Clinical trial NCT04988035
Conditions: COVID-19
Keywords: Adults covid-19 Multicenter Putative Therapeutics
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2021-08-03; Completion date: 2022-04-23
Enrollment: 201 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a platform trial to conduct a series of randomized, double-blind, placebo-controlled trials using common assessments and endpoints in hospitalized adults diagnosed with COVID-19. BET is a proof-of-concept study with the intent of identifying promising treatments to enter a more definitive study. The study will be conducted in up to 70 domestic sites and 5 international sites. The study will compare different investigational therapeutic agents to a common control arm and determine which have relatively large effects. In order to maintain the double blind, each intervention will have a matched placebo. However, the control arm will be shared between interventions and may include participants receiving the matched placebo for a different intervention.

The goal is not to determine clear statistical significance for an intervention, but rather to determine which products have clinical data suggestive of efficacy and should be moved quickly into larger studies. Estimates produced from BET will provide an improved basis for designing the larger trial, in terms of sample size and endpoint selection. Products with little indication of efficacy will be dropped on the basis of interim evaluations. In addition, some interventions may be discontinued on the basis of interim futility or efficacy analyses.

One or more interventions may be started at any time. The number of interventions enrolling are programmatic decisions and will be based on the number of sites and the pace of enrollment. At the time of enrollment, subjects will be randomized to receive any one of the active arms they are eligible for or placebo. Approximately 200 (100 treatment and 100 shared placebo) subjects will be assigned to each arm entering the platform and a given site will generally have no more than 3 interventions at once.

The BET-C stage will evaluate the combination of remdesivir with danicopan vs remdesivir with a placebo. Subjects will be assessed daily while hospitalized. Once subjects are discharged from the hospital, they will have a study visit at Days 8, 15, 22, 29, and 60 as an outpatient. The Day 8, Day 22 and Day 60 visits do not have laboratory tests or collection of samples and may be conducted by phone. All subjects will undergo a series of efficacy and safety laboratory assessments. Safety laboratory tests and blood (serum, plasma and RNA) research samples on Day 1 (prior to study product administration) and Days 3, 5, 8, and 11 while hospitalized. Blood research samples plus safety laboratory tests will be collected on Day 15 and 29 if the subject attends an in-person visit or is still hospitalized. However, if infection control considerations or other restrictions prevent the subject from returning to the clinic, Day 15 and 29 visits may be conducted by phone and only clinical data will be obtained.

The primary objective is to evaluate the clinical efficacy of danicopan relative to the control arm in adults hospitalized with COVID-19 according to clinical status (8-point ordinal scale) at Day 8.

Detailed description:
This is a platform trial to conduct a series of randomized, double-blind, placebo-controlled trials using common assessments and endpoints in hospitalized adults diagnosed with COVID-19. BET is a proof-of-concept study with the intent of identifying promising treatments to enter a more definitive study. The study will be conducted in up to 70 domestic sites and 5 international sites. The study will compare different investigational therapeutic agents to a common control arm and determine which have relatively large effects. In order to maintain the double blind, each intervention will have a matched placebo. However, the control arm will be shared between interventions and may include participants receiving the matched placebo for a different intervention.

The goal is not to determine clear statistical significance for an intervention, but rather to determine which products have clinical data suggestive of efficacy and should be moved quickly into larger studies. Estimates produced from BET will provide an improved basis for designing the larger trial, in terms of sample size and endpoint selection. Products with little indication of efficacy will be dropped on the basis of interim evaluations. In addition, some interventions may be discontinued on the basis of interim futility or efficacy analyses.

One or more interventions may be started at any time. The number of interventions enrolling are programmatic decisions and will be based on the number of sites and the pace of enrollment. At the time of enrollment, subjects will be randomized to receive any one of the active arms they are eligible for or placebo. Approximately 200 (100 treatment and 100 shared placebo) subjects will be assigned to each arm entering the platform and a given site will generally have no more than 3 interventions at once.

The BET-C stage will evaluate the combination of remdesivir with danicopan vs remdesivir with a placebo. Subjects will be assessed daily while hospitalized. Once subjects are discharged from the hospital, they will have a study visit at Days 8, 15, 22, 29, and 60 as an outpatient. The Day 8, Day 22 and Day 60 visits do not have laboratory tests or collection of samples and may be conducted by phone. All subjects will undergo a series of efficacy and safety laboratory assessments. Safety laboratory tests and blood (serum, plasma and RNA) research samples on Day 1 (prior to study product administration) and Days 3, 5, 8, and 11 while hospitalized. Blood research samples plus safety laboratory tests will be collected on Day 15 and 29 if the subject attends an in-person visit or is still hospitalized. However, if infection control considerations or other restrictions prevent the subject from returning to the clinic, Day 15 and 29 visits may be conducted by phone and only clinical data will be obtained.

The primary objective is to evaluate the clinical efficacy of danicopan relative to the control arm in adults hospitalized with COVID-19 according to clinical status (8-point ordinal scale) at Day 8. The key secondary objectives are 1) to evaluate the clinical efficacy of danicopan as assessed by time to recovery compared to the control arm 2) to evaluate the proportion of subjects alive and without respiratory failure through Day 29.

