................55 
12.3. 
Protocol Deviations.........................................................................................................55 
12.4. 
Publication and Data Sharing Policy ..............................................................................55 
13. 
Study Leadership ..........................................................................................................57 
14. 
Summary of Changes....................................................................................................58 
15. 
References ......................................................................................................................65 


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ACTIV-6 Protocol [v7.0] 
 
 
6 
16. 
Appendix A (Enrollment Closed 04FEB2022) – Ivermectin 
400 ..................................................................................................................................71 
16.1. 
Risk Assessment .............................................................................................................71 
16.2. 
Additional Appendix-Level Exclusion Criteria ..............................................................72 
16.2.1.  Precautions ......................................................................................................................72 
16.3. 
Ivermectin Information ...................................................................................................73 
16.3.1.  Formulation, Appearance, Packaging, and Labeling ......................................................73 
16.3.2.  Drug Dispensing, Storage, and Stability .........................................................................73 
16.3.3.  Dosing and Administration .............................................................................................73 
16.3.4.  Rationale for Selection of Dose ......................................................................................73 
16.4. 
Placebo Information ........................................................................................................75 
16.4.1.  Formulation, Appearance, Packaging, and Labeling ......................................................75 
16.4.2.  Drug Dispensing, Storage, and Stability .........................................................................75 
16.4.3.  Dosing and Administration .............................................................................................75 
16.5. 
Events of Special Interest ...............................................................................................75 
17. 
Appendix B (Enrollment Closed 27May2022) – Fluvoxamine 
Maleate ...........................................................................................................................76 
17.1. 
Risk Assessment .............................................................................................................76 
17.2. 
Additional Appendix-Level Exclusion Criteria ..............................................................77 
17.2.1.  Precautions ......................................................................................................................78 
17.3. 
Fluvoxamine Information ...............................................................................................78 
17.3.1.  Formulation, Appearance, Packaging, and Labeling ......................................................78 
17.3.2.  Drug Dispensing, Storage, and Stability .........................................................................79 
17.3.3.  Dosing and Administration .............................................................................................79 
17.3.4.  Rationale for Selection of Dose ......................................................................................79 
17.4. 
Placebo Information ........................................................................................................82 
17.4.1.  Formulation, Appearance, Packaging, and Labeling ......................................................82 
17.4.2.  Drug Dispensing, Storage, and Stability .........................................................................82 
17.4.3.  Dosing and Administration .............................................................................................82 
17.5. 
Events of Special Interest ...............................................................................................82 
18. 
Appendix C (Enrollment Closed 08FEB2022) – Fluticasone 
Furoate ...........................................................................................................................83 
18.1. 
Risk Assessment .............................................................................................................83 
18.2. 
Additional Appendix-Level Exclusion Criteria ..............................................................84 
18.2.1.  Precautions ......................................................................................................................84 
18.3. 
Fluticasone Furoate Information .....................................................................................84 
18.3.1.  Formulation, Appearance, Packaging, and Labeling ......................................................85 
18.3.2.  Drug Dispensing, Storage, and Stability .........................................................................85 
18.3.3.  Dosing and Administration .............................................................................................85 
18.3.4.  Rationale for Selection of Dose ......................................................................................85 
18.4. 
Placebo Information ........................................................................................................86 
18.4.1.  Formulation, Appearance, Packaging, and Labeling ......................................................86 
18.4.2.  Drug Dispensing, Storage, and Stability .........................................................................87 
18.4.3.  Dosing and Administration .............................................................................................87 
18.5. 
Events of Special Interest ...............................................................................................87 


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18.6. 
Safety Reporting for Fluticasone Furoate .......................................................................87 
19. 
Appendix D – Ivermectin 600 ......................................................................................88 
19.1. 
Risk Assessment .............................................................................................................88 
19.2. 
Additional Appendix-Level Exclusion Criteria ..............................................................88 
19.2.1.  Precautions ......................................................................................................................88 
19.3. 
Ivermectin Information ...................................................................................................88 
19.3.1.  Formulation, Appearance, Packaging, and Labeling ......................................................88 
19.3.2.  Drug Dispensing, Storage, and Stability .........................................................................88 
19.3.3.  Dosing and Administration .............................................................................................88 
19.3.4.  Rationale for Selection of Dose ......................................................................................89 
19.4. 
Placebo Information ........................................................................................................89 
19.4.1.  Formulation, Appearance, Packaging, and Labeling ......................................................89 
19.4.2.  Drug Dispensing, Storage, and Stability .........................................................................89 
19.4.3.  Dosing and Administration .............................................................................................89 
19.5. 
Events of Special Interest ...............................................................................................89 
20. 
Appendix E – Fluvoxamine Maleate 100 ....................................................................90 
20.1. 
Risk Assessment .............................................................................................................90 
20.2. 
Additional Appendix-Level Exclusion Criteria ..............................................................90 
20.2.1.  Precautions ......................................................................................................................90 
20.3. 
Fluvoxamine Information ...............................................................................................90 
20.3.1.  Formulation, Appearance, Packaging, and Labeling ......................................................90 
20.3.2.  Drug Dispensing, Storage, and Stability .........................................................................90 
20.3.3.  Dosing and Administration .............................................................................................90 
20.3.4.  Rationale for Selection of Dose ......................................................................................90 
20.4. 
Placebo Information ........................................................................................................91 
20.4.1.  Formulation, Appearance, Packaging, and Labeling ......................................................91 
20.4.2.  Drug Dispensing, Storage, and Stability .........................................................................91 
20.4.3.  Dosing and Administration .............................................................................................91 
20.5. 
Events of Special Interest ...............................................................................................92 
21. 
Appendix F – Montelukast ...........................................................................................93 
21.1. 
Risk Assessment .............................................................................................................93 
21.2. 
Additional Appendix-Level Exclusion Criteria ..............................................................94 
21.2.1.  Precautions ......................................................................................................................94 
21.3. 
Study Drug Information ..................................................................................................94 
21.3.1.  Formulation, Appearance, Packaging, and Labeling ......................................................94 
21.3.2.  Drug Dispensing, Storage, and Stability .........................................................................94 
21.3.3.  Dosing and Administration .............................................................................................94 
21.3.4.  Rationale for Selection of Dose ......................................................................................94 
21.4. 
Placebo Information ........................................................................................................97 
21.4.1.  Formulation, Appearance, Packaging, and Labeling ......................................................97 
21.4.2.  Drug Dispensing, Storage, and Stability .........................................................................97 
21.4.3.  Dosing and Administration .............................................................................................97 
21.5. 
Events of Special Interest ...............................................................................................97 
 


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Abbreviations 
ACE 
Angiotensin-converting Enzyme 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ARB 
Angiotensin II Receptor Blockers 
ARNI 
Angiotensin Receptor Neprilysin Inhibitor 
BiPAP 
Bilevel Positive Airway Pressure 
BMD 
Bone Mineral Density 
BMI 
Body Mass Index 
CCC 
Clinical Coordinating Center 
CEA 
Clinical Event Ascertainment  
CFR 
Code of Federal Regulations 
CNS 
Central Nervous System 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
Chronic Obstructive Pulmonary Disease 
cOR 
Common Odds Ratio 
COVID-19 
Coronavirus Disease 2019 
CPAP 
Continuous Positive Airway Pressure 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DCC 
Data Coordinating Center 
DIC 
Disseminated Intravascular Coagulation 
DUA 
Data Use Agreement 
ECMO 
Extracorporeal Membrane Oxygenation 
EDC 
Electronic Data Capture 
ESI 
Event of Special Interest 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IA 
Interim Analysis 
IC50 
Half-Maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ICS 
Inhaled Corticosteroid 
ICU 
Intensive Care Unit 
IDMC 
 
IDS 
Investigational Drug Service 
IRB 
Institutional Review Board 
KO 
Knockout 
LPS 
Lipopolysaccharide  
MAOI 
Monoamine Oxidase Inhibitors 
mITT 
Modified Intention to Treat 
MOP 
Manual of Procedures 
NCATS 
National Center for Advancing Translational Sciences 
NIH 
National Institute of Health 


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OCD 
Obsessive Compulsive Disorder 
OHRP 
Office for Human Research Protections 
OR 
Odds Ratio 
PASC 
Post-Acute Sequelae of SARS-CoV-2 Infection 
PCORI 
Patient-Centered Outcomes Research Institute 
PCR 
Polymerase Chain Reaction 
PHI 
Personal Health Information 
PHQ 
Patient Health Questionnaire 
PI 
Principal Investigator 
PPOS 
Predicted Probability of Success 
PROMIS 
Patient-reported Outcomes Measurement Information System 
QOL 
Quality of Life 
RNA 
Ribonucleic Acid 
RRT 
Renal Replacement Therapy  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-1/2 
Severe Acute Respiratory Syndrome Coronavirus 1/2 
SD 
Standard Deviation 
sIA 
Screening Interim Analysis 
SNRI 
Selective Norepinephrine Reuptake Inhibitor 
SSRI 
Selective Serotonin Norepinephrine Reuptake Inhibitor  
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
UADE 
Unanticipated Adverse Device Effect 
UP 
Unanticipated Problems 
US 
United States 
WT 
Wildtype 
 
 


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Table of Figures 
Figure 1: ACTIV-6 Study Schema ............................................................................................... 19 
Figure 2. ACTIV-6 Interim Analysis Schema .............................................................................. 20 
Figure 3: Operational Structure Diagram ..................................................................................... 57 
Figure 4: Survival curve of WT and S1R KO mice ...................................................................... 80 
Figure 5: Summary of JAMA Randomization Clinical Trial of Fluvoxamine for Early COVID-
19................................................................................................................................................... 81 
Figure 6: Summary of study results for the prospective, nonrandomized observational cohort 
study with fluvoxamine in participants diagnosed with COVID-19. ........................................... 81 
Figure 7. Probability of efficacy for the primary outcome in the ITT and mITT populations of 
TOGETHER ................................................................................................................................. 91 
 


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List of Tables 
Table 1: Schedule of Events ......................................................................................................... 34 
Table 2: ACTIV-6 Sample Size Estimates and Power ................................................................. 45 
Table 3: Ivermectin Adverse Event Table for Doses ≥ 300 µg/kg ............................................... 71 
Table 4: Ivermectin 400 Dosing Schedule .................................................................................... 73 
Table 5. Fluvoxamine Adverse events occurring in 10-week studies of adult OCD or depression
....................................................................................................................................................... 76 
Table 6. Fluvoxamine Adverse events that occurred in COVID-19 study participants receiving 
300 mg/day for 15 days................................................................................................................. 77 
Table 7. Fluticasone Adverse reactions that occurred in ≥3% of adults and adolescents with 
asthma in a 24-week trial. ............................................................................................................. 83 
Table 8. Ivermectin 600 Dosing Schedule .................................................................................... 88 
Table 9. Montelukast sodium adverse reactions occurring at a higher incidence than placebo, in 
≥1% of adults and adolescents ≥ 15 years of age. ........................................................................ 93 
Table 10. Ongoing clinical trials with montelukast ...................................................................... 96 
 
 


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1. 
Protocol Summary 
1.1. 
Synopsis 
 
Title 
ACTIV-6: COVID-19 Outpatient Randomized Trial to Evaluate 
Efficacy of Repurposed Medications 
Clinical study phase 
III 
Rationale 
Coronavirus Disease 2019 (COVID-19) is caused by a novel 
coronavirus, severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2), that first emerged in December 2019 and has since 
resulted in a global pandemic unseen in almost a century in cases 
and mortality. Since 2020, advances have been made for treatment 
of COVID-19 and vaccination for prevention of SARS-CoV-2 
infection. However, the pandemic continues to evolve with new 
variants and surges of infections in different regions of the world, 
requiring an ongoing evidence-generating clinical trial platform, in 
particular for the treatment of COVID-19 in the outpatient setting. 
This platform protocol can serve as an evidence generation system 
for prioritized drugs, repurposed from other Food and Drug 
Administration (FDA) indications with an established safety record 
in humans and preliminary data of efficacy. The ultimate goal is to 
evaluate if repurposed medications can make participants feel better 
faster and reduce death and hospitalization. 
Primary Objective 
 
To evaluate the effectiveness of repurposed medications [(study 
drug(s)] in nonhospitalized participants with mild to moderate 
COVID-19 
Secondary 
Objectives 
 
To evaluate the clinical outcomes in participants in a study drug 
arm versus those in the placebo arm 
 
To describe symptom resolution in participants in a study drug 
arm versus those in the placebo arm 
 
To describe the quality of life (QOL) in participants in a study 
drug arm versus those in the placebo arm 
 
To compare illness severity trajectories in participants in a study 
drug arm versus those in the placebo arm 
Exploratory 
Objectives 
 
To describe long-term COVID-19-related symptoms in 
participants in a study drug arm versus those in the placebo 
arm  


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ACTIV-6 Protocol [v7.0] 
 
 
13 
Intervention 
All interventions will occur in addition to standard of care. Each 
study drug appendix describes a different study drug and 
matching placebo. The following arms will be included in each 
study appendix: 
 Study Drug Arm: repurposed medications (see 
Appendices) 
 Placebo Arm: placebo control 
While each appendix describes the placebo that matches the 
study drug, for comparative analysis the control group will 
comprise eligible, concurrently enrolled participants from all 
study arms who were assigned to placebo.  
Study Design 
This study is a platform protocol designed to be flexible so that 
it is suitable for a wide range of settings within healthcare 
systems and in community settings where it can be integrated 
into routine COVID-19 testing programs and subsequent 
treatment plans. This platform protocol will enroll participants in 
an outpatient setting with a confirmed positive polymerase chain 
reaction (PCR) or antigen test for SARS-CoV-2. Each appendix 
will describe a repurposed medication (study drug) to meet the 
protocol objectives. 
When only one study drug/appendix is under study, allocation 
between study drug and placebo will be 1:1. If multiple study 
drugs/appendices are under study, participants will also be 
randomized among the study drugs for which eligibility is 
confirmed. Since the route of administration of each study drug 
may differ, the placebos may also differ. To achieve blinding 
and an equitable randomization probability, a two-step 
randomization process will be used. 
In the first step, the participant will be randomized m:1 active 
study drug to placebo, where m is the number of active study 
drugs for which the participant is eligible (note, if the same 
study drug is tested at multiple doses, each dose will count as 
one study drug). Then, participants will be randomized among 
the m study drugs for which they are eligible. Participants will 
carry their ‘study drug’ versus ‘placebo’ randomization with 
them into the study drug appendix. In this way, a participant 
allocated to placebo who is randomized to study drug A will be 
given the placebo that matches study drug A. This achieves 
equal probability of exposure among the placebo and active 
study drugs for which the participant is eligible, and equitable 
distribution among all study arms for which a participant is 
eligible. Sites will be informed to which study drug appendix the 


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ACTIV-6 Protocol [v7.0] 
 
 
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participant is randomized, but not whether they are allocated to 
the study drug arm or placebo arm within that appendix.  
For analysis, concurrent placebo participants who were eligible 
for the study drug appendix will be pooled. This will result in 
approximately a 1:1 allocation ratio for any study drug to 
placebo. If a study drug appendix is stopped for efficacy and 
becomes standard of care, the active study drug arm may serve 
as a concurrent placebo for other study drugs.  
Each study drug appendix will go through Screening Interim 
Analyses to assess efficacy/futility prior to evaluation of the 
primary objective. This Screening Interim Analysis provides an 
innovative approach to evaluate the potential for repurposed 
drugs to reduce symptom burden and prevent disease 
progression in the outpatient setting at various points throughout 
enrollment. 
Participants will receive complete supply of repurposed 
medication (study drug) or placebo with length of treatment and 
amount of study drug/placebo depending on the study drug 
appendix and arm to which they are randomized. 
This study is designed so that it can be done completely 
remotely. However, screening and enrollment may occur in- 
person at sites and unplanned study visits may occur in-person 
or remotely, as deemed appropriate by an investigator for safety 
purposes. Participants will be on-study for 120 days1, during 
which they will complete various questionnaires. 
Population 
Up to 15,000 adults   
Study Duration 
24 months 
Study Location 
Up to 280 sites  
Inclusion Criteria 
1. Completed Informed Consent 
2. Age ≥ 30 years old 
3. Confirmed SARS-CoV-2 infection (or reinfection) by any 
authorized or approved PCR or antigen test collected within 10 
days of screening 
4. Two or more current symptoms of acute infection for ≤ 7 days. 
Symptoms include the following: fatigue, dyspnea, fever, cough, 
                                                 
1 120 days on-study was implemented after closing arms Ivermectin 400, Fluvoxamine Maleate, and Fluticasone 
Furoate; in those arms, participants were on study for 90 days. 


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nausea, vomiting, diarrhea, body aches, chills, headache, sore 
throat, nasal symptoms, new loss of sense of taste or smell. 
Exclusion Criteria 
1. Current or recent (within 10 days of screening) hospitalization 
for COVID-19 infection 
2. Current or planned participation in another interventional trial to 
treat COVID-19, at the discretion of the study principal 
investigator (PI) 
3. Current or recent use (within the last 14 days) of study drug or 
study drug/device combination*  
4. Known allergy/sensitivity or any hypersensitivity to 
components of the study drug or placebo* 
5. Known contraindication(s) to study drug including prohibited 
concomitant medications (see Appendices)* 
*If only one study drug appendix is open at the time of enrollment. 
If multiple study drug appendices are open, a participant may opt-
out of any study drug appendix or be excluded from any study drug 
appendix based on contraindications listed in the study drug 
appendix, current use of study drug, or known 
allergy/sensitivity/hypersensitivity and still remain eligible for the 
remaining study drug appendices. 
Sample Size 
Considerations 
This study will enroll up to 15,000 adults, depending on the 
number of study drug appendices that are added and adjustments 
to sample size depending on the data.  
An estimated sample size of approximately 1,200 participants 
per study drug appendix is expected to be sufficient to conclude 
whether there is meaningful evidence of benefit. A screening 
interim analyses (sIA) will occur at n=300 and n=600 to inform 
termination of the arm, continuation of enrollment, or transition 
to assessment of the primary objective. Interim analyses (IAs) of 
the primary objective are planned at n=300, n=600 and n=900.  
As described in the statistical analysis plan (SAP), the type I 
error for the primary objective is controlled at < 0.05. 
General Statistical 
Consideration for 
Primary Analysis 
The primary objective of effectiveness will be determined based on 
the endpoints of hospitalization/death or time to recovery over 28 
days, the choice of which will be specified per appendix. The 
choice will be documented prior to interim analyses or prior to 
unblinding. The choice will be guided by emerging data on study 
drugs in the platform and on overall event rates in the trial, as well 


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ACTIV-6 Protocol [v7.0] 
 
 
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as external drivers, such as case rates, availability of other effective 
therapies, and vaccine effectiveness. 
The outcomes of interest for this platform (symptoms, 
hospitalization, and mortality) are collected using a web-assisted 
symptom diary according to the schedule in Table 1. Symptoms 
will be graded on an ordinal scale as none, mild, moderate, or 
severe.  
The risk difference in hospitalization or death will be used to draw 
conclusions about clinical events. Time to recovery, measured as 
the time to achieving three consecutive days of self-reported 
symptom freedom, will be used to draw conclusions about symptom 
burden.  
The primary analysis will be implemented separately for each study 
drug, where the matching placebo arm will consist of concurrently 
randomized participants that meet the inclusion and exclusion 
criteria for that study drug appendix. A modified intention to treat 
(mITT) approach will be used for primary analyses; all participants 
who receive study drug will be included as assigned. It is possible 
that the delivery of medications (placebo or study drug) does not 
occur (failure of delivery, participant death, or participant 
withdrawal); this will result in exclusion of the participant for the 
mITT analysis. All available data will be used to compare each 
study drug versus placebo control, regardless of post-randomization 
adherence to study protocols.  
Independent Data 
Monitoring 
Committee (IDMC)  
Frequent IDMC reviews will be conducted to ensure the safety of 
study participants and evaluate the accumulating endpoint data by 
treatment group. Regular IDMC meetings will monitor the 
following parameters at a minimum: 
 Recruitment progress 
 Enrollment overall and by subgroups 
 Adherence, retention, and status of data collection 
 Serious adverse events  
 Assessment for futility  
 Probability for benefit across endpoints 
Interim Analysis 
Interim analyses (IA) will be performed per study drug appendix, 
after approximately every 300 participants (~150 in study drug arm 
and ~150 in placebo arm) have completed the Day 14 Visit. 
Placebo control participants contributing to this count will be drawn 
from across study drug appendices, and will include participants 
who were eligible for the study drug appendix of interest regardless 


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ACTIV-6 Protocol [v7.0] 
 
 
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of final study drug arm allocation. The following decision 
thresholds will be checked during IA(s): 
i) 
Screening IA (n=300): 
a. The study drug is found to have benefit (efficacy). 
Study drug appendix will proceed to primary 
objective IA at n=300. Note: this is also a check for 
harm as all assessments are two-tailed.  
b. The study drug is not found to have benefit, 
enrollment continues in the study drug appendix and 
sIA is repeated at n=600. 
ii) 
Screening IA (n=600): 
a. It would be futile to attempt to show a benefit of the 
study drug based on the predicted probability of 
success (PPOS) and other factors. The study drug 
appendix will be terminated.  
b. Futility is not determined. Study drug appendix will 
proceed to primary objective IA at n=600. 
iii) 
Primary Objective IA (n=300): if the criteria for 
proceeding to the primary objective are met when 
n=300, a primary objective IA will be conducted for the 
primary objective when n=300. The following decisions 
will be assessed: 
a. The study drug is found to have benefit (efficacy), 
the study drug appendix will be terminated as the 
primary endpoint has been met. 
b. It would be futile to attempt to show a benefit of the 
study drug based on the PPOS and other factors. The 
study drug appendix will be terminated.  
c. Efficacy/futility is undeterminable, enrollment will 
continue in the study drug appendix and the primary 
objective IA will be assessed at n=600.  
iv) 
Primary Objective IA (n=600, 900): if the criteria for 
proceeding to the primary objective IA are met when 
n=600 or n=900, a primary objective IA will be 
conducted. The following decisions will be assessed: 
a. The study drug is found to have benefit (efficacy), 
the study drug appendix will be terminated as the 
primary endpoint has been met. 
b. It would be futile to attempt to show a benefit of the 
study drug based on the PPOS and other factors. The 
study drug appendix will be terminated.  