Contacts:

20-0013 Central Contact

Telephone: 1 (301) 7617948

Email: DMIDClinicalTrials@niaid.nih.gov

Arms: arm 1: For participants \< 70 years, 200 mg intravenous (IV) loading dose of Remdesivir on Day 1, followed by a 100 mg once-daily IV maintenance dose up to a 10-day total course while hospitalized, and 400 mg oral (PO) (or via nasogastric \[NG\] or gastrostomy \[G\] tube) loading dose danicopan, followed by 250 mg 4 times daily (QID) for the duration of the hospitalization up to a 14-day total course. End of danicopan treatment tapered as 250 mg 3 times daily (TID) for 2 days, followed by 250 mg twice daily (BID) for 2 days, until complete cessation (total treatment duration up to 18 days or 4 days after discharge). Total danicopan participants, N=100. arm 2: For participants \>/= 70 years, 200 mg intravenous (IV) loading dose of Remdesivir on Day 1, followed by a 100 mg once-daily IV maintenance dose up to a 10-day total course while hospitalized, and 300 mg oral (PO) (or via nasogastric \[NG\] or gastrostomy \[G\] tube) loading dose danicopan, followed by 200 mg 4 times daily (QID) for the duration of the hospitalization up to a 14-day total course. End of danicopan treatment tapered as 200 mg 3 times daily (TID) for 2 days, followed by 200 mg twice daily (BID) for 2 days, until complete cessation (total treatment duration up to 18 days or 4 days after discharge). Total danicopan participants, N=100. arm 3: For participants \< 70 years, 200 mg intravenous (IV) loading dose of Remdesivir on Day 1, followed by a 100 mg once-daily IV maintenance dose up to a 10-day total course while hospitalized, and 400 mg oral (PO) (or via nasogastric \[NG\] or gastrostomy \[G\] tube) loading dose danicopan matching placebo, followed by 250 mg 4 times daily (QID) for the duration of the hospitalization up to a 14-day total course. End of danicopan matching placebo treatment tapered as 250 mg 3 times daily (TID) for 2 days, followed by 250 mg twice daily (BID) for 2 days, until complete cessation (total treatment duration up to 18 days or 4 days after discharge). Total danicopan matching placebo participants, N=100. arm 4: For participants \>/= 70 years, 200 mg intravenous (IV) loading dose of Remdesivir on Day 1, followed by a 100 mg once-daily IV maintenance dose up to a 10-day total course while hospitalized and 300 mg oral (PO) (or via nasogastric \[NG\] or gastrostomy \[G\] tube) of loading dose danicopan matching placebo followed by 200 mg 4 times daily (QID) for the duration of the hospitalization up to a 14-day total course. End of danicopan matching placebo treatment tapered as 200 mg 3 times daily (TID) for 2 days, followed by 200 mg twice daily (BID) for 2 days, until complete cessation (total treatment duration up to 18 days or 4 days after discharge). Total danicopan matching placebo participants, N=100.
Interventions: intervention 1: Danicopan intervention 2: Placebo intervention 3: Remdesivir
Intervention descriptions: intervention 1: Danicopan is a small molecule, orally administered complement factor D (FD) inhibitor intervention 2: Danicopan matching placebo tablet intervention 3: Remdesivir is a single diastereomer monophosphoramidate prodrug for the intracellular delivery of a modified adenine nucleoside analog GS-441524.

Protocol documents:
ICF_000.pdf: 
Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious 
Diseases (NIAID), National Institutes of Health (NIH) / Protocol Number 20-0013
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RESEARCH PARTICIPANT INFORMED CONSENT FORM 
FOR STUDY C 
 
Sponsor / Study Title: 
  
Division of Microbiology and Infectious Diseases (DMID), 
National Institute of Allergy and Infectious Diseases 
(NIAID), National Institutes of Health (NIH) / “A 
Multicenter Platform Trial of Putative Therapeutics for the 
Treatment of COVID-19 in Hospitalized Adults” 
ACTIV5/BET 
 
Protocol Number: 
 
UAB IRB Protocol #: 
20-0013 
 
IRB-300007626 
 
Principal Investigator: 
(Study Doctor) 
 
 
 
Telephone: 
 
 
 
 
Address: 
  
 
    
 
 
 
 
This form is for use in a research study that may involve participants who may or may not have 
the capacity to consent to take part in the study.  When the participant cannot legally consent to 
take part, pronouns “you” and “your” should be read as referring to the participant rather than the 
person (legally authorized representative) who is signing and dating this form for the participant. 
In cases where the participant’s representative gives consent, the participant should be informed 
about the study to the extent possible given his/her understanding. During the course of the 
study, if the participant regains the capacity to consent, informed consent will be obtained from 
the participant and the participant offered the ability to leave the study if desired. 
 
KEY INFORMATION 
This consent form describes a clinical research study and is designed to help you decide if you 
would like to be a part of the study. A clinical research study helps doctors test new ways to treat 
a disease. One way to do this is by studying new drugs, to see if they could be used as medicines. 
In a study, the drugs are “experimental,” which means they have not been proven to work. That 
is why studies are needed to find out if new drugs are safe and work in people. 
 
This section provides the information we believe is most helpful and important to you in making 
your decision about participating in this study. More information that may help you decide can 
be found in other sections of the document. 