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ACTIV-6 Protocol [v7.0] 
 
 
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c. Efficacy/futility is undeterminable, enrollment will 
continue in the study drug appendix and the primary 
objective will be assessed after another 300 
participants have been enrolled, or until n=1200.  
A posterior probability of meaningful benefit for a study drug in 
comparison to the placebo control of greater than the appendix-
specified threshold will result in a declaration of overall superiority. 
A PPOS when n=1200 of less than the appendix-specified threshold 
will result in a declaration of futility. 
Futility is a low probability of achieving any conclusions within a 
reasonable time frame or based on other factors for the trial. Prior to 
each IA, the target date for study completion will be specified, and 
accrual will be projected by that target date. The PPOS of any study 
drug given expected accrual at a prespecified point in time will be 
provided to the IDMC. A statistical model may be used to predict 
accrual. Futility assessment will use the lowest of either the planned 
accrual or predicted accrual at study closure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2. 
Schema 
 
 
Figure 1: ACTIV-6 Study Schema 


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ACTIV-6 Protocol [v7.0] 
 
 
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Figure 2. ACTIV-6 Interim Analysis Schema 


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ACTIV-6 Protocol [v7.0] 
 
 
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2. 
Introduction 
2.1. 
Study Rationale 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel betacoronavirus that 
first emerged in December 2019 and has since caused a global pandemic unseen in almost a 
century with respect to the number of cases and overall mortality.[1, 2] The clinical disease 
related to SARS-CoV-2 is referred to as Coronavirus Disease 2019 (COVID-19). Since 2020, 
advances have been made for treatment of COVID-19 and vaccinations for prevention of SARS-
CoV-2 infection, through emergency use authorization or FDA approval.[3-8] However, the 
pandemic continues to evolve with new variants and surges of infections in different regions of 
the world, requiring an ongoing evidence-generating platform, in particular for the treatment of 
COVID-19 infection in the outpatient setting. This platform protocol operates in addition to 
usual care and can serve as an evidence generating system for prioritized drugs repurposed from 
other indications with an established safety record and preliminary evidence of clinical efficacy 
for the treatment of COVID-19. The ultimate goal is to evaluate if repurposed medications can 
make participants feel better faster and reduce death and hospitalization. 
2.2. 
Background 
In December 2019, numerous patients in Wuhan, China were diagnosed with pneumonia caused 
by an unknown virus. By January 7, 2020, Chinese scientists had isolated SARS-CoV-2. This is 
a novel betacoronavirus closely related to severe acute respiratory syndrome coronavirus 1 
(SARS-CoV-1).[2]  In the subsequent months the spread of the virus led to a global pandemic. 
As of February 7, 2022 there were approximately 395,540,912 confirmed COVID-19 cases 
resulting in 5,741,726 deaths worldwide.[1] 
The virus continues to spread despite social distancing and masking measures, vaccination 
campaigns/requirements, and travel restrictions. COVID-19 vaccinations continue to be 
distributed and administered globally; however, new SARS-CoV-2 strains continue to emerge, 
with potential for reduced monoclonal antibody therapeutic and vaccine efficacy.[9] As new 
strains have emerged that confirm transmission, infection, and even severe disease after 
vaccination is possible, highlighting the need to establish treatment regimens despite vaccination 
availability. Furthermore, acceptance and uptake of booster shots has been lower than uptake of 
the initial vaccination series, further justifying the need for safe and effective therapies. Thus, 
there remains a need to identify safe and efficacious treatments that can be administered in the 
outpatient setting.  
As of February 2022, multiple clinical trials have been reported, providing guidance to clinical 
providers on management of COVID-19, particularly in the hospital setting. Various drugs, 
including monoclonal antibodies and antivirals, have been authorized or approved by the FDA 
for use in the inpatient and outpatient setting for treatment of COVID-19.  Multiple repurposed 
immunomodulatory agents are clinically used for the treatment of severe COVID-19 in the 
inpatient setting. Thus, multiple medications have been reported to improve clinical disease and 
in some cases, mortality.[10, 11] Few of these are FDA approved and few are therapies that can 
be administered at home.    


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2.3. 
Benefit/Risk Assessment 
The risks for participation in this study include taking study drug (see Appendices) and loss of 
confidentiality. There may be some benefit to the participant if the therapy is effective against 
COVID-19. 
2.3.1. 
Risk Assessment 
Loss of confidentiality risks: There is a potential risk of loss of confidentiality. Every effort will 
be made to protect the participant’s confidential medical information, but this cannot be 
guaranteed. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the IRB, FDA, National Institutes of Health 
(NIH), Office for Human Research Protections (OHRP), other local, US, and international 
regulatory authorities/entities as part of their duties. 
Risk lowering measures: Study procedures to manage and minimize risks include careful 
selection of the participants and monitoring over time to check on participants’ health. 
Additional guidance to manage any risks or any change to the risk to the participant based on 
emerging data will be provided to the study teams, as needed. In addition, an Independent Data 
Monitoring Committee (IDMC) will monitor safety of the participants throughout the study. 
2.3.2. Benefit Assessment 
Participants who randomize to a study drug arm may benefit from study drug administration.  
There is no direct benefit to participants randomized to the placebo arm apart from participating 
in generating evidence that may ultimately support treatment for SARS-CoV-2 infection. In 
addition, they will benefit from involvement with the team following their health status during 
the study. The knowledge gained will be a benefit to others in the future.  


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3. 
Objectives and Endpoints 
Objectives 
Outcome Measurements 
Reported Endpoints 
Primary 
 
 
To evaluate the 
effectiveness of repurposed 
medications [(study drug(s)] 
in nonhospitalized 
participants with mild to 
moderate COVID-19 
 Hospitalization or death 
by Day 28 
 Time to recovery over 28 
days, wherein time to 
recovery is the time to 
achieving three 
consecutive days of self-
reported symptom 
freedom 
Relative risk for clinical 
events or difference in time 
to recovery will be used to 
estimate treatment effect. 
Secondary 
 
 
To evaluate the clinical 
outcomes in participants in 
a study drug arm versus 
those in the placebo arm 
 COVID Clinical 
Progression Scale on Day 
7, Day 14, and Day 28 
(see Section 8.2) 
 Mortality through Day 28 
 Hospitalization, urgent 
care visit, emergency 
room visit through Day 28 
The following model-
assisted endpoints will be 
reported for the COVID 
Clinical Progression Scale: 
 The OR describing the 
overall difference in 
clinical progression  
 The OR describing the 
difference in clinical 
progression at each 
measured time point 
 The overall risk difference 
for hospitalization or death 
The following endpoints for 
the composite of 
unscheduled medically 
assisted care will be directly 
assessed and reported: 
 The overall risk difference 
for any of urgent care, 
emergency care, 
hospitalization or death 


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 Time to first urgent care, 
emergency care, 
hospitalization or death  
 Risk and time to event for 
each component of the 
composite  
To describe symptom 
resolution in participants in 
a study drug arm versus 
those in the placebo arm 
Symptom resolution, defined as  
three consecutive days without 
symptoms 
Time to symptom resolution 
To describe the quality of 
life (QOL) in participants in 
a study drug arm versus 
those in the placebo arm 
Modified Patient-Reported 
Outcomes Measurement 
Information System (PROMIS)-
29 at baseline, Day 7, Day 14, 
Day 28, Day 90, and Day 1202 
Follow-up 
 Overall common odds ratio 
(cOR)  
 Odds ratios (cORs) specific 
to days 7, 14, 28, 90, and 
1202 
 Mean difference in QOL 
scores at each time point 
To compare illness severity 
trajectories in participants in 
a study drug arm versus 
those in the placebo arm 
Ordinal outcome including 
symptom severity, 
hospitalization, and death 
measured daily for 14 days 
 Difference in mean time 
unwell 
 Mean days of benefit 
Exploratory 
 
 
To describe long-term 
COVID-19-related 
symptoms in participants in 
a study drug arm versus 
those in the placebo arm 
Symptom occurrence, type, and 
severity at Day 90, Day 1202, or 
Day 1802 Follow-up 
 
Directly measured mean and 
median symptom count and 
QOL score at Day 90, Day 
1202, or Day 1802 in study 
drug arm(s) versus placebo. 
                                                 
2 Day 180 is applicable only for participants who were consented to the study after protocol v7.0 was implemented; 
Day 120 is applicable only for participants consented under protocol v6.0; Day 90 was the final follow-up day for 
Ivermectin 400, Ivermectin 600, Fluvoxamine Maleate, and Fluticasone Furoate. 


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4. 
Study Design 
Refer to Section 1.2 for the Study Schema. 
This study includes an innovative screening approach using sIAs to make decisions about 
dropping ineffective agents quickly, or to accelerate study of potentially effective agents. Each 
study drug appendix will go through sIAs to assess efficacy/futility prior to evaluation of the 
primary objective. This sIA provides an innovative approach to evaluate the potential for 
repurposed drugs to reduce symptom burden and prevent disease progression at various points 
throughout enrollment in a broad population. 
4.1. 
Overall Design 
This study is a platform protocol designed to be flexible so that it is suitable for a wide range of 
settings within healthcare systems and in community settings where it can be integrated into 
routine COVID-19 testing programs and subsequent treatment plans. The platform protocol will 
enroll participants with mild to moderate COVID-19 in an outpatient setting with a confirmed 
positive polymerase chain reaction (PCR) or antigen test for SARS-CoV-2 infection. Each 
appendix will describe a repurposed medication (study drug arm) that is sized to meet the master 
protocol objectives. 
Participants will be randomized to one of the study drug appendices that are actively enrolling at 
the time of randomization. Study drug appendices may be added or removed according to 
adaptive design and/or emerging evidence. When there are multiple study drug appendices 
available, randomization will occur based on appropriateness of each drug for the participant as 
determined by the study protocol and investigator and participant equipoise. Each participant 
will be required to randomize to at least one study drug versus placebo. The probability of 
placebo to treatment will remain the same regardless of eligibility decisions.  
Eligible participants will be randomized (1:1), in a blinded fashion, to either the study drug 
arm or placebo arm in addition to standard of care, when one active drug is on the platform or 
when a participant is only eligible for one of the active drugs on the platform. As additional 
study drug appendices are added, the randomization will be altered to leverage placebo data 
across arms. If a study drug is offered at two doses, each dose will be treated as separate study 
arm. If a participant is eligible for 1 study arm, they have a 1:1 chance of receiving an active 
study drug. If a participant is eligible for two study arms, they have a 2:1 chance of receiving 
an active study drug, for 3 arms it is 3:1, for 4 arms it is 4:1, and so on. This is because each 
participant assigned to a placebo group is shared among all appendices, and the goal is that 
within appendices the allocation probability to study drug versus placebo is 1:1.  Participants 
will receive a complete supply of repurposed medication (study drug) or placebo with the 
quantity depending on the study drug/placebo to which they are randomized. 
All study visits are designed to be remote. However, screening and enrollment may occur in-
person at sites and unplanned study visits may occur in-person or remotely, as deemed 
appropriate by the site investigator for safety purposes. Participants will be asked to complete 
questionnaires and report safety events during the study, according to Table 1. Participants will 
be prompted by the online system to report safety events and these will be reviewed and 
confirmed via medical records and site staff, as necessary.  


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4.2. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed the applicable 
Long-term Follow-up assessments, refer to Table 1. 
The end of the study is defined as the date of the last follow-up of the last participant in the 
study. Data from interim analyses or recommendations by the IDMC may result in protocol 
modifications or early termination of the study.  
 


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5. 
Study Population 
All Eligibility Criteria will be obtained per participant.   
5.1. 
Inclusion Criteria 
1. Completed Informed Consent 
2. Age ≥ 30 years old 
3.   Confirmed SARS-CoV-2 infection (or reinfection) by any authorized or approved PCR or 
antigen test collected within 10 days of screening 
4. Two or more current symptoms of acute infection for ≤7 days. Symptoms include the 
following: fatigue, dyspnea, fever, cough, nausea, vomiting, diarrhea, body aches, chills, 
headache, sore throat, nasal symptoms, new loss of sense of taste or smell  
5.2. 
Exclusion Criteria 
1. Current or recent (within 10 days of screening) hospitalization for COVID-19 infection 
2. Current or planned participation in another interventional trial to treat COVID-19, at the 
discretion of the study principal investigator (PI) 
3. Current or recent use (within the last 14 days) of study drug or study drug/device 
combination*  
4. Known allergy/sensitivity or any hypersensitivity to components of the study drug or 
placebo* 
5. Known contraindication(s) to study drug including prohibited concomitant medications 
(see Appendices)* 
*If only one study drug appendix is open at the time of enrollment. If multiple study drug 
appendices are open, a participant may opt-out of any study drug appendix or be 
excluded from any study drug appendix based on contraindications listed in the study 
drug appendix, current use of study drug, or known allergy/sensitivity/hypersensitivity 
and still remain eligible for the remaining study drug appendices. 
5.3. 
Recruitment and Engagement 
5.3.1. 
Participant Recruitment 
Participants who are eligible based on positive SARS-CoV-2 PCR or antigen test will be 
identified by participating sites or will self-identify to a central study hotline(s) and be referred to 
the closest site. Site investigators, or their designee, may contact eligible participants to introduce 
the study and discuss study participation.  
5.3.2. 
Participant Engagement 
Participants will be engaged in the study through multiple channels. This includes, but is not 
limited to, ongoing participation in other registries partnering with ACTIV or healthcare systems.  
Additionally, participant engagement will include:  


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 compensation for participants who complete the applicable Final Visit (Day 90, 120, or 
180);  
 creating a study-wide ACTIV-6 Advisory Group;  
 developing participant-centered approaches that recognize the needs and preferences of 
COVID-19 survivors locally and nationally; and 
 multifaceted approaches that combine engagement tools, leverage the online system, use 
of social media, and representative COVID-Participants. 
5.3.3. 
Participant Randomization Process 
This trial is a double-blind, placebo-controlled trial. Participants and investigators will be 
blinded. A participant who is eligible for m study drug arms/appendices will be randomized m:1 
study drug to placebo (Figure 1). The participant will then be randomized with 1/m probability 
to each of the study drug appendices. A participant entering a study drug appendix carries their 
study drug or placebo designation with them and will get either the study drug or matching 
placebo. Participants who receive placebo will be pooled across study drug arms for those study 
drug arms/appendices that the participant is eligible. This reduces overall sample size by 
facilitating sharing of data from concurrent controls while maintaining a 1:1 allocation to study 
drug or placebo within an appendix. Randomization sequences will not be pre-generated. Given 
the adaptive nature of the trial and the unknown number of study drug appendices, arm 
assignment will be implemented at the time of confirming eligibility for randomization using a 
random number generator. The participant eligibility criteria will be checked for each study drug 
appendix, and the randomization probabilities will be set. The two step procedure will then 
occur, and the assignment to both study drug appendix and study drug versus placebo will be 
made. The participant and study teams will know which study drug appendix the participant is 
allocated to, but will be blinded to study drug versus placebo because they will be matching.  
The participant, treating clinicians, and study personnel will remain blinded to study drug versus 
placebo assignment until after the database is locked and blinded analysis is completed. Only the 
biostatistical team who is preparing closed IDMC interim reports will be unblinded. Specifically, 
study drug/placebo will be dispensed with packaging and labelling that would blind treatment 
assignment. Unblinding will occur only if required for participant safety or treatment at the 
request of the treating clinician. Refer to the Manual of Procedures (MOP) for further details. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study, who 
fulfill inclusion and exclusion criteria, but are not subsequently randomized. Screen failures also 
include participants who consent, then on review by the site, are found to be ineligible for the 
study. A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities.  
Individuals who are considered screen failures may not be re-screened. 


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5.5. 
Enrollment 
Participants who are randomized and receive study drug/placebo will be considered enrolled. 
Participants who are randomized, but do not receive study drug/placebo for any reason (e.g., 
study drug lost in the mail, death prior to receipt of study drug, participant withdrawal prior to 
receipt of study drug), will not be considered enrolled on the study and will be identified as 
randomized not enrolled. 
Receipt of study drug will be defined as evidence that the study drug was delivered to the 
address of record. 


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6. 
Study Drug(s) 
6.1. 
Repurposed Medication Treatments 
See Appendices 
6.2. 
Placebo 
See Appendices 
6.3. 
Study Drug Accountability  
Use of study drug will be tracked via the online system, call center, or sites. Participants will 
dispose of any unused study drug as they would normally when stopping a medication. 
6.4. 
Concomitant Therapy 
Select concomitant medications of interest that the participant is receiving at the time of 
enrollment or receives during the course of the study will be recorded along with dosing 
information. Select concomitant medications of interest include the following and will be 
verified at each remote visit by designated study personnel: 
 Any therapeutics that is thought to have potential or purported COVID activity including 
hydroxychloroquine 
 Antibiotics  
 Antifungals  
 Antiparasitic 
 Antivirals including HIV protease inhibitors and ribavirin 
 Immunosuppressants including steroids  
 Angiotensin-converting-enzyme (ACE)/angiotensin II receptor blockers 
(ARB)/angiotensin receptor neprilysin inhibitor (ARNI) 
 Statin 
 Anticoagulants and antiplatelets 
 COVID-19 vaccine (before, during, or after study intervention) 
Refer to the MOP for more details on concomitant therapy. Refer to the appendices for 
contraindicated medications for each of the study drugs. 
6.5. 
Intervention After the End of the Study 
No additional study drug will be provided to the participant following completion of the study.   


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7. 
Participant Withdrawal/Termination and Study Termination 
7.1. 
Participant Withdrawal/Termination 
Participants will be followed until participant closeout, withdrawal of consent, or death. 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon. 
Those who request withdrawal from the study will be asked to continue on study follow-up with 
limited participation through the Final Visit (Section 8.1.4). Limited participation may include a 
call(s) to assess safety at study visits following withdrawal. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
7.2. 
Premature Termination or Suspension of the Study 
The study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification will be provided documenting reason for study suspension 
or termination to the investigators, funding agency, and regulatory authorities, as appropriate. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to participants 
 Insufficient compliance to protocol requirements 
 Data that are not sufficiently complete and/or evaluable 
 Determination of futility after a sufficient time has passed for accrual of the primary and 
secondary outcomes 
 Recommendation by the IDMC 
7.3. 
Lost to Follow-up 
Participants will be asked for proxy contacts to assess vital status and/or other clinical events, 
including safety, if a participant fails to provide the information. Provision of proxy information 
is not required for study participation. A participant will be considered lost to follow-up if he or 
she repeatedly fails to complete study assessments/procedures as outlined below and neither the 
participant nor the participant’s proxy can be contacted by the study site. 
The following actions must be taken if a participant fails to provide baseline information, if he or 
she fail to complete daily symptom reporting by midnight the day after receiving the first dose of 
study drug/placebo (Day 2), if he or she miss one daily symptom reporting during Days 3 to 14, 
if he or she miss either the Day 14 or Day 28 Remote Visits, and/or he or she fail to complete the 
applicable Final Visit assessments: 
 
The site or call center must attempt to contact the participant and counsel the participant 
on the importance of completing study assessments/procedures. 
 
The site or call center will contact the participant’s proxy to assess vital status and/or 
other clinical or safety events. 
 
The site or call center will attempt to collect all missing survey responses. 


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 
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, three telephone calls 
and, if necessary, a certified letter to the participant’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
participant’s research record. 
 
Online obituary search.    
 
Should the participant continue to be unreachable, they will be considered lost to 
follow-up.  
 


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8. 
Study Assessments and Procedures 
Screening and eligibility confirmation will be participant-reported. A positive SARS-CoV-2 test 
result must be verified prior to randomization (refer to the MOP for details). Sites will be 
responsible for notifying the coordinating center for participant withdrawals, lost to follow-up, 
permanent cessation of study drug, study drug dose modifications (if allowed, per Appendix), or 
change in vital status. Data will be collected directly from the participant and supported by 
medical records, as needed. 
 
 


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8.1. 
Schedule of Events  
 
Table 1: Schedule of Events 
 
                                                 
3 Day 180 is applicable only for participants who were consented after protocol v7.0 was implemented; Day 120 is applicable 
only for participants consented on protocol v6.0; Day 90 was the final follow-up day for Ivermectin 400, Ivermectin 600, 
Fluvoxamine Maleate, and Fluticasone Furoate 
4 Refer to study drug appendix for length of study drug administration. 
5 Only for enrollment in Study Drug Appendices that have pregnancy listed as a contraindication for females of childbearing 
potential. Participants will self-report pregnancy using the Pregnancy Reasonably Excluded Guide. 
6 Review only during study drug/placebo administration if contraindicated medications provided for the study drug arm, per 
Appendix. 
7 Day 14 only. 
8 Daily symptom reporting; continued daily beyond day 14 through day 28 until symptoms resolve for > 3 consecutive days. All 
participants will complete symptom reporting on Days 21 and 28, regardless of symptom resolution. 
9 Day 7 and 14 only. 
10 Day 3, 7, and 14 only. 
11 At Day 7 and 14 for participants enrolled in Appendix E – Fluvoxamine Maleate 100. 
12 Participant’s medical record will be reviewed to confirm Serious Adverse Events (SAEs), Unanticipated Adverse Device 
Events (UADEs) [as applicable], and Events of Special Interest (ESIs). 
 
Screening 
Intervention 
Period 
Follow-up Period 
 
Final 
Visit 
Unplanned 
Study Visit 
Day 
Within 2 days
of Day 1 
Day 1 
Days 2 - 14 
Day 15 - 20 
Day 21 ± 2 
Day 22 - 27 
Day 28 + 5  
Day 903 + 5 
Day 1203 + 5 
Day 1803 + 7 
 
ACTIV-6 Trial 
 
 
 
 
 
 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria confirmed 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
Receipt of study drug or placebo 
 
X 
 
 
 
 
 
 
 
 
 
Continued use study drug  
 
Continuous4 
 
 
 
 
 
 
 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated medical history 
X 
 
 
 
 
 
 
 
 
 
 
Self-reported Pregnancy 
X5 
 
 
 
 
 
 
 
 
 
 
Concomitant Therapy 
X 
X6 
X6 
 
 
 
 
 
 
 
 
Remote Visit 
 
 
X7 
 
 
 
X 
 
 
 
 
Drug Adherence 
 
X 
X 
 
 
 
 
 
 
 
 
COVID-19 Outcomes 
 
X 
X9 
 
X 
 
X 
X 
X 
X 
 
Symptom Reporting 
X8 
X 
X8 
X8 
X8 
X8 
X8 
X 
X 
X 
 
PASC Symptom Questionnaire 
 
 
 
 
 
 
 
 
 
X 
 
QOL Questionnaire 
X 
 
X9 
 
 
 
X 
X 
X 
X 
 
At-home pulse oximetry 
 
 
X10 
 
 
 
 
 
 
 
 
Columbia-Suicide Severity Rating 
Scale (C-SSRS) 
 
 
X11 
 
 
 
 
 
 
 
 
Safety Assessment12 
 
Continuous via online system and medical record review 
X 


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8.1.1. 
Screening 
The following events will occur at Screening: 
 Consent: Participants will be consented either via an e-consent process or paper process. 
The consent process should be done in accordance with local and central IRB regulations. 
Phone consenting may be facilitated through the e-consent or paper process. 
 Demographic information will be collected including, but not limited to, age, sex, race, 
ethnicity, and occupation  
 Eligibility criteria confirmation by the participant via the online system or by site staff via 
a paper process 
 Abbreviated medical history  
 Self-reported pregnancy, for women of childbearing potential (only for enrollment in 
Study Drug Appendices that include pregnancy as a contraindication)  
 Concomitant therapy  
 Symptom reporting, daily during screening period 
 QOL questionnaire 
 Randomization (see Section 5.3.3) 
8.1.2. 
Intervention Period 
The following events will occur during the Intervention Period, starting with receipt of study 
drug/placebo: 
Day 1: 
 Receipt of study drug or placebo 
 Study drug self-administration (see Appendices for specific study drug/placebo 
administration) 
 Concomitant therapy  
 Drug adherence questionnaire 
 COVID-19 Outcomes 
 Symptom reporting 
 SAE, UADE (as applicable), and ESI collection 
Days 2 – 14: 
 Study drug self-administration (see Appendices for specific study drug/placebo 
administration) 
 Concomitant therapy, including contraindicated medications provided for the study drug 
arm, per Appendix, during study drug/placebo administration. 
 Remote visit (Day 14 only) 
 Drug adherence questionnaire, daily 
 COVID-19 Outcomes (Day 7 and 14 only) 
 Symptom reporting, daily 
 QOL questionnaire (Day 7 and 14 only) 
 At-home pulse oximetry readings (Day 3, 7, and 14 only)  


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 C-SSRS (Day 7 and 14 for Appendix E – Fluvoxamine Maleate 100 only) 
 SAE, UADE (as applicable), and ESI collection 
8.1.3. 
Follow-up Period 
Day 15 – 20:  
 Symptom reporting, daily from Day 14 for participants who have not yet reported three 
consecutive days of no symptoms. Participants who experience three days of 
improvement before Day 14 but who then experience symptoms again will not be 
followed daily. 
 SAE, UADE (as applicable), and ESI collection 
Day 21 ± 2 days: 
 COVID-19 Outcomes 
 Symptom reporting 
 SAE, UADE (as applicable), and ESI collection 
Day 22 – 27:  
 Symptom reporting, daily from Day 14 for participants who have not yet reported three 
consecutive days of no symptoms. Participants who experience three days of 
improvement before Day 14 but who then experience symptoms again will not be 
followed daily. 
 SAE, UADE (as applicable), and ESI collection 
Day 28 + 5 days: 
 Remote visit 
 COVID-19 Outcomes 
 Symptom reporting 
 QOL questionnaire 
 SAE, UADE (as applicable), and ESI collection 
Day 90 + 5 days:  
 COVID-19 Outcomes 
 Symptom reporting 
 QOL questionnaire 
 SAE, UADE (as applicable), and ESI collection 
The Day 120 + 5 days Follow-up visit is only applicable for participants consented on protocol 
v6.0 or later and will include the following:  
 COVID-19 Outcomes 
 Symptom reporting 
 QOL questionnaire 
 SAE, UADE (as applicable), and ESI collection 


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8.1.4. 
Final Visit 
Depending on when the participant was consented, the Final Visit may have occurred at Day 90 
or Day 120. Following implementation of protocol v7.0, Day 180 + 7 days will serve as the Final 
Visit. The Final Visit will include the following:  
 COVID-19 Outcomes 
 Symptom reporting 
 Post-acute Sequelae of SARS-CoV-2 Infection (PASC) Symptom Questionnaire (Day 
180 participants only) 
 QOL questionnaire 
 SAE, UADE (as applicable), and ESI collection 
8.2. 
Clinical Assessments 
Abbreviated Medical History: smoking status, estimated body mass index (BMI)/obesity, pre-
existing underlying lung disease (e.g., chronic obstructive pulmonary disease, asthma, idiopathic 
pulmonary fibrosis), underlying immunosuppression (transplant, malignancy, human 
immunodeficiency virus (HIV), autoimmune disease), medical conditions that may increase risk 
of COVID-19 infections or complications (e.g., diabetes, cardiovascular disease, hypertension, 
chronic kidney disease), venous thromboembolism, chronic liver disease, COVID-19 vaccination 
status 
Concomitant Medications of Interest: Concomitant medications of interest, including study drug 
specific contraindicated medications, will be collected. Refer to Section 6.4 for concomitant 
medications of interest and to the study drug specific appendices for contraindicated 
medications. 
Self-reported Pregnancy: Participants will be asked to self-report pregnancy, as needed, per 
Study Drug Appendix. The 3-item “Pregnancy Reasonably Excluded Guide” will be used to 
assess pregnancy at screening. The “Pregnancy Reasonably Excluded Guide” uses traditional and 
World Health Organization criteria to exclude pregnancy via participant self-report.[12] Refer to 
the MOP for details.  
Remote Visit: Designated study personnel will contact the participant directly via a phone call or 
other form of direct contact (e.g., text or e-mail survey) in order to conduct study assessments, 
including, but not limited to, COVID-19 outcomes, drug adherence (at Day 14), and safety 
events. A missed remote visit will be considered a protocol deviation (non-major). If a 
participant misses a remote visit, site study staff should take immediate action to contact the 
participant, per Section 7.3 follow-up processes. Refer to the MOP for details.  
Drug Adherence: Adherence to the study drug administration schedule will be collected via the 
online system and confirmed at the Day 14 remote visit. 
COVID-19 Outcomes: The COVID-19 outcomes for this trial are based on the World Health 
Organization’s Ordinal Scale for Clinical Improvement and will be collected via the online 
system and from the medical record.[13] The following outcomes will be assessed as part of the 
COVID Clinical Progression Scale:   
0. No clinical or virological evidence of infection 


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1. No limitation of activities 
2. Limitation of activities 
3. Hospitalized, no oxygen therapy 
4. Hospitalized, on oxygen by mask or nasal prongs 
5. Hospitalized, on non-invasive ventilation or high-flow oxygen 
6. Hospitalized, on intubation and mechanical ventilation 
7. Hospitalized, on ventilation + additional organ support – pressors, RRT, ECMO 
8. Death 
Symptom Reporting: Symptoms and symptom-related responses will be reported by the 
participant via the online system. Additional symptom reporting may occur from the sites, as 
available. Each of pre-defined symptoms will be assessed on an ordinal severity scale of none, 
mild, moderate, and severe. The following symptoms will be collected:  
 Overall symptom burden 
 Fatigue 
 Dyspnea - shortness of breath or difficulty breathing at rest or with activity 
 Fever 
 Cough  
 Nausea  
 Vomiting 
 Diarrhea 
 Body aches 
 Sore throat 
 Headache 
 Chills 
 Nasal symptoms 
 New loss of sense of taste or smell 
 Other COVID-related symptom  
Post-acute Sequelae of SARS-CoV-2 Infection (PASC) Symptom Questionnaire: COVID-19 has 
affected many lives through lingering symptoms, often debilitating long after acute SARS-CoV-
2 infection. The syndrome of PASC is a chronic condition present in up to 80% of infected, 
hospitalized patients and 40% to 70% of non-hospitalized patients. [14-18] The PASC Symptom 
Questionnaire includes symptoms that are associated with PASC and asks for severity 
(mild/moderate/severe) related to any symptoms identified by the participants. 
At-home pulse oximetry measurements: Participants will provide pulse oximetry readings using 
a study-provided FDA-approved pulse oximeter. Two consecutive pulse oximetry readings must 
be reported at each required time point. Day 3, 7, and Day 14 are study-required time points for 
pulse oximetry readings. Participants can report pulse oximetry readings at other times 
throughout the study, at their own discretion.   
8.3. 
Quality of Life Questionnaires 
The following QOL questionnaire will be used in this study: 


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 Modified PROMIS-29: PROMIS measures were developed through a collaborative 
process funded by the NIH.[19] The PROMIS-29 consists of seven health domains with 
four 5-level items associated with each and a pain intensity assessment using a 0-10 
numeric rank. The seven health domains include physical function, fatigue, pain 
interference, depressive symptoms, anxiety, ability to participate in social roles and 
activities, and sleep disturbance.[20] The PROMIS-29 measures will be modified for this 
study and will include select questions from each of the seven health domains, refer to the 
MOP for details. 


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9. 
Safety Assessments 
9.1. 
Adverse Events and Serious Adverse Events 
An AE is any untoward medical occurrence in humans, whether or not considered drug-related, 
which occurs during the conduct of a clinical trial. An AE can therefore be any change in clinical 
status, routine labs, x-rays, physical examinations, etc., that is considered clinically significant by 
the study investigator.  
An SAE or serious suspected adverse reaction or serious adverse reaction as determined by the 
investigator or the sponsor is an AE that results in any of the following serious outcomes:  
 Death  
 Life-threatening AE (“life-threatening” means that the study participant was, in the 
opinion of the investigator or sponsor, at immediate risk of death from the reaction as it 
occurred and required immediate intervention)  
 Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
 Inpatient hospitalization or prolongation of existing hospitalization  
 Congenital abnormality or birth defect  
 Important medical event that may not result in one of the above outcomes, but may 
jeopardize the health of the study participant or require medical or surgical intervention 
to prevent one of the outcomes listed in the above definition of serious event 
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline does not meet the definition of an SAE. Hospitalization is defined as a stay in the 
hospital exceeding 24 hours.  
An unexpected AE is defined as any AE, the specificity or severity of which is not consistent 
with the package insert. 
9.1.1. 
Adverse Device Effect (ADE) and Unanticipated Adverse Device Effect (UADE) 
For those repurposed medications that are a part of a combination product, which includes a drug 
and a device, the following additional definitions will apply. 
An ADE is an AE related to the use of an investigational medical device. This includes any AE 
resulting from insufficiencies or inadequacies in the instructions for use, the deployment, the 
implantation, the installation, the operation, or any malfunction of the repurposed medical 
device. This also includes any event that is a result of a use error or intentional misuse. 
 Device malfunction – the failure of a device to perform in accordance with the 
instructions for use or clinical investigative plan. 
 User error or intentional misuse – A device is used in a manner that is an act or omission 
of an act that results in a different medical device response than intended by the 
manufacturer or expected by the user. 
A UADE is any SAE caused by, or associated with, a device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of incidence in the investigational 
plan or applications (including a supplemental plan or application), or any other unanticipated 


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serious problem associated with a device that relates to the rights, safety, or welfare of 
participants. 
Unanticipated Adverse Device Effects (UADEs) will include events meeting either A or B as 
stated below: 
A. Events meeting ALL of the following criteria: 
 Not included in the relevant appendices or Product Label 
 Related to the device per site PI and/or IND sponsor 
 Serious (meets any of the following criteria): 
o Is life-threatening illness or injury 
o Results in permanent impairment of a body function or a body structure 
o Necessitates medical or surgical intervention to prevent permanent 
impairment of a body function or a body structure 
o Results in hospitalization 
o Led to fetal distress, fetal death, or congenital abnormality or birth defect 
o Led to death 
(Permanent means irreversible impairment or damage to a body structure or function, excluding 
trivial impairment or damage). 
B. Any other unanticipated serious problem associated with the device that relates to the 
rights, safety, or welfare of participants. 
9.1.2. 
Collection Period for AE and SAE Information 
Study participants (and their designated emergency proxies) will be instructed to report ESIs per 
appendix and Section 9.1.5, SAEs, and UADEs through their access to the study’s online system. 
Each day for 14 days, the participant will be asked to report on their symptoms and health state, 
including hospitalization and/or other change in health condition. The assessments include 
specific questions pertaining to ESIs, as well as symptoms and severity, health care visits, 
medications and a notification to the participant to contact the study team with any concerns or 
questions. If the participant is still reporting symptoms at Day 14, they will continue to be 
assessed until they have experienced three consecutive days without symptoms, or until Day 28, 
whichever is shorter. At Day 28, Day 90, Day 120, and Day 180, participants will complete 
assessments. Safety reporting will be available to the participant continuously throughout the 
study, but will only be required at the aforementioned collection points.   
The daily and follow-up assessments, as described in the paragraph above, will be monitored and 
sites will be actively notified of events requiring review, including for reporting that meets 
criteria for ESIs, SAEs, or UADEs. Refer to the MOP for details. In addition, participants will be 
invited during assessments to request contact from the study team, or to report any unusual 
circumstances that might be relevant, if they so wish. Failure to complete daily assessments is 
also a trigger for review of a possible SAE. A missed assessment on the day after receiving the 


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first dose of study medication (Day 2) or any day of missed assessments up to Day 14 will 
prompt a notification to the site to contact the participant. 
All participants will be instructed to self-report concerns either via an online event reporting 
system, by calling the site, or by calling a 24-hour hotline. Participants will have access to event 
reporting via the online system from the signing of the informed consent form (ICF) until the 
Final Visit (Day 90, Day 120, or Day 180 depending on the time of consent). 
Events of special interest (ESIs) and SAEs will be extracted by site personnel from the 
participant’s medical record if the participant seeks medical care or if hospitalization occurs, 
each of which notifies the site to conduct follow up.  
Medical occurrences that begin before the start of study drug/placebo, but after obtaining 
informed consent, will not be considered an AE. 
Non-serious AEs (or ADEs, as applicable) may be reported by the participant, but will not be 
further assessed by the site or study personnel unless the event meets the criteria of an ESI.  
Events of Special Interest (ESIs), SAEs, and UADEs (as applicable) will be collected from the 
start of study drug/device combination until the Final Visit (Day 90, Day 120, or Day 180 
depending on the time of consent) or until 30 days after the last dose/use of device if participant 
terminates the study early. 
9.1.3. 
Assessing Causality of a Serious Adverse Event 
If an SAE occurs, the site investigator or medical monitor will assess the relationship to study 
drug by using the following criteria: 
 Related:  
o Study drug – there is a temporal relationship between study drug and event onset 
or the event abates when study drug is discontinued or known to occur with study 
drug. 
o Device – an event is due to the use of the device and cannot be reasonably 
explained by an alternative cause. 
 Not related: The event has no temporal relationship to study drug (or study device, as 
applicable) or the AE (or ADE, as applicable) has a much more likely alternate etiology 
or is due to an underlying or concurrent illness or effect of another drug (or device, as 
applicable). 
9.1.4. 
Reporting and Monitoring of SAEs 
All of the study drugs used in this platform protocol are repurposed medications that are 
approved for marketing in the US for another medical condition. However, their investigational 
use for treatment of COVID-19 infection is not an approved indication and will be under an IND 
and subject to IND regulations in 21 CFR 312. The IND sponsor or designee will review SAEs 
weekly, and will perform aggregate reviews of SAEs every two weeks. The IND sponsor or her 
designee will be responsible for determining if the safety reporting criteria are met per 21 CFR 
312.32(c)(1)(i)(C) and 21 CFR 312.32(c)(1)(iv) and will notify the Data Coordinating Center 
(DCC) to prepare an aggregate report for submission to the FDA. An aggregate safety report will 