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What you should know about this study:   
 You are being asked to join this clinical research study because you are currently 
hospitalized with an illness known as COVID-19 caused by the new coronavirus, 
SARS-CoV-2.  
 This study is taking place at more than one site. 
 This is a study that will test a series of different drugs, so drugs will be added or removed 
over time. However, the drugs that are currently being studied at this site are described in 
this consent. 
 Read this consent form carefully or have someone you trust read it to you. Take as much 
time as you need to understand the study. 
 Ask the study team to explain any words or information that you do not understand. 
 You are a volunteer and you do not have to join this study. Your other option is to 
continue receiving any other care you have already been receiving. If you join the study, 
you can change your mind later. You can decide not to take part, or you can quit at any 
time. There will be no penalty or loss of benefits if you decide not to join or to quit the 
study. However, please note that the United States Food and Drug Administration (FDA) 
requires that any information collected up to the point of your withdrawal cannot be 
removed from the study. 
 The study doctor or the sponsor can stop your participation at any time without your 
consent for the following reasons: 
o If it appears to be medically harmful to you; 
o If you fail to follow directions for participating in the study; 
o If it is discovered that you do not meet study requirements; 
o If the study is cancelled; or 
o For administrative reasons. 
 During the study, we will tell you if we learn any new information that might affect 
whether you wish to continue to be in the study. 
 As a part of this research, we will take blood from you to do genetic testing, which 
identifies your DNA. DNA is inherited material in your cells that tells us how your body 
works. We will do these tests to learn how your body responds to COVID-19.  
 
What is this study about? 
There are few approved medicines to treat COVID-19 illness. Some people who become sick 
with COVID-19 have serious disease and must be hospitalized, and a small number of people 
die. Research studies suggest that a recently approved drug called remdesivir (VEKLURY®) 
helps hospitalized people with COVID-19 recover faster than people who do not get remdesivir. 
We want to find out if other drugs given with remdesivir can improve recovery and are safe.  
 
Over time, we will test a series of different drugs, so drugs will be added or removed over time. 
However, the drugs that are currently being studied at this site are described in this consent. 
 
What drugs are being studied? 
This study is designed to test remdesivir in combination with either 1 other study drug or 
placebo. A placebo is an inactive agent that looks exactly like the study drug but does not have 


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any active drug in it. Using a placebo is common in research studies. It will help us know 
whether the results of the study are actually caused by the study drug(s). 
 
There may be more than 1 study drug that is available to be combined with remdesivir at a given 
time. The study drugs currently available to be combined with remdesivir at this site are 
described below (see Section 3). 
 
What study drugs will you get? 
Remdesivir is given to all people who enroll in this study. In addition to remdesivir, you will get 
1 other study drug (see Section 3) or placebo. What you are assigned to receive in combination 
with remdesivir is decided by chance, like rolling dice. We will first check your health to see 
how many of the study drugs would be safe for you to use. Then, you will be assigned to receive 
one of the study drugs that you are eligible for or placebo. If 1 study drug is being tested at this 
site, you will have an equal chance of being assigned to the study drug or placebo.  If more than 
1 study drug is being tested at this site, you will have a higher chance of receiving a study drug 
than placebo. You can ask someone on the study team if you have any questions about what 
study drug or placebo you may get. 
 
If you join this study, you will be randomly assigned to a study drug group. We will tell you 
which study drug group you have been assigned to, however, we cannot tell you if you will 
receive the actual study drug or placebo. The study doctors will not know this either, but they 
can find out in case of emergency. This is called a double-blind study, since neither you nor the 
study doctors know if you got the study drug or placebo. 
 
What will happen during this study? 
If you agree to join this study, we will first check your health to make sure it is safe for you to 
join. If you qualify for this study and decide to join, you will get remdesivir once daily for up to 
10 days. It is given as an infusion into your bloodstream through an intravenous tube placed in a 
vein in your arm using a needle (IV line). You will also receive 1 other study drug or placebo, 
depending on your study drug assignment. More information about the study drugs and how they 
are given is provided below. 
 
While you are in the hospital, we will collect information from your hospital records. We will 
take one or more blood sample(s) from you about 7 times, depending on how long you remain in 
the hospital. On 2 days, we may take blood before and at different times after study drug or 
placebo doses to check how much of the study drug is in your blood. 
 
You will have up to 5 follow-up study visits after you leave the hospital. The exact number will 
depend on when you are discharged. At least 3 follow-up visits will be conducted over the 
phone. The others may be in-person visits at the study site or may be conducted over the phone. 
During follow-up visits, we will collect information about your health since your last visit. For 
in-person visits, we will also take one or more blood sample(s) and one swab. 
 
We will use the blood collected on this study for research and safety tests.  
 
Your total amount of time on this study will be about 2 months.  


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What are the main study risks? 
The main risks of being in this study are related to the study drugs. The study drug remdesivir 
has been studied in healthy (not sick) people and in people with COVID-19 or other viral 
infections. Some of these people had side effects which were temporary and went away after a 
few days. Some people did not have side effects. The most common side effects included 
abnormal liver function test results, abnormal blood clotting test results, constipation, nausea, 
vomiting, decreased appetite, headache, and pain or infection around the IV line. The abnormal 
liver function tests lasted longer than a few days but came back to normal levels during the 
studies. 
 
Risks of the other study drugs currently being tested at this site are given below (see Section 3). 
 
Some people may have some side effects from the study drugs. Other people may have no side 
effects. Allergic reactions to these drugs, including hives, trouble breathing, or other allergic 
responses are very rare but are a possible effect of any drug. Allergic reactions may be severe or 
life-threatening. There may also be side effects and risks that we do not know about yet, even 
serious or life-threatening ones. We will watch you carefully for side effects during this study. 
We will provide short-term medical care if there are side effects from the study drugs that can be 
treated. 
 