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be submitted to FDA as soon as possible, but in no case later than 15 calendar days after the IND 
sponsor determination. If the IND sponsor determines that an unexpected fatal or life-threatening 
suspected adverse reaction occurs markedly more frequently in a study drug arm than in the 
placebo arm, an aggregate safety report will be submitted to the FDA as soon as possible, but in 
no case later than 7 calendar days after the IND sponsor determination. Information on 
individual SAEs will be available upon request from the Agency following the submission of any 
aggregate reports. 
Any UADE(s) that the IND sponsor determines is/are reportable will be submitted to the FDA, 
manufacturer, all reviewing IRBs, and all participating investigators within 10 working days of 
when the sponsor makes that determination. 
If the IND sponsor determines that a UADE presents an unreasonable risk to participants, all 
investigations or parts of investigations presenting that risk shall be terminated as soon as 
possible. Termination shall occur not later than 5 working days after the sponsor makes this 
determination and no later than 15 working days after the sponsor first received notice of the 
effect. 
All hospitalization and death events will be adjudicated (see Section 10.9), any event that is 
determined to be COVID-19-related will not be reportable as an expedited SAE, with the 
exception of events that are related to study drug and unexpected, which will be reportable 
regardless of relatedness to COVID-19. All events that are not COVID-19-related per the 
adjudication process will be reviewed by the DCRI Safety Medical Monitor to determine if the 
event is a reportable SAE. 
Individual SAEs and UADEs must be entered into the data system within 24 hours of site 
awareness. The DCRI Safety Surveillance team will notify pharmaceutical partners of SAEs 
within 1 business day of their receipt that occur involving the specific appendix of the supplied 
study drug/placebo, as required. Serious Adverse Events that are related and confirmed unlisted 
by the DCRI Safety Medical Monitor will be reported to the FDA as SUSARs; as 7-day reports 
for unexpected fatal or life-threatening adverse reactions and 15-day reports for serious and 
unexpected adverse reactions. If the IND sponsor, IDMC, or FDA note a clinically important 
increase in the rate of a SUSAR, the IND sponsor or her designee will notify investigators no 
later than 15 calendar days after determining that the information qualifies for reporting. The 
investigator will follow all reportable events until resolution, stabilization or the event is 
otherwise explained. The DCRI Safety Surveillance Team will follow all SAEs until resolution, 
stabilization, until otherwise explained. 
Pregnancies that occur while on-study will be collected and will not be followed to outcome if 
outcome occurs beyond the participant’s Final Study Visit, however, any associated ESI or SAE 
should be reported if information can be collected and entered into the EDC. The DCRI Safety 
Surveillance team will notify pharmaceutical partners of a pregnancy within 1 business day of 
receipt that occur involving the specific appendix of the supplied study drug/placebo, as 
required. 
9.1.5. Events of Special Interest  
The following are also considered ESIs to the study and will be collected by study personnel via 
medical record review when concern for ESIs are observed for hospitalized participants:  


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 Hypoxia, defined as two consecutive pulse oximetry readings ≤ 93% 
Each study drug may have a unique list of possible related ESIs. Refer to the relevant 
appendices. 
9.2. 
Unanticipated Problem (UP) and Terminations 
9.2.1. Definition of Unanticipated Problem  
The OHRP considers UPs involving risks to participants or others to include, in general, any 
incident, experience, or outcome that meets all of 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 participant 
population being studied. 
 Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research). 
 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. 
9.2.2. Reporting of an Unanticipated Problem  
The site investigator will report UPs for their participants to the DCC. The site may also be 
required to inform their reviewing IRB about a UP occurring at the local institution. The UP 
report to the DCC will include the following: 
 A detailed description of the event, incident, experience, or outcome  
 An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP  
 A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP 
 The DCC will document and review all UPs.  Details of the UP reporting process will be 
located in the MOP. 


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10. 
Statistical Considerations 
10.1. 
Statistical Hypotheses 
10.1.1. 
Primary Hypothesis 
The primary hypothesis in this trial is that participants who receive study drug will have reduced 
disease progression to hospitalization or death and/or more rapid resolution of symptoms as 
compared to those who receive placebo. 
10.2. 
Sample Size Determination 
This study is designed to be analyzed using a Bayesian approach, accepting the possibility of 
adding and dropping of arms as the trial progresses. There is also the potential for extending 
accrual in a study drug appendix if there is the potential to demonstrate benefit. Detailed 
simulations will be used to demonstrate the operating characteristics common to each study 
drug appendix. Decision thresholds will be set to balance overall power with control of the 
Type I error rate in the context of the appendix-specific goal.  
To aid planning for this trial, symptom count and clinical event data were estimated from 
participants in a clinical trial with similar inclusion criteria. Data were not collected daily in that 
study, but evaluations were completed on Day 10 after randomization, which is considered a 
clinically meaningful point in time. Based on the observed distribution, it is estimated that 
studies of about n=600 (300 study drug and 300 placebo) will be sufficiently sized to determine 
whether there is evidence of meaningful benefit with > 85% power (Table 2). Moreover, when 
a study drug demonstrates overall effectiveness, the planned adaptations to increase targeted 
accrual for the purpose of demonstrating benefit on clinical events is a reasonable extension 
within the context of this platform. The final decision thresholds and operating characteristics 
selected for each appendix, if deviating from the common approach described in the SAP, will 
be customized in an appendix-specific SAP. It is expected that this study will enroll up to 
15,000 adults, depending on the number of study drug appendices that are added and 
adjustments to sample size depending on the data.[21]  
Table 2: ACTIV-6 Sample Size Estimates and Power 
OR 
Corresponding 
difference in mean 
symptom burden 
Power 
Corresponding Risk 
Difference in clinical 
events 
Power 
80% 
85% 
90% 
80% 
85% 
90% 
0.4 
2.10 
75 
86 
101 
0.025 
343 
392 
459 
0.5 
1.98 
132 
150 
176 
0.021 
455 
520 
608 
0.6 
1.86 
242 
277 
324 
0.017 
675 
772 
903 
0.7 
1.74 
496 
567 
664 
0.012 
1004 
1148 
1343 
0.8 
1.61 
1267 
1449 
1696 
0.009 
1652 
1889 
2211 
The sample sizes given are the sample size for the study drug arm only. Placebos will be borrowed across study drug 
appendices. The total size of the placebo arm will be equal to the size of the study drug arm. The total number of 
placebos in the trial will depend on eligibility of participants among the study drug appendices and the number of study 
drugs. The calculations are based on symptom burden, hospitalization, and death at Day 10. 
10.3. 
Randomization 
See Section 5.3.3 for additional details.  


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10.4. 
Blinding 
The investigators, treating clinicians, and study participants will all remain blinded to study drug 
versus placebo assignment until after the database is locked and blinded analysis is completed. 
Only the Investigational Drug Service (IDS) and staff who are handling randomization codes and 
unblinded members of the biostatistical team who are preparing closed IDMC interim reports 
will be unblinded. The statistical staff responsible for preparing IDMC reports will not directly 
interact with the clinical team that delivers care to the study participants. Specifically, study 
medication will be dispensed with packaging and labelling that would blind treatment 
assignment. Unblinding will occur only if required for participant safety or treatment at the 
request of the treating clinician.  
The web-based randomization system will include blind-breaking instructions. Participant safety 
must always be the first consideration in making an unblinding determination. If the investigator 
decides that unblinding is warranted, the investigator should complete an unblinding request, 
which will immediately notify the Medical Monitor (see MOP for details).  
10.5. 
Populations for Analyses 
Modified Intention to Treat (mITT) Population:  
● All participants who receive study drug/placebo. 
● Participants who do not receive study drug, for any reason, will be excluded; while this 
modifies the intention to treat principle, the failure of delivery of medications from site to 
participant is not under the control of either investigator nor participants and is expected 
to occur infrequently and randomly. Similarly, early death of a participant or withdrawal 
prior to the study drug being received is possible, but unlikely and expected to occur 
randomly between study drug appendices. All other participants will be included, and 
they will be analyzed according to which arm they were assigned. Thus, the mITT 
analysis set includes all participants who were randomized and received the study drug. 
Safety Population: 
● The safety population will include those persons in the mITT population who report 
taking at least one dose of study drug or matching placebo. In the unlikely case a 
participant receives the incorrect study drug, participants will be grouped according to the 
treatments that they received.  
10.6. 
Statistical Analyses 
The main trial SAP will be finalized prior to the primary analysis. It will include a description of 
the statistical analyses and detailed simulations used to inform the sample size estimates. 
Appendix-specific decisions, such as choice of covariates for the model, and context specific 
decisions such as deviations in decision making thresholds or in targeted accrual, will be made 
blinded to data and prior to analyses. Such decisions will be documented in the trial master file.  
This section is a brief summary of the planned approach to statistical analyses of the most 
important endpoints including primary and secondary endpoints. 


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10.6.1. General Considerations 
Baseline demographic and clinical variables will be summarized for each randomized arm of the 
study. Descriptive summaries of the distribution of continuous variables will be presented in 
terms of percentiles (e.g., median, 25th and 75th percentiles) along with means and standard 
deviations. Categorical variables will be summarized in terms of frequencies and percentages. 
Histograms and boxplots may be used to visualize the data. 
If an efficacy signal is observed at n=300 or n=600 following sIA, the trial will enter assessment 
of the primary objective. At that time, the pre-determined primary clinical endpoint for the 
appendix will be evaluated as either clinical events (hospitalization or death) or time to recovery. 
The unselected endpoint will be reported as part of the secondary objective. Both clinical 
endpoints will be analyzed using a covariate-adjusted statistical model.  
10.6.2. Statistical modeling 
Estimation and inferences about the effect of each study drug versus matching placebo will be 
made using Bayesian regression methods. For each study drug, the matching placebo arm will 
consist of concurrently randomized participants that meet the inclusion and exclusion criteria for 
that study drug. The statistical models are described in detail in the SAP. Briefly, a longitudinal 
ordinal regression model will be used for the sIA, a logistic regression model will be used for 
clinical events, and proportional hazards models will be used for time to event analyses. All 
models will be adjusted for covariates, including baseline symptom severity and time from 
symptom onset. Covariates will be formally specified prior to an analysis, taking into account 
emerging data and changing context. 
10.6.3. 
Assessing Effectiveness (Primary Objective) 
The overall effect of each study drug versus matching placebo will be quantified using one of the 
following two primary endpoints, which will be defined and documented per study drug 
appendix prior to the initial IA: clinical events (hospitalization or death) or time to recovery. 
The primary analysis will be implemented separately for each study drug appendix where the 
matching placebo arm will consist of concurrently randomized participants that meet the 
inclusion and exclusion criteria for that study drug. Decision thresholds, priors, and meaningful 
effect sizes may change during the course of the pandemic, as vaccination rates, case rates, and 
new therapies continue to evolve. Thresholds, effect sizes and priors, that vary during the trial 
from those described in the main SAP will be documented in the trial master file or other 
designated document. Prior to any interim or final analysis, all decision thresholds, priors and 
effect sizes will be confirmed and evaluated using extensive simulations to demonstrate the 
overall Type I error rate remains below 0.05. An mITT approach will be used for primary 
analyses. All available data will be used to compare each study drug versus placebo control, 
regardless of post-randomization adherence to study protocols.  
10.6.4. 
Interim Analyses (IA), Early Stopping, and Type-I Error Control 
Individual study drugs may require different sample sizes, and the sample sizes may be adjusted 
based on the results of IA. Therefore, fixed enrollment triggers will be used for IA. An IA will 
occur after enrollment and completion of 14 day follow-up of approximately every 300 


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participants in a study arm (150 in study drug arm and 150 in placebo arm). Study drug 
appendices may be stopped early for efficacy or futility (see Figure 2). Thresholds are described 
in the SAP to guide stopping of each appendix if there is clear evidence of benefit or if there is 
sufficient evidence to declare futility.  
The following schedule and decision thresholds will be followed for IAs: 
i) 
Screening IA (n=300): 
a. The study drug is found to have benefit (efficacy). Study drug appendix will 
proceed to primary objective IA at n=300. Note: this is also a check for harm as 
all assessments are two-tailed.  
b. The study drug is not found to have benefit, enrollment continues in the study 
drug appendix and sIA is repeated at n=600. 
ii) 
Screening IA (n=600): 
a. It would be futile to attempt to show a benefit of the study drug based on the 
predicted probability of success (PPOS) and other factors. The study drug 
appendix will be terminated.  
b. Futility is not determined. Study drug appendix will proceed to primary objective 
IA at n=600. 
iii) 
Primary Objective IA (n=300): if the criteria for proceeding to the primary objective 
are met when n=300, a primary objective IA will be conducted. The following 
decisions will be assessed: 
a. The study drug is found to have benefit (efficacy), the study drug appendix will 
be terminated as the primary endpoint has been met. 
b. It would be futile to attempt to show a benefit of the study drug within the PPOS 
and other factors. The study drug appendix will be terminated.  
c. Efficacy/futility is undeterminable, enrollment will continue in the study drug 
appendix and the primary objective IA will be assessed at n=600.  
iv) 
Primary Objective IA (n=600, 900): if the criteria for proceeding to the primary 
objective IA are met when n=600 or n=900, a primary objective IA will be 
conducted. The following decisions will be assessed: 
a. The study drug is found to have benefit (efficacy), the study drug appendix will 
be terminated as the primary endpoint has been met. 
b. It would be futile to attempt to show a benefit of the study drug based on the 
PPOS and other factors. The study drug appendix will be terminated.  
c. Efficacy/futility is undeterminable, enrollment will continue in the study drug 
appendix and the primary objective will be assessed after another 300 participants 
have been enrolled, or until n=1200.  
The analysis for the sIA will use a covariate adjusted statistical model. The outcome is an ordinal 
variable, which is the overall symptom burden measured on a none / mild / moderate / severe 
scale with hospitalization and death added as the 5th and 6th level of the ordinal scale. The 
outcome is measured daily for 14 days. The outcome is compared between participants receiving 
study drug and participants receiving placebo each of the 14 days using a longitudinal statistical 
model that takes into account the repeated measurements on each participant. The statistical 


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model can be used to estimate the days of benefit – the number of days for which being on an 
active study drug results in a better outcome than being on a comparator. Days benefit, restated 
in terms of concordance and discordance probabilities, is the difference between (a) the 
probability that the intervention is better and (b) the probability that the non-intervention is 
better, summed over all the days of follow-up. This is the main quantity, or estimand, that will be 
used to make early go/no-go decisions for each appendix.  
The primary objective IA will follow processes described in Section 10.6.3 for assessment of 
efficacy. The primary endpoint used for the primary objective IA will be selected per appendix 
prior to the initial IA.  
A posterior probability of meaningful benefit for a study drug in comparison to the placebo 
control of greater than the specified threshold will result in a declaration of overall superiority. A 
PPOS when n=1200 is less than the specified threshold will result in a declaration of futility. 
Futility is a low probability of achieving any conclusions within a reasonable time frame or 
within the context of the trial. Prior to each IA, the target date for study completion will be 
specified, and accrual will be projected by that target date. A statistical model may be used to 
predict accrual. Futility assessment will use the lowest of either the planned accrual or predicted 
accrual at study closure. 
The combination of decision thresholds and effect sizes have been selected to balance the ability 
to observe a meaningful effect on symptoms, to observe the potential for an effect on clinical 
outcomes, and to maximize power while controlling the Type 1 error rate. For each appendix, 
decision making thresholds will be set to achieve appendix-specific goals and simulations will be 
used to demonstrate that the operating characteristics are consistent with a Type I error control of 
at least 5%, as described in the SAP. 
10.6.5. 
Sensitivity and Supplementary Analyses 
The sensitivity analyses described in the SAP are designed to test robustness of the results to 
assumptions in the statistical models. In addition to checking assumptions about the modeling 
approach, association of adherence with outcomes will also be ascertained. In the main statistical 
model, the number of doses of study drug consumed will be added as a covariate. 
10.6.6. 
Differential Treatment Effects and Subgroup Analyses 
Differential treatment effect, also referred to as heterogeneity of treatment effect, refers to 
differences in treatment efficacy as a function of pre-existing participant characteristics such as 
baseline variables. This is often assessed by forming subgroups. However, these subgroups do 
not inherit the baseline covariate adjustment of the full participant outcome model, and are 
problematic because of improper subgrouping when a continuous variable is used. For example, 
dichotomizing age at 65 years is arbitrary and it is very unlikely that any study drug effect has a 
discontinuity in effect at 65 years old. Also, subgroup estimates and statistical assessments of 
them are unreliable and are often taken out of context when a more systematic analysis does not 
find evidence for an interaction between the covariate and study drug.  
For these reasons, analysis of differential study drug effect will be prespecified and model based.  
For example, effectiveness variability can be estimated with continuous age by adding a smooth 
age by study drug interaction into the model and using this model and using this model to 


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estimate treatment contrast and their uncertainties across age = 10, 11, …, 100. Differential 
treatment effects by sex, body mass index, and age will be examined. Prior to the final analysis, 
additional important subgrouping variables will be defined and listed in the SAP. Knowledge 
about concomitant therapies, risk factors, and vaccinations are expected to continue to evolve 
and inform the final decision on their inclusion in these analyses.  
Studies under this master protocol will be sized only for assessing overall study drug effects. 
Thus, there may be inadequate power to (1) examine interactions and to (2) estimate covariate-
specific treatment effects (e.g., odds ratio at age 70 or for females). 
10.6.7. 
Secondary Clinical Endpoint 
The COVID Clinical Progression Scale score on Day 14 will be compared between participants 
in each study drug arm and the placebo arm using a covariate adjusted proportional odds model. 
A similar approach will be used for QOL outcomes. Covariates will be prespecified and will 
include at a minimum: age, baseline severity, and duration of illness. The proportional odds 
assumption will mainly be examined using graphical methods—e.g., the logit of the empirical 
cumulative distribution function of the ordinal scale should be parallel among categories of 
covariates. If proportionality is clearly violated, a partial proportional odds or non-proportional 
odds models will be considered. As before, a Bayesian approach to model interpretation will be 
used. For estimating time to symptom resolution based on the definition of at least three 
consecutive days without symptoms, a proportional hazards model will be used. Since death is a 
competing risk, cause-specific hazards will be estimated. Observations will be censored at 28 
days. 
10.6.8. 
Exploratory Analysis 
Exploratory analyses involve the same outcome variables, measured at 90, 120, or 180 days. 
Exploratory analysis will focus on describing long term outcomes, particularly symptoms and 
severity, clinical status, and QOL. Statistical models will use a similar form as for the main 
analysis. As well as simple analysis that consider the effect of treatment on long term outcomes, 
the SAP will describe how participant state during the intervention period will be used to inform 
longer term outcomes.  
10.6.9. 
Adherence and Retention Analysis 
Withdrawals from study drug and consent withdrawals will be tracked via the online system.  
Participants will be asked about their use of study drug. Those reporting discontinuation or 
switching will be asked about the reasons for discontinuation/switching.   
Measures of study retention to inform follow-up time will be based on several measures, 
including web-based check-ins for symptoms and COVID-19 outcome reporting. 
10.7. 
Interim Reporting  
In addition to routine evaluation of decision thresholds pursuant to the statistical design of this 
study, regular IDMC reviews will be conducted to ensure the safety of study participants.  
Regular IDMC meetings will monitor the following parameters at a minimum: 
 Recruitment progress 


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 Enrollment overall and by subgroups 
 Adherence, retention, and status of data collection 
 Events of special interest (ESIs) 
 Unanticipated problems 
 Serious adverse events (SAEs) 
Interim examination of clinical endpoints will be based on the accrual of primary endpoint data.  
It is expected that reviews of the data will occur approximately after each 300 participants are 
enrolled in each study drug appendix (150 in study drug arm and 150 in placebo arm).  
For ethical reasons, interim examinations of key safety and process data will be performed at 
regular intervals during the course of the trial. The DCC will create reports to track participant 
enrollment, rates of adherence with the assigned treatment strategy, and frequency of protocol 
violations. Prior to each meeting, the DCC will conduct any requested statistical analyses and 
prepare a summary report along with the following information: participant enrollment reports, 
rates of adherence with the assigned treatment, and description of SAEs.  
Safety reports will be prepared for the IDMC approximately weekly once enrollment begins. The 
prespecified stopping thresholds are intended to guide the interpretation of interim analyses and 
are not a strict rule for early termination. It is expected that both internal and external factors will 
influence the decisions of the IDMC. The SAP will describe the planned interim analyses and 
futility monitoring in detail. 
10.8. 
Independent Data Monitoring Committee (IDMC) 
The IDMC will monitor participant safety and study performance. An IDMC charter that outlines 
the operating guidelines for the committee and the procedures for the interim evaluations of 
study data will be developed and agreed upon by the IDMC. Reports will be prepared by the 
DCC in accordance with the plan outlined in the charter, or as requested by the IDMC chair, and 
will include interim analyses of primary and secondary endpoints, additional safety events, and 
other information as requested by the committee. After each scheduled closed meeting, the 
IDMC will send a recommendation to the IND sponsor to continue, modify, or terminate the 
study. After approval, the recommendations will be forwarded by the clinical coordinating center 
(CCC) to investigators for submission to their local, regional and national IRB/Ethic 
Committees, as applicable. Please refer to the IDMC Charter for further details. 
10.9. 
Adjudication Committee 
The medical records will be requested for all participants reporting a hospitalization and/or death 
at any point during the study. For each participant-reported hospitalization or death event, the 
DCRI Clinical Event Ascertainment (CEA) group will review the medical records and confirm 
the occurrence and root cause of the event as part of an adjudication process. The CEA group 
includes specialists relevant to the hospitalization or death events of interest, additional details 
about review procedures will be provided in an adjudication charter.  
 