If you are pregnant or nursing a child during the study, there may be risks to you, the embryo, 
fetus, or nursing child from the study drugs. Therefore, you cannot join this study if you are 
pregnant or breastfeeding. If you are nursing a child, you must agree to discontinue breastfeeding 
while on this study.  
 
If you can become pregnant, you must agree to remain abstinent (not having any sexual 
relations) or use birth control while taking part in this study and for 30 days after your last dose 
of the study drug or placebo. If you can get a partner pregnant, you must remain abstinent or use 
birth control during the study and for 90 days after your last dose of the study drug or placebo. 
Acceptable methods of birth control are condoms or diaphragms with spermicide, intrauterine 
devices (IUDs), or hormonal contraceptives (for example, an implant, injections, pills, a vaginal 
ring, or a skin patch). Please speak to the study doctor or study staff about acceptable methods of 
birth control.  
 
Are there benefits to being in the study? 
You may or may not benefit from being in this study. Results from studies suggest that your time 
in the hospital may be shorter by taking remdesivir. Everyone in this study receives remdesivir. 
 
What are your other options? 
You do not have to join this study if you do not want to. You can keep getting treated with 
standard care for COVID-19, which may include treatment with remdesivir. 
 
There might be other clinical trials that you can join for experimental treatments for COVID-19. 
However, you cannot participate in this study and other clinical trials for experimental treatments 
for COVID-19 at the same time.  


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The rest of this document will describe more about the research study. This information should 
be considered before you make your choice. Members of the study team will talk with you about 
the information described in this document. 
 
1. 
What will happen if you want to join this study? 
 
If you think you may want to join this study, we will describe the study and answer any 
questions you may have. You can also talk to your friends and family about the study.  
 
If you agree to be in the study, we will ask you or your Legally Authorized Representative 
(LAR) to sign and date this consent form. When you sign your name or put your mark on the 
consent form and date it, it means that you agree to be in the study. You can change your mind at 
any time and leave the study. If you decide not to join the study or to leave the study later, you 
will not lose any regular health care services you already are getting. Approximately 200 
hospitalized adults with COVID-19 will be asked to participate in each stage of this study. 
 
To determine if you qualify for this study, we will ask you some questions about your health, 
including any chronic medical conditions and medications you take for them, allergies to 
medications, any COVID-19 symptoms you have had, and which medications you received from 
your regular doctor during this COVID-19 illness. We will perform a physical exam and measure 
your height and weight. We will review your hospital records for the result(s) of your SARS-
CoV-2 test and any X-rays or CT scans you have had during this COVID-19 illness, and may 
also collect some of the other information listed above, such as COVID-19 symptoms, 
medications, etc. If you have had blood tests done within the past 48 hours to check how well 
your liver and kidneys are working, we will review the results of these tests in your hospital 
records; otherwise, we will collect a blood sample to do these tests. If you are a woman who is 
capable of getting pregnant, we will do a pregnancy (urine or blood) test. A member of the study 
team will explain these tests further. When we have the results, we will explain them to you. 
 
2. 
What does the study involve? 
 
If you qualify for the study and decide to join, you will get up to 10 days of remdesivir while you 
are in the hospital. You will also receive another study drug or placebo, depending on which one 
you were assigned to. You might also need to take an antibiotic starting before the first dose to 2 
days after the last dose of study drug or placebo. More information about the study drugs, how 
they are given, and their risks is provided below in Section 3. After you are discharged from the 
hospital, you will take the study drug or placebo for 4 days, but you will not receive any more 
remdesivir. If you are readmitted to the hospital before Day 11, you may receive the rest of your 
remdesivir infusions, up to Day 10. 
 
On the first day of study treatment, we will take your height and weight and check your vital 
signs. These include your temperature, blood pressure, heart rate, respiratory (breathing) rate, 
and blood oxygen level. Each day you are in the hospital, we will obtain some information about 
you from your inpatient hospital records, such as whether you are receiving oxygen or need 


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additional help breathing and what types of other medicines you are being given as part of your 
clinical care. This information will help us determine how sick you are and whether you are 
improving. We will take one or more blood sample(s) from you on Days 1, 3, 5, 8, and 11 as 
long as you remain in the hospital. On 2 days, we may take blood before and at different times 
after study drug or placebo doses to check how much of the study drug is in your blood. 
 
You will have follow-up visits on Days 8, 15, 22, 29, and 60 if you have already been discharged 
from the hospital. The Day 15 and Day 29 visits will be in-person visits, if possible. If you have 
already been discharged from the hospital at these timepoints, we may ask you to come back to 
the site for these visits. However, if this is not possible due to quarantine restrictions or similar 
reasons, we will call you to collect information over the phone. All Day 8, 22, and 60 visits will 
be conducted over the phone (if you have already been discharged). For all follow-up visits (both 
in-person and by telephone), we will ask how you are feeling and if you have been sick. If you 
were already discharged, we will ask if you had any additional hospital stays or clinic visits or 
needed additional treatments or medicines since your discharge. On Days 29 and 60, we will ask 
you to answer a survey about your quality of life. If you have in-person visits on Days 15 and 29, 
we will also take one or more blood sample(s).  
 
You may be given an optional memory aide that will help remind you when you took your study 
drug on the days after you are discharged. 
 
The total amount of blood that we will collect from you for this study is about 34 tablespoons. If 
we take additional blood before and after doses of the study drug or placebo to check study drug 
levels, the total amount will be about 7 tablespoons more. We will use the blood samples 
collected on this study for research and safety tests.  
 