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11. 
Ethical Standards 
11.1. 
Institutional Review Board (IRB) 
The protocol, ICF(s), recruitment materials, and all participant materials will be submitted to the 
IRB(s) of record for review and approval. This approval must be obtained before any participant 
is enrolled. Any amendment to the protocol will require review and approval by the IRB(s) 
before being implemented in the study. All changes to the consent form will also be IRB-
approved and a determination will be made regarding whether previously consented participants 
need to be re-consented. 
11.2. 
Informed Consent Process 
All consenting will occur either via an electronic consent process or a paper process. Consent 
forms describing in detail the study drug/placebo, study procedures, and risks will be given to the 
participant and documentation of informed consent is required prior to starting study procedures. 
Informed consent is a process that is initiated prior to the individual’s agreement to participate in 
the study and continues throughout the individual’s study participation. A description of risks 
and possible benefits of participation will be provided to the participants. A description of the 
current available therapies as part of usual care outside of this trial will be provided to the 
participants and clarification that receipt of such therapies are not part of exclusion criteria will 
also occur. Consent forms will be IRB-approved and the participant will be asked to read and 
review the document. The participant will be provided a phone number and email in the event 
they have questions about study participation. This will allow them to communicate with the 
investigators (or their delegate), for further explanation of the research study and to answer any 
questions that may arise, as necessary. Participants will have the opportunity to carefully review 
the consent form and ask questions prior to signing. 
The participants should have the opportunity to discuss the study and think about it prior to 
agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. The participants may withdraw consent at any 
time throughout the course of the study. A copy of the informed consent document will be 
provided to the participants for their records. The rights and welfare of the participants will be 
protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
The study team will distinguish between the desire to discontinue study drug and the desire to 
withdraw consent for study follow-up. In the event that a participant withdraws consent, the 
investigator or his/her designee will clarify with the participant and document whether the 
withdrawal is temporary or permanent, and if a full or partial withdrawal. 
11.3. 
Participant and Data Confidentiality 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
and the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
samples in addition to the clinical and private information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 


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53 
third party without prior written approval of the sponsor. The study participant’s contact 
information will be securely stored in the clinical study database. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the DCC. The study data entry and study 
management systems used by clinical sites and by research staff will be secured and password 
protected. At the end of the study, all study-related data storage systems will be archived 
according to local processes. 
11.4. 
Site Management and Quality Assurance 
The study team will work in tandem to ensure that the data collected in this study are as complete 
and correct as possible. A four-step, multi-functional approach to quality control will be 
implemented: 
 Training: Prior to the start of enrollment, the clinician investigators and key study 
personnel at each site will be trained with the clinical protocol and data collection 
procedures, including how to use the Electronic Data Capture (EDC) system. Follow-up 
training and training for new study personnel or new versions of the protocol will be 
conducted as needed. 
 Monitoring: The CCC, along with the DCC, will ensure that data collection is handled 
properly, will provide in-service training, and will address questions from site investigators 
and coordinators. Electronic review of data quality and completeness will occur on a 
regular and ongoing basis. Any issues will be addressed. At a minimum, source document 
verification will occur, as needed, for confirmation of COVID-19 diagnosis and 
hospitalization(s). 
 Managing data: After the data have been transferred for statistical summarization, data 
description, and data analysis, further crosschecking of the data will be performed with 
discrepant observations being flagged and appropriately resolved through a data query 
system. 
 Reviewing data: Data regarding events of interest will be reviewed to ensure appropriate 
documents are collected for IDMC review. The DCC will monitor standardized 
classification of symptoms and contact site study teams when events comprising the 
primary endpoint are not complete. 
11.5. 
Site Monitoring 
This study will employ a centralized risk-based approach to monitoring with routine and periodic 
review of participant-submitted data to validate the informed consent process, select eligibility 
criteria, hospitalization, identify and follow-up on missing data, inconsistent data, data outliers, 
etc. and ensure completion of administrative and regulatory processes. The study team will 
facilitate regular communication through training sessions, teleconferences, videoconferencing, 
email, etc. Using quality-by-design principles, steps will be taken at the study design stage to 
foresee and limit problems that might occur during the study conduct. Follow-up from the online 
system and call center is expected to keep participants engaged. Minimal levels of intervention 
and a focus on observing rather than influencing the study participants greatly increases the 
likelihood that Good Clinical Practices will be followed. Central statistical monitoring is 


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particularly useful for identifying unusual patterns in data. An integrated approach to quality 
surveillance will be deployed, which will be detailed in the appropriate study management plans. 


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12. 
Data Handling and Record Keeping 
12.1. 
Data Collection and Management Responsibilities 
Minimizing research activities and conducting the trial in a pragmatic manner will increase the 
ability to complete the trial in the face of strained clinical and research resources during the 
COVID-19 pandemic. Data will be collected by electronic methods, supplemented by telephone 
or videophone follow-up and from the electronic health record.  
Data will be collected directly from participants using REDCap through text messaging or email 
with a survey link, or phone call as back up. The process for using text messaging is Health 
Insurance Portability and Accountability Act (HIPAA) compliant.  
Site personnel or participants will enter study data into a secure online database. Data will be 
maintained in a secure online database until the time of study publication. At the time of 
publication, the DCC will generate a de-identified version of the database for archiving (see 
Section 12.4). 
12.2. 
Study Records Retention 
Study documents should be retained for a minimum of six years after the study has ended. 
However, if required by local regulations, these documents should be retained for a longer 
period. No records will be destroyed without the written consent of the sponsor, if applicable. It 
is the responsibility of the sponsor to inform the investigator when these documents no longer 
need to be retained. 
12.3. 
Protocol Deviations 
A protocol deviation is defined as non-compliance with the clinical study protocol, GCP, or 
MOP requirements. The non-compliance may be on the part of the participant, site investigator, 
or the site staff.  
A major protocol deviation is a significant divergence from the protocol that may have 
significant effect on the participant’s safety, rights, or welfare and/or on the integrity of the study 
data. Major protocol deviations must be sent to the study IRB and local IRB per their guidelines, 
recorded in source documents, and reported to the coordinating center. Major protocol deviations 
will be tracked. For this study, any missed or delayed survey completion will not be considered a 
major protocol deviation. Refer to the MOP for details. 
12.4. 
Publication and Data Sharing Policy 
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the results of NIH-funded research. Methods of data sharing will include 1) archiving 
de-identified data in a data repository and 2) sharing of limited datasets under a Data Use 
Agreement (DUA) and IRB approval. Data will be made available to qualified investigators by 
archiving a fully de-identified dataset in a platform to be determined at the end of the trial. Both 
repositories allow users to search, view study information, and then submit an application to 
receive data. Prior to archiving study data, the DCC will produce a final dataset that will be 
stripped of all personal health information (PHI) in compliance with the HIPAA privacy rule. 


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The relative timing of an event will be retained in the dataset converting to study days instead of 
dates.  
The study result will be returned, including some participant specific results, to enhance value from 
participation. Study results will be disseminated to the public and the medical community through 
presentations at scientific meetings and publishing manuscripts in high impact peer-reviewed 
journals. The International Committee of Medical Journal Editors (ICMJE) member journals have 
adopted a clinical studies registration policy as a condition for publication. The ICMJE defines a 
clinical study as any research project that prospectively assigns human participants to 
intervention or concurrent comparison or control groups to study the cause-and-effect 
relationship between a medical intervention and a health outcome. The ICMJE policy, and the 
Section 801 of the Food and Drug Administration Amendments Act of 2007, requires that all 
clinical studies be registered in a public registry such as ClinicalTrials.gov, which is sponsored 
by the National Library of Medicine. For interventional clinical trials performed under NIH IC 
grants and cooperative agreements, it is the grantee’s responsibility to register the study in an 
acceptable registry, so the research results may be considered for publication in ICMJE member 
journals.  


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13. 
Study Leadership 
The Steering Committee is a multi-stakeholder committee that oversees the study and includes 
representatives from clinical sites, the trial coordinating center, the NIH, PCORI, Operation 
Warp Speed, the FDA, National Center for Advancing Translational Sciences (NCATS), ACTIV 
representatives with no conflict of interest, and academic and industry advocates.  
The CCC and DCC are each overseen by PI(s). The CCC is responsible for study coordination, 
site management, communication, and financial administration. The DCC is responsible for 
treatment allocations, receipt and processing of data, quality control programs, and statistical 
analysis and reporting.   
An independent IDMC will oversee the safety and welfare of trial participants as well as provide 
recommendations for continuation, discontinuation or revision of the trial. 
 
 
Figure 3: Operational Structure Diagram 


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14. 
Summary of Changes 
Protocol Version (version #, date) 
Summary of Changes 
Version 1.0, 01APR2021 
N/A, Version 1.0 
Version 2.0, 25MAY2021 
 Added current use of study drug or 
study drug/device combination as an 
exclusion criteria (Sections 1.1 and 
5.2); 
 Added a phone call follow-up the day 
after first study drug dose, clarified that 
follow-up will occur if two consecutive 
days of reporting are missed during 
Days 3-14, and added that sites/call 
center will collect missing survey 
information during follow-up calls 
(Section 7.3); 
 Added at-home pulse oximetry readings 
and description of at-home pulse 
oximetry reading collection (Table 1 
and Section 8.2); 
 Added symptom severity scale (Section 
8.2); 
 Added Adverse Device Effect and 
Unanticipated Adverse Device Effects 
definitions, collection/reporting period 
details, and causality assessment details 
(Sections 9.1.1, 9.1.2, 9.1.3, 9.1.4); 
 Clarified that hypoxia ESI will only be 
collected from hospitalized participants 
(Section 9.1.5); 
 Clarified that any missing or delayed 
survey completion will not be 
considered a major protocol deviation 
(Section 12.3); 
 Updated Ivermectin and matched 
placebo information and packaging 
(Sections 16.3, 16.3.1, 16.3.3, 16.4.1); 
 Added Appendix B – Fluvoxamine 
maleate (Section 17); 
 Added Appendix C – Fluticasone 
Furoate (Section 18); 


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 Changed symptom freedom to 
symptom resolution for consistency 
throughout; 
 Other administrative changes 
throughout. 
Version 3.0, 06JUL2021 
 Clarified that the sample size increase 
will included 1:1 active study drug to 
placebo (Section 1.1); 
 Added footnote 6 to COVID-19 
Outcomes during Intervention Period to 
clarify that these will be assessed on 
Day 7 and 14 (Table 1); 
 Added that events that are COVID-19 
related AND study drug related and 
unexpected will be considered 
reportable (Section 9.1.4); 
 Updates made to fluvoxamine 
appendix: excluded linezolid, use of 
fluoxetine within 45 days of consent, 
and bipolar disorder per FDA feedback 
(Section 17.2); added precautions of 
additional drugs including tramadol, 
buspirone, fentanyl, lithium, 
amphetamines, St. John’s Wart, 
carbamazepine, quinidine, and tacrine 
per FDA feedback (Section 17.2.1); 
 Updates made to fluticasone furoate 
appendix: brand name Arnuity Ellipta 
replaced with fluticasone furoate 
throughout (Section 18); changed liver 
failure exclusion criteria to “moderate 
to severe hepatic impairment, defined 
as Child-Pugh B or C” (Section 18.2); 
removed hepatic impairment 
precautions as it was added to exclusion 
criteria (Section 18.2.1); 
 Other minor administrative changes 
throughout. 
Version 4.0, 20DEC2021 
 Removed protocol number as no 
protocol number will be assigned; 


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 Changed primary objective from 
symptom reduction to effectiveness 
based on clinical outcome endpoints of 
hospitalization/death or time to 
recovery (Sections 1.1 and 3);  
 Removed unnecessary “e.g., 
hospitalization and death” from first 
secondary objective (Sections 1.1 and 
3);  
 Added rationale for sIA (Sections 1.1 
and 4);  
 Inclusion criterion #3: added 
reinfection (Sections 1.1 and 5.1); 
 Exclusion criteria updates: Removed 
“prior diagnosis of COVID-19 infection 
(>10 days from screening)” as it was 
causing confusion for sites and is 
already covered by Inclusion criterion 
#3; specified that current or recent 
hospitalization for COVID-19 infection 
is exclusionary, not all hospitalizations; 
added a time window for current or 
recent use of study drug or combination 
for within the last 14 days; added 
“current or planned participation in 
another interventional trial to treat 
COVID-19, at the discretion of the 
study PI” (Sections 1.1 and 5.2); 
 Sample size considerations updated to 
include sIA (Sections 1.1 and 10.2); 
 Statistical considerations for Primary 
Analysis updated to align with change 
in primary objective and IAs (Sections 
1.1, 10.6.1, and 10.6.3); 
 Interim Analysis updated to specify that 
IA will occur ~ every 300 participants 
instead of every 200, included sIA, and 
primary objective IA (Sections 1.1, 
10.6.4, and 10.7); 
 Added Figure 2 to portray IA process 
(Section 1.2); 


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 Updated study background and 
rationale based on new data (Sections 
2.1 and 2.2); 
 Updated secondary outcome measures 
and reported endpoints (Section 3);  
 Added additional information regarding 
arm eligibility depending on the 
number of arms open to provide clarity 
for sites (Section 4.1); 
 Added that screen failures also include 
participants who consent, then on 
review by the site, are found to be 
ineligible for the study (Section 5.4); 
 Added additional reasons why 
participant may not receive study 
drug/placebo and specified that these 
participants would be identified as 
randomized not enrolled, instead of 
consented not enrolled (Section 5.5); 
 Specified that participants will be 
contacted directly if the miss one daily 
symptom reporting during Days 3 to 14 
(Sections 7.3 and 9.1.2); 
 Clarified that all participants will be 
asked to complete symptom reporting 
on Days 21 and 28, regardless of 
symptom resolution (Table 1, Section 
8.1.3); 
 Added that “overall symptom burden” 
is collected as part of Symptom 
Reporting (Section 8.2); 
 Updated primary hypothesis to align 
with updated primary objective 
(Section 10.1.1); 
 Model priors section removed and 
Statistical modeling simplified to refer 
to detailed description in SAP as 
models will be adjusted per appendix 
(Section 10.6.2); 
 Removed details of sensitivity analysis 
and referred to SAP (Section 10.6.5); 


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 Clarified that additional subgrouping 
variables may be added to the SAP 
prior to final analysis (Section 10.6.6); 
 Changed Appendix A – Ivermectin title 
to Ivermectin 400 (Section 16); 
removed CYP3A4 and P-gp 
precautions as not noted in the IB for 
the ivermectin study drug (Section 
16.2.1); in Section 16.2, deleted “use of 
warfarin, CYP3A4, P-gp inhibitor 
drugs, or CYP3A4 substrates” 
appendix-level exclusion criteria and 
added “Current or planned use of the 
following drugs: 
o Antiarrhythmic/antihypertensive 
drug class: quinidine, 
amiodarone, diltiazem, 
spironolactone, verapamil 
o Antibiotic-macrolides drug 
class: clarithromycin, 
erythromycin 
o Antifungal drug class: 
itraconazole, ketoconazole 
o Immunosuppresant drug class: 
cyclosporine, tacrolimus 
o Anti-HIV drug class: indinavir, 
ritonavir”; 
 Added Appendix D – Ivermectin 600 
(Section 19); 
 Other administrative changes 
throughout. 
Version 5.0, 17MAR2022 
 Added illness severity objective 
(Sections 1.1 and 3); 
 Removed reference to appendix-
specific SAP, only significant 
deviations from the main SAP analysis 
will require appendix-specific SAPs. 
Choice of primary objective, covariates, 
etc. will be documented outside of the 
SAP (Sections 1.1, 10.2, 10.6, 10.6.3, 
10.6.4); 


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 Clarified that primary objective occurs 
at 28 days (Sections 1.1 and 3); 
 Updated COVID-19 status, vaccination, 
and treatment options background 
(Sections 1.1 and 2.1); 
 Defined “receipt of study drug” 
(Section 5.5); 
 COVID-19 vaccination added to 
abbreviated medical history (Section 
8.2); 
 Updated instructions for unblinding 
(Section 10.4); 
 Specified that covariates will take into 
account emerging data and changing 
context (Section 10.6.2); 
 Added that this study operates in 
addition to usual care in additional 
protocol locations (Sections 11.2 and 
2.1); 
 Appendix A closed to enrollment on 
04FEB2022; 
 Appendix C closed to enrollment on 
08FEB2022; 
 Added Appendix E – Combination 
Fluvoxamine Maleate and Fluticasone 
Furoate; 
 Added Appendix F – Montelukast 
(Section 21); 
 Other administrative changes 
throughout. 
Version 6.0, 17JUN2022 
 Appendix B closed to enrollment on 
27FEB2022; 
  Removed appendix for combination 
fluvoxamine maleate and fluticasone 
furoate arm;  
 Added Appendix E – Fluvoxamine 
Maleate 100;  
 Added neuropsychiatric events of 
special interest in Montelukast 
appendix; 
 Updated the final visit from 90 to 120 
days, effective only for arms 


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Fluvoxamine Maleate 100 and 
Montelukast (footnotes added 
throughout for Day 120); 
 Other administrative changes 
throughout.  
Version 7.0, 08DEC2022 
 Added C-SSRS collection to the 
Fluvoxamine Maleate 100 Appendix on 
Day 7 and Day 14 and included in the 
Schedule of Events (Section 8.1.2, 20.5, 
and Table 1); 
 Changed the Final Visit to Day 180 for 
participants consented to protocol v7.0 
(Section 3, 5.3.2, 8.1.3, 8.1.4, 9.1.2, 
10.6.8, and Table 1); 
 Added PASC Symptom Questionnaire 
(Section 8.1.4, 8.2, and Table 1);  
 Added C-SSRS and PASC as 
abbreviations; 
 Other administrative changes 
throughout. 


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Caly, L., et al., The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-
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binding Domain Attached to ACE2. In Vivo, 2020. 34(5): p. 3023-3026. 
38. 
Guzzo, C.A., et al., Safety, tolerability, and pharmacokinetics of escalating high doses of 
ivermectin in healthy adult subjects. Journal of clinical pharmacology, 2002. 42(10): p. 
1122-1133. 
39. 
Chaccour, C., et al., Ivermectin and COVID-19: Keeping Rigor in Times of Urgency. Am 
J Trop Med Hyg, 2020. 102(6): p. 1156-1157. 
40. 
Arshad, U., et al., Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities 
Based on Plasma and Target Site Concentrations Derived from their Established Human 
Pharmacokinetics. Clin Pharmacol Ther, 2020. 108(4): p. 775-790. 
41. 
Bray, M., et al., Ivermectin and COVID-19: A report in Antiviral Research, widespread 
interest, an FDA warning, two letters to the editor and the authors' responses. Antiviral 
research, 2020. 178: p. 104805-104805. 
42. 
Zhang, X., et al., Ivermectin inhibits LPS-induced production of inflammatory cytokines 
and improves LPS-induced survival in mice. Inflamm Res, 2008. 57(11): p. 524-9. 
43. 
Ci, X., et al., Avermectin exerts anti-inflammatory effect by downregulating the nuclear 
transcription factor kappa-B and mitogen-activated protein kinase activation pathway. 
Fundam Clin Pharmacol, 2009. 23(4): p. 449-55. 
44. 
DiNicolantonio, J.J., J. Barroso-Arranda, and M. McCarty, Ivermectin may be a clinically 
useful anti-inflammatory agent for late-stage COVID-19. Open Heart, 2020. 7(2): p. 
e001350. 
45. 
Ahmed, S., et al., A five-day course of ivermectin for the treatment of COVID-19 may 
reduce the duration of illness. Int J Infect Dis, 2021. 103: p. 214-216. 
46. 
Chachar, A.Z.K., et al., Effectiveness of Ivermectin in SARS-CoV-2/COVID-19 Patients. 
International Journal of Sciences, 2021. 
47. 
Abu Taiub Mohammed Mohiuddin, C., et al., A Randomized Trial of Ivermectin-
Doxycycline and Hydroxychloroquine-Azithromycin therapy on COVID19 patients. 
Research Square, 2021. 
48. 
Soto-Becerra, P., et al., Real-World Effectiveness of Hydroxychloroquine, Azithromycin, 
and Ivermectin Among Hospitalized COVID-19 Patients: Results of a Target Trial 
Emulation Using Observational Data from a Nationwide Healthcare System in Peru. 
SSRN Electronic Journal, 2020. 


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49. 
Hashim, H.A., et al., Controlled randomized clinical trial on using Ivermectin with 
Doxycycline for treating COVID-19 patients in Baghdad, Iraq. medRxiv, 2020: p. 
2020.10.26.20219345. 
50. 
Khan, M.S.I., et al., Ivermectin Treatment May Improve the Prognosis of Patients With 
COVID-19. Arch Bronconeumol, 2020. 56(12): p. 828-830. 
51. 
Morgenstern, J., et al., The use of compassionate Ivermectin in the management of 
symptomatic outpatients and hospitalized patients with clinical diagnosis of COVID-19 at 
the Medical Center Bournigal and the Medical Center Punta Cana, Rescue Group, 
Dominican Republic, from may 1 to august 10, 2020. medRxiv, 2020: p. 
2020.10.29.20222505. 
52. 
Krolewiecki, A., et al., Antiviral Effect of High-Dose Ivermectin in Adults with COVID-
19: A Pilot Randomised, Controlled, Open Label, Multicentre Trial. 2020, SSRN. 
53. 
Podder, C.S., et al., Outcome of ivermectin treated mild to moderate COVID-19 cases: a 
single-centre, open-label, randomised controlled study. IMC Journal of Medical Science, 
2020. 14(2). 
54. 
Ravikirti, et al., Ivermectin as a potential treatment for mild to moderate COVID-19 – A 
double blind randomized placebo-controlled trial. medRxiv, 2021: p. 
2021.01.05.21249310. 
55. 
Morteza Shakhsi, N., et al., Research Square, 2021. 
56. 
Espitia-Hernandez, G., et al., Effects of Ivermectin-azithromycin-cholecalciferol 
combined therapy on COVID-19 infected patients: A proof of concept study. Biomedical 
Research, 2020. 
57. 
Babalola, O., et al., Ivermectin shows clinical benefits in mild to moderate COVID19: A 
randomised controlled double blind dose response study in Lagos. medRxiv, 2021: p. 
2021.01.05.21249131. 
58. 
NIH. COVID-19 Treatment Guidelines Fluvoxamine. 2021  [cited 2021 April 23]; 
Available from: 
https://www.covid19treatmentguidelines.nih.gov/immunomodulators/fluvoxamine/. 
59. 
Apotex, Higlights of Fluvoxamine Maleate Tablets Prescribing Information. 
60. 
Lenze, E.J., et al., Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients 
With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA, 2020. 324(22): p. 
2292-2300. 
61. 
Rosen, D.A., et al., Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in 
preclinical models of inflammation and sepsis. Science Translational Medicine, 2019. 
11(478): p. eaau5266. 
62. 
Rafiee, L., V. Hajhashemi, and S.H. Javanmard, Fluvoxamine inhibits some inflammatory 
genes expression in LPS/stimulated human endothelial cells, U937 macrophages, and 
carrageenan-induced paw edema in rat. Iran J Basic Med Sci, 2016. 19(9): p. 977-984. 
63. 
Seftel, D. and D.R. Boulware, Prospective Cohort of Fluvoxamine for Early Treatment of 
Coronavirus Disease 19. Open Forum Infectious Diseases, 2021. 8(2). 


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64. 
GlaxoSmithKline, Highlights of Prescribing Information for Arnuity Ellipta. 2018: 
Online. 
65. 
Yamaya, M., et al., Inhibitory effects of glycopyrronium, formoterol, and budesonide on 
coronavirus HCoV-229E replication and cytokine production by primary cultures of 
human nasal and tracheal epithelial cells. Respir Investig, 2020. 58(3): p. 155-168. 
66. 
Peters, M.C., et al., COVID-19-related Genes in Sputum Cells in Asthma. Relationship to 
Demographic Features and Corticosteroids. Am J Respir Crit Care Med, 2020. 202(1): p. 
83-90. 
67. 
Finney, L.J., et al., Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 
in COPD through suppression of type I interferon. J Allergy Clin Immunol, 2021. 147(2): 
p. 510-519.e5. 
68. 
Kern, C., et al., Modeling of SARS-CoV-2 Treatment Effects for Informed Drug 
Repurposing. Front Pharmacol, 2021. 12: p. 625678. 
69. 
Krolewiecki, A., et al., Antiviral effect of high-dose ivermectin in adults with COVID-19: 
A proof-of-concept randomized trial. EClinicalMedicine, 2021. 37. 
70. 
Navarro, M., et al., Safety of high-dose ivermectin: a systematic review and meta-
analysis. J Antimicrob Chemother, 2020. 75(4): p. 827-834. 
71. 
Smit, M.R., et al., Safety and mosquitocidal efficacy of high-dose ivermectin when co-
administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated 
malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial. The Lancet 
Infectious Diseases, 2018. 18(6): p. 615-626. 
72. 
Reis, G., et al., Effect of early treatment with fluvoxamine on risk of emergency care and 
hospitalisation among patients with COVID-19: the TOGETHER randomised, platform 
clinical trial. The Lancet Global Health, 2022. 10(1): p. e42-e51. 
73. 
Barré, J., J.-M. Sabatier, and C. Annweiler, Montelukast Drug May Improve COVID-19 
Prognosis: A Review of Evidence. Frontiers in Pharmacology, 2020. 11(1344). 
74. 
Copertino, D.C., et al., Montelukast drug activity and potential against severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2). J Med Virol, 2021. 93(1): p. 187-
189. 
75. 
Sanghai, N. and G.K. Tranmer, Taming the cytokine storm: repurposing montelukast for 
the attenuation and prophylaxis of severe COVID-19 symptoms. Drug Discov Today, 
2020. 25(12): p. 2076-2079. 
76. 
Al-Kuraishy, H.M., et al., Role of leukotriene pathway and montelukast in pulmonary and 
extrapulmonary manifestations of Covid-19: The enigmatic entity. Eur J Pharmacol, 
2021. 904: p. 174196. 
77. 
Mao, L., et al., Neurologic Manifestations of Hospitalized Patients With Coronavirus 
Disease 2019 in Wuhan, China. JAMA Neurology, 2020. 77(6): p. 683-690. 
78. 
Marschallinger, J., et al., Structural and functional rejuvenation of the aged brain by an 
approved anti-asthmatic drug. Nat Commun, 2015. 6: p. 8466. 


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79. 
Khan, A.R., et al., Montelukast in hospitalized patients diagnosed with COVID-19. The 
Journal of asthma : official journal of the Association for the Care of Asthma, 2021: p. 1-
7. 
80. 
Kerget, B., et al., Effect of montelukast therapy on clinical course, pulmonary function, 
and mortality in patients with COVID-19. J Med Virol, 2022. 94(5): p. 1950-1958. 
 
 
 


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16. 
Appendix A (Enrollment Closed 04FEB2022) – Ivermectin 400  
16.1. 
Risk Assessment 
The most commonly reported adverse events for ivermectin are pruritus (25.3%), headache 
(13.9%), and dizziness (7.5%) (ICH working group, 2003). Since the 1980s, the use of 
ivermectin in humans for the treatment of filariasis, especially onchocerciasis, has been 
associated with SAEs, including coma, seizure and death only when administered in regions 
where onchocerciasis and loiasis are co-endemic.[22] 
The issue of SAEs due to ivermectin is a threat to adherence to mass drug administration and the 
control and elimination of disease in communities co-endemic with O. volvulus and Loa. Mass 
drug administration were suspended from 2004 to 2006 in some health zones in the Equateur, 
Bas Congo, and Oriental provinces in the Democratic Republic of the Congo because of 
ivermectin-associated SAEs in the Bas Congo and Oriental provinces in 2003.[23] It has been 
thought that co-infection with L. loa is a risk factor for the development of these reactions.[24] 
Additionally, a study investigating escalating high doses of ivermectin in healthy adults was 
performed to explore the safety of its use in the treatment of head lice. The authors documented 
no evidence of Central Nervous System (CNS) toxicity in doses up to 10 times the highest FDA-
approved dose of 200 µg/kg.[25] 
Table 3 shows safety events that occurred in greater than 5% of the clinical trial population who 
received ≥ 300 µg/kg of ivermectin.[26]  For a detailed list of the adverse reactions that occurred 
during clinical trials with ivermectin, refer to the product label and the Investigator’s Brochure. 
Ivermectin is pregnancy category C and is not contraindicated per FDA. Analyses of outcomes 
of pregnancies in women inadvertently exposed to ivermectin through mass administration 
campaigns show no evidence of increased birth defects, neonatal deaths, maternal morbidity, 
preterm births, or low birthweight over baseline rates.[27, 28] 
Table 3: Ivermectin Adverse Event Table for Doses ≥ 300 µg/kg 
Indication (dose) 
Wuchererua bancrofti 
(200-400 µg/kg) [29] 
Wuchererua bancrofti 
(200 µg/kg, then 400 
µg/kg on day 4) [30] 
Stage II or III tungiasis 
lesions (300 µg/kg, 
days 1 & 2) [31]  
Loa loa infection (300 
or 400 µg/kg) [32] 
Symptomatic 
Plasmodium 
falciparum malaria 
(600 µg/kg) [33] 
Adverse Reactions 
Abdominal Pain 
 
 
7% 
 
 
Cough 
42% 
 
 
 
 
Diarrhea 
 
 
 
6.5% 
 
Eye disorders 
 
 
 
 
9% 


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Fever 
69% 
46% 
 
8% 
 
Gastrointestinal  
 
18% 
 
 
 
Headache 
75% 
 
11% 
16% 
 
Local Inflammation 
 
9% 
 
 
 
Local Pain 
 
9% 
 
 
 
Lumber myalgia 
 
 
 
6.5% 
 
Malaise 
 
27% 
 
 
 
Myalgia 
37% 
 
 
 
 
Neurological 
 
15% 
 
 
 
Pneumonia 
 
 
 
 
9% 
Pruritus 
 
 
 
60% 
 
Renal 
 
33% 
 
 
 
Respiratory 
 
33% 
 
 
 
16.2. 
Additional Appendix-Level Exclusion Criteria 
1. End-stage renal disease on renal replacement therapy 
2. Liver failure or decompensated cirrhosis 
3. Current or planned use of the following drugs during the study, listed by drug class: 
a. Antiarrhythmic/antihypertensive drug class: quinidine, amiodarone, diltiazem, 
spironolactone, verapamil 
b. Antibiotic-macrolides drug class: clarithromycin, erythromycin 
c. Antifungal drug class: itraconazole, ketoconazole 
d. Immunosuppresant drug class: cyclosporine, tacrolimus 
e. Anti-HIV drug class: indinavir, ritonavir 
4. Nursing mothers 
5. Pregnancy*  
*Participants must agree to use an effective method of contraception during study drug 
administration and for at least 3 days after their final dose of study drug. Effective methods 
include any of the following: abstinence, partner vasectomy, bilateral tubal ligation, intrauterine 
device, progestin implants, or barrier (condom, diaphragm, cervical cap) plus spermicide. 
16.2.1. 
Precautions 
While rare, post-marketing reports indicate an increased International Normalized Ratio (INR) 
when ivermectin was co-administered with warfarin. With a 3-day dosing period this is unlikely 


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to be a significant issue, but INR monitoring can be recommended to the care provider if felt 
warranted by site investigator.   
16.3. 
Ivermectin Information  
Ivermectin is a semisynthetic oral agent used primarily as an anti-parasitic agent. It is derived 
from highly active, broad-spectrum, anti-parasitic agents isolated from Streptomyces avermitilis 
fermentation products. It binds selectively, and with high affinity, to glutamate-gated chloride 
ion channels, therefore increasing cell membrane permeability to chloride ions resulting in death 
of the parasite.[34] It is currently FDA-approved for the following indications: strongyloidiasis 
of the intestinal tract due to the nematode parasite Strongyloides stercoralis and onchocerciasis 
due to the nematode parasite Onchocerca volvulus.[26] Per the FDA-approved labelling of 
ivermectin, the recommended dose is 200 µg/kg/day to treat strongyloidiases and 150 µg/kg/day 
to treat onchocerciasis in the form of a 3 mg tablet.   
16.3.1. 
Formulation, Appearance, Packaging, and Labeling 
Ivermectin is a white to yellowish-white, nonhygroscopic, crystalline powder. For this study, 
ivermectin will be supplied as fifteen 7-mg tablets in a bottle with a single panel label. The 
tablets are white, round, biconvex tablets with “123” over the scoring on one side. All packaging 
will be labeled to indicate that the product is for investigational use. 
16.3.2. 
Drug Dispensing, Storage, and Stability 
Ivermectin will be supplied as 7-mg tablets and must be stored at temperatures below 30°C. 
16.3.3. 
Dosing and Administration 
Ivermectin should be taken on an empty stomach with water (30 minutes before a meal or 2 
hours after a meal). Each participant will receive a bottle of fifteen 7-mg tablets and will be 
instructed to take a pre-specified number of tablets for 3 consecutive days based on their weight 
(see Table 4) for a daily dose of approximately 300-400 µg/kg. 
Table 4: Ivermectin 400 Dosing Schedule 
Weight (kg) 
Day 1 (# of 7-
mg tablets) 
Day 2 (# of 7-
mg tablets) 
Day 3 (# of 7-
mg tablets) 
Daily Dose 
(µg/kg) 
35-52 
2 
2 
2 
269-400 
53-69 
3 
3 
3 
304-396 
70-89 
4 
4 
4 
315-400 
> 90 
5 
5 
5 
≤ 389 
16.3.4. 
Rationale for Selection of Dose 
Pre-clinical studies: 
Reports from in vitro studies suggest that ivermectin acts against ribonucleic acid (RNA) viruses 
such as SARS-CoV-2 by inhibiting the host importin α/β-mediated nuclear transport that prevent 


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viral proteins from entering the nucleus to alter host cell function.[35] A single dose addition of 
ivermectin to Vero-hSLAM cells 2 hours post infection with SARS-CoV-2 was able to effect a 
5000-fold reduction in viral RNA at 48 hours and may interfere with the attachment of SARS-
CoV-2 spike protein to the human cell membrane.[36, 37] 
Ivermectin has been shown to inhibit the replication of SARS-CoV-2 in cell culture. However, 
pharmacokinetic and pharmacodynamic studies suggest that ivermectin doses up to 100-fold 
higher than those approved for use in humans would be required to achieve the plasma 
concentrations necessary to duplicate the drug’s antiviral efficacy in vitro.[38, 39] Even though 
ivermectin appears to accumulate in lung tissue, with the doses used in most clinical trials, 
predicted systemic plasma and lung tissue concentrations are much lower than 2 µM, the half-
maximal inhibitory concentration (IC50) against SARS-CoV-2 in vitro.[40, 41] 
Ivermectin demonstrates potential anti-inflammatory properties in some in vitro 
studies, properties which have been postulated to be beneficial in the treatment of COVID-
19.[42-44] The dose range for an anti-inflammatory effect may be lower than for the anti-viral 
effects.[44]   
Clinical studies: 
A number of retrospective cohort studies and the results of several randomized trials of 
ivermectin use in patients with COVID-19 have been published in peer-reviewed journals or 
made available as preliminary, non-peer-reviewed reports. Some clinical studies showed no 
benefits after ivermectin use, whereas others reported shorter time to resolution of disease 
manifestations attributed to COVID-19, greater reduction in inflammatory markers, shorter time 
to viral clearance, or lower mortality rates in patients who received ivermectin than in patients 
who received comparator drugs or placebo.[45-50] 
Most of the studies reported to date are limited by their small sample size, varying dosing 
schedules and the adjunctive use of various concomitant medications (e.g., doxycycline, 
hydroxychloroquine, azithromycin, zinc, corticosteroids), confounding assessment of the true 
efficacy or safety of ivermectin. Clinical studies in outpatients with COVID-19 did not always 
describe the severity of COVID-19 and the study outcome measures were not always defined. 
Nonetheless, while some have shown no difference, most clinical trials of outpatients with 
mild/moderate COVID-19 have shown clinical improvement with even a single dose or a short 
two to five-day course of ivermectin given orally shortly after symptom onset.[39, 49, 51, 52]  
There is a dose-dependent relationship between ivermectin dose and clinical efficacy. Trials 
using lower doses of ivermectin tend to show no or minimal clinical benefit in COVID-19 
patients treated in the outpatient or hospital setting.[53, 54] Higher doses, at least 0.4 mg/kg, 
particularly when administered in multiple doses, have been shown to significantly reduce time 
to recovery and mortality as compared with lower doses or placebo/standard care.[51, 55-57] 
There is a concentration-dependent virologic response seen using higher-than-usual doses of 
ivermectin (600 μg/kg vs 200 μg/kg once daily for 5 days) that have been shown to significantly 
reduce the time to PCR viral positivity over standard doses with minimal associated 
toxicities.[52]  
The safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin was tested 
in healthy adult subjects.[38] Doses from 30 mg/day (347-571 µg/kg) to 120 mg/day (1404-2000 


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µg/kg) given for 3 days were all well tolerated.[38] These data coupled with evidence of superior 
clinical efficacy of doses in the lower of this range provide the rationale for the 300-400 µg/kg 
dose given for 3 days in the proposed trial. 
16.4. 
Placebo Information  
16.4.1. 
Formulation, Appearance, Packaging, and Labeling 
Placebo will match the appearance of the 7-mg ivermectin tablets: white, round, biconvex tablets 
with “123” over the scoring on one side. A total of fifteen tablets will be provided in a bottle 
with a single panel label. The placebo formulation includes the following ingredients in a 210 mg 
tablet: microcrystalline cellulose, NF (MC-102; pregelatinized starch, NF (Starch 1500); 
croscarmellose sodium, NF (Vivasol, GF Grade); colloidal silicon dioxide, NF (Aerosil 200) and 
magnesium stearate, NF (2257). All packaging will be labeled to indicate that the product is for 
investigational use. 
16.4.2. 
Drug Dispensing, Storage, and Stability 
Placebo must be stored at temperatures below 30°C. 
16.4.3. 
Dosing and Administration 
Dosing and administration will occur according to Section 16.3.3 in order to maintain blinding. 
16.5. 
Events of Special Interest 
None 