As part of this study, we will collect some extra blood samples from you (included in the total 
amount given above) that we do not need for our current study goals. We will use your coded 
information, leftover samples, and extra blood samples collected during your participation on 
this study for secondary research. Secondary research is research that is not part of this study, 
and the research is not planned yet. This research will occur in the future and it will help us to 
understand how the study drugs work and to develop new treatments and lab tests. This 
secondary research will not include genetic testing. More information about secondary research 
is provided below.  
 
The last visit for this study is at Day 60. Your study participation will be complete after this visit. 
Your total amount of time on this study will be about 60 days. 
 
3. 
What are the study drugs and their risks? 
 
Remdesivir 
Description: Remdesivir is an antiviral drug that blocks viruses like SARS-CoV-2 from 
replicating, or reproducing. The U.S. FDA recently approved remdesivir as a treatment for 
COVID-19, which means it can be given to COVID-19 patients as standard treatment. 
 


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Remdesivir is given as an infusion into your bloodstream through an intravenous tube placed in a 
vein in your arm using a needle (IV line). It is given once daily for up to 10 days. Each dose 
takes about 30 minutes to give, but could take up to 2 hours.  
 
Risks: The most common side effects seen in people who received remdesivir in research studies 
included: 
 Abnormal liver function test results 
 Abnormal blood clotting test results 
 Constipation 
 Nausea 
 Vomiting 
 Headache 
 Dizziness 
 Pain or infection around the IV line 
 
The abnormal liver function tests lasted longer than a few days but came back to normal levels 
during the studies. We have not seen any long-lasting kidney problems in humans who have 
taken remdesivir. We will be following your liver and kidney function during the study. If you 
have any abnormal test results that may require medical care, we will share these results with 
you. 
 
In a previous study with participants hospitalized with COVID-19, the most common adverse 
events included:  
 Decreased renal function 
 Decreased hemoglobin (anemia) 
 Decreased lymphocyte count 
 Respiratory failure 
 Fever 
 Increased blood glucose 
 
The occurrence of these adverse events were similar in the remdesivir and placebo groups. 
 
None of the side effects in studies of remdesivir have been serious. Some people may have some 
side effects after the infusion. Other people may have no side effects. These side effects are 
temporary and should not last more than a few days. 
 
We will monitor you closely for side effects while you are getting remdesivir. We will have 
medicine and equipment available to treat any side effects, including severe effects, if needed. If 
you have severe side effects that do not get better, we will not give you any more doses of 
remdesivir. 
 
Danicopan 
Description: Danicopan is a study drug that is under investigation as a potential treatment for 
COVID-19. It has been given to more than 266 people in completed studies, including healthy 
people and people with certain conditions that affect the liver, kidneys, or blood. Danicopan 
targets the immune system, part of the body that fights infections. We think that COVID-19 can 


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make people’s immune systems overreact and attack their own bodies, which can damage their 
organs. Danicopan blocks part of the immune system that we think overreacts to COVID-19, so 
we think that this drug may be helpful as a treatment. Danicopan is not approved by the FDA to 
treat COVID-19, but they have given us permission to test it in this study. 
 
Danicopan is given as a tablet that you swallow. It can also be given through a gastric or 
nasogastric tube if you have one. It is given 4 times a day until you are discharged from the 
hospital or up to 14 days. After that, you will take it 3 times a day for 2 days, and then 2 times a 
day for 2 days.  
 
Risks: Other drugs that are similar to danicopan can lower the immune system’s ability to fight 
some infections. They might also increase the risk for some serious, life-threatening infections 
such as infection with the bacteria meningococcus, which can cause complications like 
meningitis (swelling around the brain or spinal cord). It is possible that danicopan might also 
have these risks. It is also possible that this risk may continue even after you stop taking 
danicopan.  
 
You must take an antibiotic during the study unless you are already taking one for another reason 
or you have been vaccinated against meningococcal infections in the past 3 years. The antibiotic 
will be given by mouth or IV once or twice a day starting before the first dose to 2 days after the 
last dose of study drug or placebo. Taking antibiotics can have some side effects, which are 
described below in Section 4. 
 
Taking danicopan can cause abnormal results on liver function tests. These results have been 
seen in 3 people taking danicopan on other studies. Two of these people were healthy and one 
had a blood condition called PNH (paroxysmal nocturnal hemoglobinuria). None of these people 
showed signs of liver injury caused by danicopan, and the test results returned to normal shortly 
after stopping the study drug. We will check your liver function closely during the study, and we 
will stop giving you the study drug or placebo if needed. 
 
Placebo 
Description: The placebo for this study is an inactive tablet that is similar to danicopan, but does 
not have any active drug in it. It is given at the same schedule as danicopan: 4 times a day until 
you are discharged from the hospital or up to 14 days, then 3 times a day for 2 days, and then 
2 times a day for 2 days. 
 
Risks: There are no risks of taking the placebo.  
 
4. 
What are the other risks or discomforts of the study? 
 
General study drug risks 
Since these are new drugs that we are still studying, they may cause other changes that could hurt 
or bother you that we do not know about. People can have allergic reactions to drugs, including 
hives, trouble breathing, or other allergic responses. This is very rare but is also a possible effect 
of any drug. Allergic reactions may be severe or life-threatening. 
 


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Short-term medical care will be provided if there are side effects from the study drugs that can be 
treated. It is important that you always tell the study staff if you have any problems and always 
keep in touch with them.  
 