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17. 
Appendix B (Enrollment Closed 27May2022) – Fluvoxamine Maleate  
17.1. 
Risk Assessment 
The most common adverse effects of fluvoxamine described in the setting of treatment of 
psychiatric conditions include gastrointestinal effects, neurological effects, dermatological 
reactions, and in rare cases suicidal ideation.[58] In two 10-week controlled trials in Obsessive 
Compulsive Disorder (OCD) and depression at doses ranging from 100-300 mg/day, the most 
commonly observed adverse reactions associated with the use of fluvoxamine maleate tablets 
(incidence of 5% or greater and at least twice that for placebo) were nausea, somnolence, 
insomnia, asthenia, nervousness, dyspepsia, abnormal ejaculation, sweating, anorexia, tremor, 
and vomiting (see Table 5).[59]   
Table 6 lists the complete set of adverse events identified in a randomized clinical trial of 
fluvoxamine (300 mg/day for 15 days) versus placebo in 152 COVID-19 participants.[60] 
Adverse events and serious adverse events were more common in the placebo arm and the single 
SAE in the fluvoxamine arm was dehydration and the study medication was not interrupted.[60]  
Table 5. Fluvoxamine Adverse events occurring in 10-week studies of adult OCD or 
depression 
 *Table shows events that occurred in ≥ 5% of adult OCD and depression study 
participants receiving 100-300 mg/day for 10 weeks of fluvoxamine maleate versus 
placebo.[59] 
Adverse Reaction 
Fluvoxamine, 
n=892 (%) 
Placebo, 
n=778 (%) 
Headache 
22 
20 
Asthenia 
14 
6 
Nausea 
40 
14 
Diarrhea 
11 
7 
Constipation 
10 
8 
Dyspepsia 
10 
5 
Anorexia 
6 
2 
Vomiting 
5 
2 
Somnolence 
22 
8 
Insomnia 
21 
10 
Dry Mouth 
14 
10 
Nervousness 
12 
5 
Dizziness 
11 
6 
Tremor 
5 
1 


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Anxiety 
5 
3 
 
Table 6. Fluvoxamine Adverse events that occurred in COVID-19 study participants 
receiving 300 mg/day for 15 days. 
Adverse Reaction [60] 
 
Fluvoxamine, n=80 
(%) 
Placebo, n=72 
(%) 
Pneumonia 
3.8 
8.3 
Shortness of breath 
2.5 
5.6 
Headache or head pain 
2.5 
1.4 
Gastroenteritis, nausea, or vomiting 
1.3 
6.9 
Muscle aches 
1.3 
0 
Bacterial infection 
1.3 
0 
Vasovagal syncope 
1.3 
0 
Teeth chattering 
1.3 
0 
Dehydration 
1.3 
0 
Low oxygen saturation or hypoxia 
0 
8.3 
Chest pain or tightness 
0 
2.8 
Fever 
0 
2.8 
Acute respiratory failure 
0 
1.4 
Serious adverse events 
1.3 
6.9 
Other adverse events 
13.8 
8.3 
17.2. 
Additional Appendix-Level Exclusion Criteria 
1. Use of selective serotonin (or norepinephrine) reuptake inhibitors (SSRIs/SNRIs), 
including fluvoxamine, or monoamine oxidase inhibitors (MAOIs) within 2 
weeks of consent including triptans and tryptophan. Use of fluoxetine within 45 
days of consent.  
2. Co-administration of tizanidine, thioridazine, alosetron, pimozide, diazepam, 
ramelteon, linezolid 
3. Bipolar Disorder 
4. Nursing mothers 
5. Pregnancy* 


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*Participants must agree to use an effective method of contraception during study drug 
administration and for at least 3 days after their final dose of study drug. Effective methods 
include any of the following: abstinence, partner vasectomy, bilateral tubal ligation, intrauterine 
device, progestin implants, or barrier (condom, diaphragm, cervical cap) plus spermicide.  
17.2.1. 
Precautions 
Fluvoxamine is a potent inhibitor of CYP1A2 and 2C19 and a moderate inhibitor of CYP2C9, 
2D6, and 3A4, as such, it may enhance anticoagulant effects of antiplatelets and anticoagulants 
as well as other medications. It is recommended that concomitant medications listed below be 
discussed with participants and potential effects of increased drug exposure reviewed and 
monitored by the participant and/or their prescribing clinician. 
 Tricyclic antidepressants: monitor for side effects with amitriptyline, clomipramine, 
imipramine 
 Antipsychotic drugs: neuroleptic malignant syndrome or similar; particularly 
clozapine (hypotension, seizure) 
 Benzodiazepines: particularly alprazolam; recommend dose reduction  
 Tramadol, buspirone, fentanyl, lithium, amphetamines, St. John’s Wart, 
carbamazepine, quinidine, and tacrine 
 Methadone: opioid intoxication 
 Mexiletine: monitor for side effects 
 Theophylline: recommend dose reduction and monitor for side effects 
 Warfarin: monitor INR 
 NSAIDS or aspirin: monitor for signs of bleeding 
 Diltiazem, propranolol, metoprolol: monitor for bradycardia 
Participants should be warned about fluvoxamine inhibition of caffeine metabolism. A 
description is 1 cup of coffee has the effects of 4 cups while taking fluvoxamine.  
Caution should be used in participants with hepatic dysfunction due to approximately 30% 
increase in exposures.  
17.3. 
Fluvoxamine Information  
Fluvoxamine is an FDA-approved SSRI for the treatment of OCD. Clinically it is also used for 
other conditions such as depression.[58] The active ingredient in fluvoxamine is fluvoxamine 
maleate.  
17.3.1. 
Formulation, Appearance, Packaging, and Labeling 
Fluvoxamine is a round golden 50 mg tablet that is scored on both sides - one side has “APO” 
and the other side has “F50” with a partial bisect. All packaging will be labeled to indicate that 
the product is for investigational use. 


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17.3.2. 
Drug Dispensing, Storage, and Stability 
Drug will be supplied by Apotex and distributed by Belmar Pharmacy. Study drug should be 
stored in controlled room temperature (20°C to 25°C); excursions are permitted to 15°C to 30°C. 
17.3.3. 
Dosing and Administration 
Fluvoxamine will be self-administered orally by each participant at a dose of 50 mg BID for 10 
days. 
17.3.4. 
Rationale for Selection of Dose 
The recommended starting dose of fluvoxamine for OCD in adults is 50 mg daily dose to be 
titrated up to a maximum of 300 mg/day divided into BID doses. Clinical data from the placebo-
controlled, randomized trial in nonhospitalized adults with mild COVID-19 demonstrated that a 
50 mg BID fluvoxamine dose was well-tolerated and effective (see Figure 5).[60] In the same 
study, doses of 100 mg BID in COVID-19 participants resulted in additional side effects over a 
14-day period. The 300 mg daily dose is for serotonin receptor activity, whereas the postulated 
dose for sigma-1 receptor activity as an anti-inflammatory is lower. Therefore, the proposed 
dosing regimen of 50 mg BID for 10 days will use the anticipated minimal effective dose to 
maximize efficacy and minimize toxicity. 
Pre-Clinical Studies: 
Pre-clinical studies have indicated that the anti-inflammatory effects of fluvoxamine may support 
its use for treating COVID-19. Systemic inflammation as a result of infection can damage 
vasculature which may lead to tissue hypoperfusion and multiple organ failure.[61] Reducing 
systemic inflammation thereby may avoid or mitigate the aforementioned serious clinical 
outcomes. In murine studies, administration of fluvoxamine significantly increased survival of 
S1R wildtype (WT) mice and S1R knockout (KO) mice challenged with ligand 
lipopolysaccharide (LPS) as compared to mice that received saline (Figure 4).[61] Fluvoxamine 
also reduced production of inflammatory cytokines in ex vivo and in vitro murine and human 
cells (HEK293mTLR4/MD2/CD14, primary lung fibroblasts, and mouse bone marrow-derived 
macrophages) and inflammatory genes in human endothelial cells.[61, 62] 


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Figure 4: Survival curve of WT and S1R KO mice  
Figure note: Mice were treated with vehicle (33% Kolliphor in saline) or STF (30 mg/kg) after 
administration of LPS (2 mg/kg) as indicated in (B) (n = 15 to 16 mice per group; **P < 0.01, 
***P < 0.001, log-rank test).[61] 
Clinical Studies: 
A placebo-controlled, randomized trial in nonhospitalized adults with mild COVID-19 tested the 
efficacy and safety of fluvoxamine (50 mg oral one-time dose, followed by 100 mg orally twice 
daily for 2 days, followed by 100 mg orally three times daily through day 15) versus placebo 
[60]. Results of the study reported that 8.3% (6/72) of participants who received placebo 
experienced clinical deterioration within 15 days of randomization, as opposed to 0% (0/80) in 
the fluvoxamine arm (absolute difference 8.7%; 95% CI, 1.8% to 16.5%; P = 0.009).[60]  
Clinical deterioration was defined as shortness of breath/pneumonia with hypoxia (Figure 5). 
Concomitant SSRI/SNRI dosing was not allowed per the trial protocol thus the participant’s 
SSRI/SNRI was held for the study dosing period if reported at baseline.  


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Figure 5: Summary of JAMA Randomization Clinical Trial of Fluvoxamine for Early 
COVID-19.  
A prospective, nonrandomized observational cohort study that evaluated fluvoxamine showed 
that on Day 14, 0/65 participants had persistent symptoms as opposed to 19/48 participants who 
did not receive fluvoxamine (P < 0.001) [63]. Additionally, by Day 14, none of the participants 
who received fluvoxamine were hospitalized as compared to 6 participants who were 
hospitalized who did not receive the drug (see Figure 6). In this study, all participants were 
offered fluvoxamine and decided whether or not to take the study drug. Participants who chose to 
receive the study drug received 50 mg of fluvoxamine two times a day following an upfront 100 
mg loading dose.[63]  
 
Figure 6: Summary of study results for the prospective, nonrandomized observational 
cohort study with fluvoxamine in participants diagnosed with COVID-19.  


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17.4. 
Placebo Information  
The placebo will be a fluvoxamine-matched placebo containing mannitol, magnesium stearate, 
hydroxyethyl cellulose, polyethylene glycol, titanium dioxide, yellow ferric oxide, and purified 
water. The appearance and packaging will match that of the study drug (as described in Section 
17.3.1). All packaging will be labeled to indicate that the product is for investigational use.  
17.4.1. 
Formulation, Appearance, Packaging, and Labeling 
Placebo will match the appearance of the fluvoxamine tablets: round golden 50 mg tablet that is 
scored on both sides - one side has “APO” and the other side has “F50” with a partial bisect. All 
packaging will be labeled to indicate that the product is for investigational use. 
17.4.2. 
Drug Dispensing, Storage, and Stability 
Placebo will be supplied by Apotex and distributed by Belmar Pharmacy. Placebo should be 
stored in controlled room temperature (20°C to 25°C). 
17.4.3. 
Dosing and Administration 
Participants will self-administer one placebo tablet orally, twice daily for 10 days. 
17.5. 
Events of Special Interest 
None 
 


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18. 
Appendix C (Enrollment Closed 08FEB2022) – Fluticasone Furoate 
18.1. 
Risk Assessment 
The most common adverse reactions reported in ≥ 5% of adults and adolescents with lung 
disease include nasopharyngitis, bronchitis, upper respiratory tract infection, and headache. 
Long-term use of systemic and local corticosteroids may also result in the following side effects: 
Candida albicans infection, immunosuppression, hypercorticism and adrenal suppression, 
reduction in bone mineral density (BMD), or glaucoma and cataracts.[64] 
There are insufficient data on the use of fluticasone furoate in pregnant women. There are 
clinical considerations with use of fluticasone furoate in pregnant women to inform drug-
associated risk and benefit. In animal reproduction studies, fluticasone furoate administered by 
inhalation to rats and rabbits during the period of organogenesis produced no fetal structural 
abnormalities. The highest fluticasone furoate doses in the rat and rabbit studies were 4 times and 
1 times the maximum recommended human daily inhalation dose, respectively. The estimated 
risk of major birth defects and miscarriage for the indicated populations is unknown. In the US 
general population, the estimated risk of major birth defects and miscarriage in clinically 
recognized pregnancies is 2% to 4% and 15% to 20%, respectively.[64] 
Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately 
controlled asthma, there is an increased risk of several perinatal outcomes such as pre-eclampsia 
in the mother and prematurity, low birth weight, and small for gestational age in the neonate.[64]  
Table 7. Fluticasone Adverse reactions that occurred in ≥3% of adults and adolescents 
with asthma in a 24-week trial.  
Adverse Reaction [64] 
Fluticasone furoate,  
fluticasone 200 µg, n=119 
(%) 
Fluticasone furoate, 
fluticasone 100 µg, 
n=119 (%) 
Nasopharyngitis 
13 
12 
Headache  
13 
10 
Bronchitis 
7 
12 
Influenza 
7 
4 
Upper Respiratory tract infection 
6 
2 
Sinusitis 
4 
7 
Oropharyngeal pain  
4 
3 
Pharyngitis 
3 
6 
Back pain 
3 
3 


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Dysphonia 
3 
2 
Oral candidiasis 
3 
<1 
Procedural pain 
3 
<1 
Rhinitis 
3 
<1 
Throat irritation 
3 
<1 
Abdominal pain 
3 
0 
Cough 
3 
0 
18.2. 
Additional Appendix-Level Exclusion Criteria 
1. Severe hypersensitivity to milk proteins  
2. Currently prescribed or use within 30 days of inhaled or systemic steroids 
3. Moderate to severe hepatic impairment, defined as Child-Pugh B or C 
4. Nursing mothers 
5. Pregnancy* 
*Participants must agree to use an effective method of contraception during study drug 
administration and for at least 3 days after their final dose of study drug. Effective methods 
include any of the following: abstinence, partner vasectomy, bilateral tubal ligation, intrauterine 
device, progestin implants, or barrier (condom, diaphragm, cervical cap) plus spermicide.  
18.2.1. 
Precautions 
While not contraindicated, the following should be considered while taking fluticasone furoate: 
 Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin, 
conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, 
telithromycin, troleandomycin, voriconazole) should be used with caution as 
increased systemic corticosteroid adverse effects may occur in combination with 
fluticasone furoate. Generally, due to the limited study drug administration length, 
clinically significant interactions are unlikely.  
 Paradoxical Bronchospasm may occur with an immediate increase in wheezing after 
dosing. Fluticasone furoate should be discontinued immediately if this occurs.  
 
18.3. 
Fluticasone Furoate Information  
Inhaled fluticasone furoate will be provided by GlaxoSmithKline. It is a synthetic trifluorinated 
inhaled corticosteroid (ICS) with anti-inflammatory activity. In vitro and in vivo models have 
shown that fluticasone furoate demonstrates anti-inflammatory actions by activating the 


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glucocorticoid response element, inhibiting pre-inflammatory transcription factors such as 
NFkB, and inhibiting antigen-induced lung eosinophilia, which may contribute to its efficacy in 
the approved indications. It is FDA-approved for once-daily maintenance treatment of asthma as 
prophylactic therapy in patients 5 years and older.[64]  
18.3.1. 
Formulation, Appearance, Packaging, and Labeling 
Fluticasone furoate is an inhaled powder drug product. It is a synthetic trifluorinated 
corticosteroid that is insoluble in water. Fluticasone furoate is a white powder. Fluticasone 
furoate will be provided in a two tone grey inhaler with a mouthpiece cover and separate foil 
blister strips. The blister strips used for this study will contain a white powder mix with a 
mixture of 200 µg micronized fluticasone furoate and lactose monohydrate. The inhaler will be 
packaged in a moisture-protective foil tray with a desiccant and a peelable lid.[64] All packaging 
will be labeled to indicate that the product is for investigational use. 
18.3.2. 
Drug Dispensing, Storage, and Stability 
The study drug should be stored at room temperature (20°C to 25°C) with excursions permitted 
from 15°C to 30°C. It should be stored in a dry environment away from direct heat or sunlight. 
Unopened fluticasone furoate should be stored inside the unopened moisture-protective foil tray 
and only removed immediately before use. Any unused study product should be discarded 6 
weeks after opening the foil tray or when the counter reads “0” (after all blisters have been used), 
whichever comes first. The inhaler is not reusable.[64] The study product has a shelf life of 24 
months when stored at ≤ 25°C. After removal of the secondary package and the desiccant packet 
from the inhaler, the product may be stored up to 6 weeks at ≤ 25°C.  
18.3.3. 
Dosing and Administration 
Fluticasone furoate is a self-administered inhaled drug. Participants will self-administer 200 µg 
(1 blister) of fluticasone furoate once daily for 14 days. After inhaler activation, the powder 
within the blister is exposed and the participant inhales the study drug through the mouthpiece.  
18.3.4. 
Rationale for Selection of Dose 
Inhaled corticosteroids (ICS) have been shown to be effective in improving asthma and as a 
combination therapy in chronic obstructive pulmonary disease (COPD) and thus are commonly 
prescribed medications world-wide. Corticosteroids have been shown to have a broad range of 
pharmacologic activity on multiple cell types including mast cells, eosinophils, neutrophils, 
macrophages and lymphocytes, as well as other mediators of inflammation such as histamine, 
eicosanoids, and leukotrienes. In addition to the anti-inflammatory role of ICS, there is also 
potential for regulation of gene transcription in epithelial cells.[65-67] This regulation of gene 
transcription may result in inhibition of SARS-CoV-2 replication. Furthermore, in asthmatic 
patients, ICS may lower gene expression of ACE2 and TMPRSS2. The ACE2 receptor is 
expressed on epithelial cells and binds SARS-CoV-2 for entry and the serine protease TMPRSS2 
primes the SARS-CoV-2 spike protein for binding. Lowering gene expression of ACE2 and 
TMPRSS2 may reduce binding and entry into cells therefore reducing or preventing infection.  
Clinical Studies: 


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The PRINCIPLE (Platform Randomized trial of Interventions against COVID-19 in Older 
People) trial is a multicenter, open-label, multi-arm, adaptive randomized, platform trial. The 
trial is ongoing and released an interim analysis after the Trial Steering Committee advised the 
Trial Management Group that the pre-specified superiority criterion was met on the time to 
recovery in the overall study population and the subgroup of participants with confirmed positive 
SARS-CoV-2 testing. Participants were eligible if aged >65 years, or >50 years with 
comorbidities and had ongoing symptoms from PCR confirmed or suspected COVID-19 with 
symptoms starting within the past 14 days. Participants were randomized to any open active 
intervention arm including inhaled budesonide and usual care. Participants were followed 
through an online, daily symptom diary for 28 days. Participants received usual care plus inhaled 
budesonide 800 µg daily for 14 days or usual care alone. The primary outcome of the trial at the 
start was hospitalization or death within 28 days; however, the rate of hospitalization was lower 
than initially expected thus the Trial Management Group and the Trial Steering Committee 
recommended amending the primary outcome to include a measure of illness duration. The trial 
was completed with two co-primary endpoints measured within 28 days of randomization: 1) 
time to first reported recovery defined as the first day that a participant reported feeling 
recovered; and 2) hospitalization or death related to COVID-19.  
The interim analysis included eligible SARS-CoV-2 positive participants who were randomized 
to inhaled budesonide (N=751) or usual care alone (N=1028). The mean age was 62.8 years and 
83% of participants had co-morbidities. The median days from symptom onset to enrollment was 
6 days. There was evidence of a benefit in time-to-first-recovery in the budesonide arm with an 
estimated median benefit of 3 days. The point estimate of the proportion of COVID-19 related 
hospitalizations or deaths was lower in the budesonide group (8.5%) versus usual care (10.3%), 
but this did not meet statistical significance (95% BCI -0.7 – 4.8%). There were two SAEs for 
hospitalization unrelated to COVID-19, both in the budesonide group.  
A smaller trial of 146 nonhospitalized adults with mild COVID-19 reported that inhaled 
budesonide at the same dose reduced COVID-19 related emergency assessments and 
hospitalization.  
The dose of ICS studied is PRINCIPLE is consistent with a high dose of inhaled steroid. The 
equivalent high dose of fluticasone furoate is 200 µg/day. Inhaled fluticasone furoate has a 
greater anti-inflammatory potency per microgram than budesonide, thus fluticasone furoate is 
administered at a lower daily dose and used only once daily to achieve a similar high dose.  
18.4. 
Placebo Information  
18.4.1. 
Formulation, Appearance, Packaging, and Labeling 
The placebo will be a fluticasone furoate-matched placebo containing lactose for inhalation in 
the same two tone grey inhaler that is used for the study drug. The appearance and packaging 
will match that of the study drug (as described in Section 18.3.1). All packaging will be labeled 
to indicate that the product is for investigational use. 


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18.4.2. 
Drug Dispensing, Storage, and Stability 
Placebo will be stored in the same conditions as study drug, room temperature (20°C to 25°C) 
with excursions permitted from 15°C to 30°C in a dry environment away from direct heat or 
sunlight. The placebo has a shelf life of up to 36 months when stored at ≤ 30°C. 
18.4.3. 
Dosing and Administration 
Participants will self-administer one blister of placebo via inhalation from the inhaler once daily 
for 14 days.  
18.5. 
Events of Special Interest 
None 
18.6. 
Safety Reporting for Fluticasone Furoate 
Sponsor will promptly notify GlaxoSmithKline of all SAEs, UADEs, and pregnancies (if 
applicable), and medical device deficiencies that have occurred for participants enrolled in this 
Study Drug Appendix, in accordance with the timelines and procedures specified in the 
Protocol/appendix. In addition, the sponsor will reasonably obtain and provide follow-up 
information as available, to GSK upon request.  
 
 
 


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19. 
Appendix D – Ivermectin 600 
19.1. 
Risk Assessment 
Refer to Section 16.1. 
19.2. 
Additional Appendix-Level Exclusion Criteria 
Refer to Section 16.2. 
19.2.1. 
Precautions 
Refer to Section 16.2.1. 
19.3. 
Ivermectin Information  
Refer to Section 16.3. 
19.3.1. 
Formulation, Appearance, Packaging, and Labeling 
Refer to Section 16.3.1. 
19.3.2. 
Drug Dispensing, Storage, and Stability 
Refer to Section 16.3.2. 
19.3.3. 
Dosing and Administration 
Ivermectin should be taken on an empty stomach with water (30 minutes before a meal or 2 
hours after a meal). Each participant will receive a bottle containing the number of 7-mg tablets 
they require based on their weight and will be instructed to take a pre-specified number of tablets 
for 6 consecutive days based on their weight (see Table 8) for a daily dose of approximately 
400-600 µg/kg. 
Table 8. Ivermectin 600 Dosing Schedule 
Weight 
(kg) 
Day 1 (# 
of 7-mg 
tablets) 
Day 2 (# 
of 7-mg 
tablets) 
Day 3 (# 
of 7-mg 
tablets) 
Day 4 (# 
of 7-mg 
tablets) 
Day 5 (# 
of 7-mg 
tablets) 
Day 6 (# 
of 7-mg 
tablets) 
Daily Dose 
(µg/kg) 
35-52 
3 
3 
3 
3 
3 
3 
403-600 
53-69 
4 
4 
4 
4 
4 
4 
406-528 
70-89 
6 
6 
6 
6 
6 
6 
470-600 
90-109 
7 
7 
7 
7 
7 
7 
450-540 
110-129 
8 
8 
8 
8 
8 
8 
434-509 
> 129 
10 
10 
10 
10 
10 
10 
< 540 


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19.3.4. 
Rationale for Selection of Dose 
Refer to Section 16.3.4. 
Additional relevant pre-clinical studies: 
Modeling studies have supported high dose and longer duration of ivermectin. One modeling 
study reported 600 µg/kg daily for 3 days may have clinical effect while 300 µg/kg for 3 days 
was unlikely to have efficacy.[68] Following this modeling study, a recently published proof-of-
concept randomized controlled clinical trial in hospitalized patients showed that 600 µg/kg 
ivermectin for 5 days, a dose still well within the range for safety, was associated with IC50 for 
anti-viral activity in vitro while lower doses (300 µg/kg) were not.[69] The anti-viral activity was 
identified in the subgroup of patients on ivermectin with higher mean plasma concentrations. 
When the ivermectin group was further divided into subgroups with 160 ng/mL as the plasma 
concentration cutoff, the median Cmax achieved was 202 ng/mL in those with plasma 
concentration >160 ng/mL and this group had greater reduction in viral load at day 5. These data 
argue for the use of higher dosing regimens in clinical trials. 
The safety of higher doses of ivermectin is well understood. At least six published trials have 
administered ivermectin at doses above 400 µg/kg.[70] These include over 2,500 independent 
administrations of cumulative 800 µg/kg within one week and over 2,000 single dose 
administrations of 800 µg/kg. The primary side effect of higher doses, usually due to peak 
concentrations, is transient and mild visual disturbances not found to be structural and found to 
self-resolve. One such study randomized 47 patients with malaria to receive ivermectin 600 
µg/kg daily for 3 days versus 300 µg/kg daily for 3 days versus placebo.[71] The 600 µg/kg 
group had more adverse events than the other groups. Treatment-related adverse events exhibited 
a dose-response relationship, with predominantly transient minor visual disturbances that were 
deemed non-severe.  
19.4. 
Placebo Information  
Refer to Section 16.4. 
19.4.1. 
Formulation, Appearance, Packaging, and Labeling 
Refer to Section 16.4.1. 
19.4.2. 
Drug Dispensing, Storage, and Stability 
Refer to Section 16.4.2. 
19.4.3. 
Dosing and Administration 
Dosing and administration will occur according to Section 19.3.3 in order to maintain blinding. 
19.5. 
Events of Special Interest 
 Photophobia 
 Blurred vision 
 Visual impairment 


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20. 
Appendix E – Fluvoxamine Maleate 100  
20.1. 
Risk Assessment 
Refer to Section 17.1. 
20.2. 
Additional Appendix-Level Exclusion Criteria 
Refer to Section 17.2.  
20.2.1. 
Precautions 
Refer to Section 17.2.1.  
20.3. 
Fluvoxamine Information  
Refer to Section 17.3.  
20.3.1. 
Formulation, Appearance, Packaging, and Labeling 
Refer to Section 17.3.1. Fluvoxamine tablets remain 50 mg.  
20.3.2. 
Drug Dispensing, Storage, and Stability 
Refer to Section 17.3.2. 
20.3.3. 
Dosing and Administration 
Fluvoxamine will be self-administered orally by each participant at a dose of 50 mg BID for one 
day (first two doses at 50 mg), followed by 100 mg (two 50 mg tablets) BID for 12 days 
(remaining 24 doses at 100 mg), for a total of 13 days (26 doses, 50 tablets) of fluvoxamine.  
20.3.4. 
Rationale for Selection of Dose 
Refer to Section 17.3.4. 
Additional relevant rationale: 
The recommended starting dose of fluvoxamine for OCD in adults is 50 mg daily to be titrated 
up to a maximum of 300 mg/day divided into BID doses. The 300 mg daily dose is for serotonin 
receptor activity, whereas the postulated dose for sigma-1 receptor activity as an anti-
inflammatory is lower. The TOGETHER trial is a randomized, placebo-controlled, adaptive 
platform trial that demonstrated a 100 mg BID fluvoxamine dose for 10 days was well-tolerated 
and effective (see Figure 7) in nonhospitalized adults with mild COVID-19.[72] This is a 
multicenter study conducted in Brazil. Participants were > 18 years old and with symptomatic 
confirmed COVID-19 within 7 days of the screening date or a positive rapid antigen test done at 
the time of screening. Participants were required to have at least one risk factor for severe 
disease. Participants were randomized to active drug versus placebo, and due to the concurrent 
enrollment into multiple active arms, pooled placebo was used for each active arm. The primary 
outcome was a composite endpoint of medical admission to the hospital due to COVID-19, 
which was defined as more than 6 hours in an emergency care setting (acute care areas set up to 
respond to capacity) or referral for hospitalization, within 28 days of randomization. Key 


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secondary outcomes included viral clearance, time to clinical improvement, and all-cause 
mortality. The planned accrual, based on an assumption of 15% event rate in the placebo group, 
was 681 participants per arm.  
The study randomized 741 participants to fluvoxamine and 756 to placebo. In the fluvoxamine 
group 79 (11%) participants had a primary outcome event versus 119 (16%) in the pooled 
placebo arm (relative risk 0.68 [95% Bayesian credible interval, 0.52-.88]). Secondary outcomes 
including viral clearance at day 7, hospitalization, and mortality were not different between arms. 
There was no significant difference in the number of treatment-emergent adverse events in the 
two arms. Thus, this large randomized, double-blind, controlled trial is suggestive of safety and 
efficacy of fluvoxamine dosed 100 mg twice daily in people with mild-to-moderate COVID-19.  
 
Figure 7. Probability of efficacy for the primary outcome in the ITT and mITT populations 
of TOGETHER 
20.4. 
Placebo Information  
Refer to Section 17.4.  
20.4.1. 
Formulation, Appearance, Packaging, and Labeling 
Refer to Section 17.4.1. 
20.4.2. 
Drug Dispensing, Storage, and Stability 
Refer to Section 17.4.2. 
20.4.3. 
Dosing and Administration 
Participants will self-administer one placebo tablet orally BID for one day, followed by two 
placebo tablets orally BID (four total per day) for 12 days, for a total of 13 days of placebo 
tablets. 


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20.5. 
Events of Special Interest 
Suicidal ideation and behavior will be assessed at Day 7 and Day 14 via the Columbia-Suicide 
Severity Rating Scale (C-SSRS) Screener Since Last Asked Self-Report. The C-SSRS asks a 
total of up to six questions and a minimum of three questions. Sites will follow local policies in 
response to high risk screen cases. In addition, high risk screen cases will be advised to dial 988 
to access the 988 Suicide & Crisis Lifeline.     


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21. 
Appendix F – Montelukast  
21.1. 
Risk Assessment 
The most common adverse reactions that occurred at a greater frequency in montelukast than in 
placebo and at an incidence rate ≥5% include upper respiratory infection, fever, headache, 
pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, and 
otitis. 
Post-market reports of neuropsychiatric events associated with montelukast have included 
agitation, hostility, anxiousness, depression, sleepwalking, suicidal thinking/behavior, and 
tremors. 
Table 9. Montelukast sodium adverse reactions occurring at a higher incidence than 
placebo, in ≥1% of adults and adolescents ≥ 15 years of age. 
Adverse Reaction 
Montelukast sodium  
10 mg/day, n=1955 (%) 
Placebo, n=1180 
(%) 
Pain, abdominal  
2.9 
2.5 
Asthenia/fatigue 
1.8 
1.2 
Fever 
1.5 
0.9 
Trauma 
1.0 
0.8 
Dyspepsia 
2.1 
1.1 
Pain, dental 
1.7 
1.0 
Gastroenteritis, infectious 
1.5 
0.5 
Headache 
18.4 
18.1 
Dizziness 
1.9 
1.4 
Influenza 
4.2 
3.9 
Cough 
2.7 
2.4 
Congestion, nasal 
1.6 
1.3 
Rash 
1.6 
1.2 
ALT Increase 
2.1 
2.0 
AST Increase 
1.6 
1.2 


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Pyuria 
1.0 
0.9 
21.2. 
Additional Appendix-Level Exclusion Criteria 
None 
21.2.1. 
Precautions 
Participants with known aspirin sensitivity should continue to avoid aspirin and other non-
steroidal anti-inflammatory agents while taking montelukast. Care should be taken with the 
reduction of oral corticosteroid therapy while on montelukast as systemic eosinophilia, 
sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss 
syndrome, has been reported. 
21.3. 
Study Drug Information  
The primary active ingredient in montelukast tablets is montelukast sodium, which is an orally 
active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor. It 
is indicated for prophylaxis and chronic treatment of asthma, acute prevention of exercise-
induced bronchoconstriction, relief of seasonal allergic rhinitis, and relief of perennial allergic 
rhinitis in patients ≥ 15 years of age. 
21.3.1. 
Formulation, Appearance, Packaging, and Labeling 
Montelukast sodium is a white to off-white powder. The 10 mg montelukast tablets are beige, 
rounded square-shaped, biconvex, film-coated tablets, debossed “M10” on one side and plain on 
the other side. Each tablet contains 10.4 mg of montelukast sodium, which is equivalent to 10 mg 
montelukast, and additional inactive ingredients including microcelac 100, croscarmellose 
sodium, low substituted hydroxypropyl cellulose, and magnesium stearate. The film coat 
includes hypromellose, hydroxypropyl cellulose, titanium dioxide, polyethylene glycol 6000, 
iron oxide red, and iron oxide yellow. All packaging will be labeled to indicate that the product 
is for investigational use. 
21.3.2. 
Drug Dispensing, Storage, and Stability 
A US commercial supply of montelukast tablets will be supplied by Accord Healthcare Inc. and 
distributed by Belmar Pharmacy. Montelukast tablets should be stored at 25°C with excursions 
permitted from 15°C to 30°C, protected from moisture and light. 
21.3.3. 
Dosing and Administration 
Montelukast will be self-administered orally by each participant at a dose of 10 mg (1 tablet) 
once daily for 14 days. 
21.3.4. 
Rationale for Selection of Dose 
Preclinical Studies: 
Montelukast is a potent cysteinyl leukotriene receptor antagonist with anti-inflammatory effects 
and has been proven to significantly suppress oxidative stress and cytokine production. 


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Pre-clinical in vitro studies demonstrate montelukast’s ability to act as an anti-viral agent against 
RNA viruses such as Zika, Influenza A, and Hepatitis C, among others.[73] A virtual screening 
tool, using an in silico molecular docking analysis, was used to simulate the binding of 
montelukast to catalytically active sites within the SARS‐CoV‐2 main protease and RNA 
dependent RNA polymerase. The results indicated that the Protein-Ligand ANT System chemplp 
docking score of montelukast against the main protease was −105.71, and the RNA dependent 
RNA polymerase was −104.75. These docking scores suggest that montelukast is likely to dock 
to both the main protease and the RNA dependent RNA polymerase of SARS‐CoV‐2, therefore 
demonstrating the potential to inhibit the enzymatic activity of the proteins and subsequently 
disrupting the substrate binding site.[74]   
Montelukast inhibits the signaling of NF-κB, such as interleukin-6,8,10, TNF-alpha, MCP-1, and 
other proinflammatory mediators, which may result in a corresponding reduction of 
proinflammatory mediators, thereby attenuating cytokine production and the cytokine storm.[75] 
Pulmonary and extra-pulmonary manifestations in COVID-19 are attributed to a direct effect of 
SARS-CoV-2 on expressed ACE2 receptors or indirectly through NF-κB dependent induction of 
a cytokine storm. Montelukast may ameliorate extra-pulmonary manifestations of COVID-19 
either directly through blocking of cysteinyl leukotriene receptors in different organs or 
indirectly through inhibition of the NF-κB signaling pathway.[76] 
In addition, 36.4% of patients with COVID-19 experience CNS involvement, and although the 
majority of these events include headache, anosmia, and dysgeusia; more serious events such as 
stroke, delirium, and seizures have been reported.[77] In a 6-week treatment of young (4 months) 
and old (20 months) rats with montelukast, a reduction of neuroinflammation was seen; elevation 
of hippocampal neurogenesis and improvement in learning and memory in old animals was seen. 
By using gene knockdown and knockout approaches, the authors demonstrated that the effect 
was mediated through inhibition of the GPR17 receptor.[78] 
Clinical studies: 
One published retrospective analysis of hospitalized patients with confirmed COVID-19 treated 
with or without montelukast (10 mg orally, once daily, at the discretion of the treating provider) 
included ninety-nine patients not previously on montelukast in the analysis (30 montelukast/62 
non-montelukast). Inclusion required hospitalization for at least 3 days. Montelukast was started 
on day 1 of hospitalization and all patients but 1 were on hydroxychloroquine. Steroids were 
used by 16-23% of patients during the first 3 days of hospitalization and 33-40% of patients 
during the entire hospitalization. A univariate logistic regression revealed a lower risk of clinical 
deterioration in patients who were receiving montelukast, defined as any increase in ordinal scale 
from day 1 to day 3 of hospitalization, (OR, 0.23; P =.029); however, in a multivariable logistic 
regression, the results in patients 60 years or older demonstrated that montelukast was not 
significantly associated with a reduced risk of clinical deterioration (OR, 0.28; P =.058).[79] 
A recent prospective, randomized, controlled, single-blinded, single-center study investigated 
standard of care treatment versus two doses of montelukast (10 mg/day or 20 mg/day) in addition 
to standard of care treatment in hospitalized patients with confirmed COVID-19 at the Erzurum 
Regional Training and Research Hospital in Turkey.[80] To be considered for enrollment, 
patients were required to have a PaO2/FiO2 ratio above 200 at admission and to be starting on 
standard of care treatment (per Turkish Ministry of Health this was favipiravir for a total of 5 


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days). The primary outcome was a composite of progression to ARDS and/or macrophage 
activation syndrome (MAS). MAS was assessed at Day 5 of treatment. Clinical outcomes of 
disease progression were captured during hospitalization. Based on an assumption of a 20% or 
greater reduction in the primary outcome, the sample size was determined to be total accrual of 
180 participants enrolled (60 in each group). The two montelukast arms were combined for the 
clinical outcome analysis. The standard of care arm had more MAS or ARDS events (8 vs 3, p = 
0.001) and mortality (4 vs 0) than the pooled active treatment arms. There was no adverse event 
reporting in this manuscript, and there are numerous weaknesses to the study design.  
Although the preclinical montelukast data available for SARS‐CoV‐2 is quite provoking, data 
from randomized clinical trials is lacking and the efficacy of montelukast for the treatment of 
COVID-19 warrants further studies. Ongoing clinical trials with montelukast propose a range of 
doses for testing (10 mg orally daily for 28-60 days; 60 mg orally daily for 14 days), see Table 
10. One completed observational study (NCT047145515) has not posted study results. The 
proposed dose (Section 21.3.3) of 10 mg orally daily for 14 days fills a gap for a shorter course 
of therapy at the FDA-approved dose for which comprehensive safety data exists. 
Table 10. Ongoing clinical trials with montelukast 
Study  
Study Design  
Proposed 
Montelukast Dose 
NCT Identifier 
The COvid-19 
Symptom MOntelukast 
Trial (COSMO) 
Phase 3, randomized, 
blinded, placebo-
controlled trial with 
600 participants 
10 mg daily for 60 
days 
NCT04389411 
Efficacy of 
Montelukast in Mild-
moderate Respiratory 
Symptoms in Patients 
With Long-COVID-
19: (E-SPERANZA) 
Phase 3, double-blind, 
randomized, placebo-
controlled trial with 
284 participants 
20 mg daily for 28 
days 
NCT04695704 
A National, Multi-
Center, Open-Label, 
Three-Arm, Phase II 
Study to Investigate 
the Effect of 
Montelukast Between 
Emergency Room 
Visits and 
Hospitalizations in 
COVID-19 Pneumonia 
in Comparison With 
Standard Treatment 
Phase 2, 3 arm 
(montelukast, 
montelukast plus 
favicovir, and 
favicovir), open-label, 
randomized trial with 
380 participants 
Montelukast arm 
dosing: 6x10 mg 
montelukast daily for 
14 days 
NCT04718285 


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21.4. 
Placebo Information  
The placebo will be a montelukast-matched placebo. The appearance and packaging will match 
that of the study drug (as described in Section 21.3.1). 
21.4.1. 
Formulation, Appearance, Packaging, and Labeling 
Placebo will match the appearance of montelukast tablets: beige, rounded square-shaped, 
biconvex, film-coated tablets, debossed “M10” on one side and plain on the other side. All 
packaging will be labeled to indicate that the product is for investigational use. 
21.4.2. 
Drug Dispensing, Storage, and Stability 
Placebo will be supplied by Thermo Fisher Scientific and distributed by Belmar Pharmacy. 
Placebo should be stored at controlled room temperature 25°C, excursions permitted from 15°C 
to 30°C. 
21.4.3. 
Dosing and Administration 
Participants will self-administer one placebo tablet orally daily for 14 days. Dosing and 
administration will occur according to Section 21.3.3 in order to maintain blinding. 
21.5. 
Events of Special Interest 
Neuropsychiatric events including agitation, hostility, anxiousness, depression, sleepwalking, 
suicidal thinking/behavior, and tremors.