Risks of Randomization 
You will be assigned to a group by chance, which may prove to be less effective or to have more 
side effects than the other study group or alternatives.  
Blood draws and IV line placement 
We will insert a new, clean needle into a vein in your arm to take blood samples and to insert the 
IV line. If you already have an IV line, the blood samples can be taken from that. You may feel a 
pinch when the needle goes through your skin. A bruise may appear where it was put in. You 
may also have swelling, and the area may be sore. These things are common and should go away 
in a couple of days. Drawing blood may cause brief discomfort and fainting. Fainting is usually 
for a short period and would be managed by having you lie down and elevate his/her legs. There 
is a very small chance of an infection where you have the tube in your arm. An infection could 
be treated with antibiotics. 
 
Antibiotics 
Taking antibiotics can cause side effects such as stomach pain or cramps, nausea, vomiting, and 
diarrhea. Most side effects are only mild or moderate and stop as soon as you quit taking them. 
 
Confidentiality risks 
We will be careful to keep your study information confidential, but there is a small risk that 
someone not involved in the study could get this information. 
 
Information obtained about you for this study will be kept confidential to the extent allowed by 
law. However, research information that identifies you may be shared with people or 
organizations for quality assurance or data analysis, or with those responsible for ensuring 
compliance with laws and regulations related to research.  
They include: 
 The 
). An IRB is a group that reviews the study to 
protect the rights and welfare of research participants. 
 The Division of Microbiology and Infectious Diseases (DMID) 
 The National Institute of Allergy and Infectious Diseases (NIAID) 
 The National Institutes of Health (NIH) 
 The Food and Drug Administration (FDA) 
 The Office for Human Research Protections (OHRP) 
 
The information from the research may be published for scientific purposes; however, your 
identity will not be given out. 
 
 
Genetic Testing: 
As stated above, we will perform genetic testing on your blood sample. This genetic testing will 
focus on COVID-19 and provide information about how your body responds to the disease. 
Following genetic testing, and with your consent, your genetic testing information may be 


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shared. A summary of the genetic results from all participants in this study can be placed in a 
public, unrestricted open access database that anyone can freely use. No individual genetic 
testing information or results will be placed in an open access database. The risk of anyone 
identifying you with this information is very unlikely.   
 
Since your genetic data and health information may be stored and shared with other researchers, 
there may be a risk that information resulting from research genetic testing could be misused for 
discriminatory purposes.  
 
A federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it 
illegal for health insurance companies, group health plans and most employers to discriminate 
against you based on your genetic information. 
 
This law generally will protect you in the following ways: 
 
 Health insurance companies and group health plans may not request your genetic 
information that the sponsor will get from this research. 
 Health insurance companies and group health plans may not use your genetic information 
when making decisions regarding your eligibility or premiums. 
 Employers with 15 or more employees may not use your genetic information that the 
sponsor will get from this research when making a decision to hire, promote, or fire you 
or when setting the terms of your employment. The Sponsor will generally not provide 
this information to others without your consent. Your study site also has to follow 
privacy laws to protect your information. 
 
All health insurance companies and group health plans and all employers with 15 or more people 
must follow this law. 
 
Be aware that this Federal law does not protect you against genetic discrimination by companies 
that sell life insurance, disability insurance or long-term care insurance. 
 
If you have any questions, please ask your Principal Investigator. Researchers who will have 
access to genetic information about you will take measures to maintain the confidentiality of 
your information. 
 
Please initial your decision for us to use your information and samples for genetic research 
for this research study: 
 
______ YES, you may use my information and samples for genetic research. 
 
______ NO, you may not use my information and samples for genetic research. 
 
Risks to pregnancy and nursing children 
If you are pregnant or nursing a child during the study, there may be risks to you, the embryo, 
fetus, or nursing child from the study drugs. If you are nursing a child, you must agree to 
discontinue breastfeeding while on this study. If you can get pregnant, you must agree to remain 


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abstinent or use birth control while taking part in this study and for 30 days after your last dose 
of the study drug or placebo. If you can get a partner pregnant, you must remain abstinent or use 
birth control during the study and for 90 days after your last dose of the study drug or placebo. A 
member of the study team will talk with you about acceptable forms of birth control. You should 
not participate in this study if you can become pregnant or get a partner pregnant. and cannot use 
one of these birth control methods. Be aware that women can still become pregnant even if using 
an acceptable birth control method.  
 
If you think or know you have become pregnant or gotten a partner pregnant during the time 
specified above, please contact the research team member. You will not receive any more study 
drug. The team will ask your permission to follow-up with you about your health and the health 
of the baby until delivery. 
 
5. 
Are there benefits to being in the study? 
 
You may or may not benefit from being in this study. Your participation in this study can help to 
learn more about the study drugs if they are safe and work in hospitalized participants with 
COVID-19.  
 
6. 
What instructions do you need to follow? 
 
You should not drink any alcohol for 14 days after you start receiving the study drug on Day 1. If 
you feel that you need other medicines or herbal products, you should talk to a member of the 
study team first. 
 
If you are nursing a child, you must agree to discontinue breastfeeding while on this study. If you 
can get pregnant or get a partner pregnant, you must agree to remain abstinent or use birth 
control as described above in section 4. 
 
You may not volunteer for another study that gives participants a new study drug for COVID-19 
for at least 29 days after you start receiving the study drug on Day 1. If you want to be in another 
study that follows people who have or have had COVID-19, you should talk to a member of the 
study team first, especially if the other study involves blood collection. 
 
7. 
What other choices do you have? 
 
Before you decide whether to be in this study, we will discuss other options that are available to 
you. Instead of being in this study, you could look for other studies of experimental drugs for 
COVID-19. You can also continue to receive regular supportive hospital care for patients with 
COVID-19 instead of joining a research study. This could include treatment with remdesivir. 
 
8. 
Will new findings be shared with you? 
 
If we find out any new information that may affect your choice to participate in this study, we 
will contact you to explain what we have learned. This may be information we have learned 


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while doing this study or information we have learned from other scientists doing similar 
research in other places. 
 
We are doing genetic testing (sequencing) for research purposes and not to look for inherited 
disease or defects; therefore, we will not return results from sequencing. 
 
9. 
What will happen to your samples and personal information? 
 
We will store your samples and data (information) until we are able to test all samples for SARS-
CoV-2. Your stored samples and data will be marked with a code and not with your name. Only 
researchers linked to this study can get the codes. 
 
Your study information will be placed in a secure electronic system. It will not include your 
name. This information cannot be traced back to you. Your samples will not be sold. You will 
not be paid for any products that result from this research.  
 
The only risk of allowing us to store your samples would be an accidental release of your 
identity. 
 
Some of the blood collected for this study may not be needed to do the research tests. We plan to 
store and use these leftover samples along with your information (identified only by ID codes) 
for secondary research. Secondary research is research that is not part of this study but will be 
performed in the future. You will not be told about the future research. Also, we will collect 
extra blood samples (about 3 teaspoons when other blood is drawn) to store and use for 
secondary research. Secondary research may help us understand how remdesivir and the other 
study drugs work, study other infections or diseases, or develop other treatments. The types of 
research may include development of new laboratory tests to better understand responses to 
infection or for studies to better understand virus infections, including SARS-CoV-2 infection.  
 
You may change your mind about secondary research and withdraw consent for the storage and 
use of your coded samples or information at any time. You will need to contact the study doctor 
using the contact information listed on page 1 of this form. We will do our best to follow your 
wishes but cannot promise that we will always be able to destroy your samples or data. For 
example, if your samples were already used, we would not be able to destroy them. 
 
Please initial your decision about permission for us to use your excess/leftover blood 
samples for future research: 
 
______ YES, you may collect and store my excess/leftover blood samples for an indefinite 
period of time and use them for future research. 
 
______ NO, you may not store my excess/leftover blood samples for an indefinite period of time 
and use them for future research. I understand that by saying NO, I can still take part in this 
study.    
 


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10. 
What do you need to do for follow-up on this study? 
 
If you feel sick at any time during the study, it is important that you quickly tell the study team at 
the hospital (if you are still hospitalized) or call the study contact number you were given when 
you left the hospital (if you have been discharged). We may ask you to return to the study site for 
a medical exam and possible sampling.  
 
11. 
Will it cost you anything to be in this study? 
 
It will not cost you anything to be in this study. 
 
12. 
Will you be paid if you join this study? 
 
You will not receive any monetary compensation for your participation in this study.  
 
13. 
Who is watching over this study? 
 
A Data and Safety Monitoring Board (DSMB) will be looking at the study information very 
closely. The DSMB is made up of doctors and other people who are not directly involved in the 
study and who have a good understanding of severe coronavirus infections and research studies. 
The DSMB may recommend changing the study or stopping the study earlier than planned if 
they think it is not safe to continue. The National Institutes of Health (NIH), local ethics and 
health authorities, and the U.S. FDA will also be watching over this study and have the authority 
to stop the study at any time.   
 
14. 
How will your privacy be protected? 
 
We will keep your study information private. All files with information that could identify you 
will be kept in locked cabinets or secure password protected computers. People responsible for 
making sure that the research is done properly may look at your study records. This might 
include people involved in this study from this hospital and the U.S. government including the 
NIH and their designees and the U.S. Food and Drug Administration, the Institutional Review 
Board (Advarra IRB), and the drug companies that make the study drugs (remdesivir by Gilead 
Sciences, Inc., and danicopan by Alexion Pharmaceuticals, Inc.). All of these people will also 
keep your identity private. By signing and dating this consent form, you agree that results from 
this study, but not your identity, may be shared with local medical providers, makers of the study 
drugs, or government health organizations to help them better understand COVID-19. When 
results of an NIH research study are reported in medical journals or at scientific meetings, the 
participants who take part in the study are not named or identified.  
 
To help us protect your privacy, we have a Certificate of Confidentiality (Certificate) from the 
NIH. Study staff cannot provide to any person not connected with the research your name, or any 
materials that contain identifiable, sensitive information about you, unless permitted or required 
by a legal exception, such as state laws that require reporting of some contagious diseases. The 
most important protection provided by the Certificate is that the study staff cannot be forced to 


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provide any of your identifiable, sensitive information, in any Federal, State, or local civil, 
criminal, administrative, legislative, or other proceeding, such as if there is a court subpoena, 
without your permission. The study team will use the Certificate to resist any demands for 
information that would identify you. 
 
Your information protected by the Certificate may still be disclosed or used when the 
information: 
1. Is disclosed to people connected with the research, for example, information may be used 
for program evaluation internally by the NIH; or  
2. Is required to be disclosed by Federal, State, or local laws, for example, when 
information must be disclosed to meet the legal requirements of the federal U.S. FDA);  
3. Is necessary for your medical treatment and you have consented to this disclosure;  
4. Is for other research; 
5. Is disclosed with your consent (for example, an insurer or medical care provider gets your 
written consent for us to disclose the research information). 
 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self 
or others including, for example, child abuse and neglect, and by signing and dating below you 
consent to those disclosures. 
 
15. 
Will the study require any of your other health care providers to share 
your health information with the researchers of this study? 
 
As a part of this study, the researchers may ask to see your health care records from your other 
health care providers. You will be asked to give us a list of other health care providers that you 
use. 
 
To do this research, we will need to collect, use, and share your private health information. Your 
private information may include things learned from the procedures described in this consent 
form, as well as information from your medical record. You will be asked to sign and date a 
separate document to authorize the collection, use, and disclosure of your personal health 
information. 
 
Your consent form will be placed in your medical record at 
. This may 
include either a paper medical record or electronic medical record (EMR). An EMR is an 
electronic version of a paper medical record of your care within this health system. Your EMR 
may indicate that you are on a clinical trial and provide the name and contact information for the 
principle investigator. 
 
If you are receiving care or have received care within this health system (outpatient or inpatient) 
and are participating in a research study, results of research tests or procedures (i.e. laboratory 
tests, imaging studies, and clinical procedures) may be placed in your existing medical record. 
 
If you have never received care within this health system (outpatient or inpatient) and are 
participating in a research study, a medical record will be created for you to maintain results of 
research tests or procedures. 


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Results of research tests or procedures may be placed in your medical record. All information 
within your medical record can be viewed by individuals authorized to access the record. 
 
 
16. 
What other things should you know about this research study? 
 
A. ClinicalTrials.gov 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This 
Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
B. Conflict of Interest 
 
The policy of the NIH is to evaluate investigators at least yearly for any conflicts of interest. 
This process is detailed in a Conflict of Interest (COI) Guide. You may ask your study team 
for a copy of the COI Guide or for more information. This study has investigators that are 
NIH employees and some that are not. All non-NIH investigators are required to follow the 
principles outlined in the COI Guide but they are not required to report their specific 
financial holdings to the NIH. 
 
Gilead Sciences, Inc., the company that makes remdesivir, is providing remdesivir for this 
study to NIH without charge. Alexion Pharmaceuticals, Inc., the company that makes 
danicopan, is providing danicopan for this study to NIH without charge. No NIH investigator 
involved in this study receives payments or other benefits from any company whose drug, 
product or device is being tested. However, there are some research partners not associated 
with the NIH working on this study who may receive payments or benefits, limited by the 
rules of their workplace. 
 
C. Whom to Contact About This Study? 
 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the study doctor at the 
telephone number listed on the first page of this consent document. If you seek emergency 
care, or hospitalization is required, alert the treating physician that you are participating in 
this research study.  
 
An IRB is an independent committee established to help protect the rights of research 
participants If you have any questions about your rights as a research participant, and/or 
concerns or complaints regarding this research study, contact: 
 
 By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 


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Columbia, MD 21044 
 or call toll free:    877-992-4724 
 or by email:          adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00046406. 
 
If you have questions about your rights as a research participant, or concerns, or complaints 
about the research, you may contact the 
 
 Monday 
through Friday. You may also call this number in the event the research staff cannot be 
reached or you wish to tak to someone else. 
 
 
D. What should you do if you are injured or ill as a result of being in this study? 
 
If you become ill or are injured while you are in the study, get the medical care that you need 
right away. You should inform the healthcare professional treating you that you are 
participating in this study. If you tell the study staff that you think you have been injured then 
they will help you get the care you need.  
 
The study site will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial 
compensation for research-related injuries will be provided by the NIH or the Federal 
Government.  
 
 has not provided for any payment if you are harmed as a result of taking part in this study. 
If such harm occurs, treatment will be provided. However, this treatment will not be provided 
free of charge. 
A Declaration under the Public Readiness and Emergency Preparedness (PREP) Act was 
issued by the Secretary of the United States Department of Health and Human Services on 
March 10, 2020.  This Declaration limits the legal rights of a subject participating in clinical 
studies utilizing COVID-19 countermeasures. Because this study is covered by the Prep Act 
Declaration, covered persons, such as the manufacturers, study sponsor, researchers, 
healthcare providers and others have liability immunity (that is, they cannot be sued by you 
or your family under the laws of the United States). 
 
If you believe that you may have been harmed as a result of this research study, certain 
claims for serious injury or death caused by the countermeasure may be eligible for 
compensation through the Countermeasures Injury Compensation Program. This is a 
program set up by the United States Government.  
 
Information about this program can be found at https://www.hrsa.gov/cicp/about/index.html 
or by calling 1-855-266-2427. If you are eligible for this program, you must file a claim within 
one year of the administration or use of the covered countermeasure. 
 


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


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Complete if participant is illiterate: 
 
Witness to Consent Interview 
 
On the date given next to my signature, I witnessed the consent interview for the research study 
named above in this document. I attest that the information in this consent form was explained to 
the participant, and the participant indicated that his/her questions and concerns were adequately 
addressed. 
 
____________________________________            Date: _____/_____/_____ ; Time: _____ 
Signature of witness 
dd       mm      yy 
 
____________________________________ 
Printed name of witness 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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AUTHORIZATION FOR USE/DISCLOSURE OF 
PROTECTED HEALTH INFORMATION (PHI) FOR RESEARCH 
 
Participant Name:  
 
  
Research Protocol: A Multicenter Platform Trial of 
Putative Therapeutics for the Treatment of COVID-19 
in Hospitalized Adults      
Principal Investigator: 
 
Sponsor: DMID, NIAID, NIH  
 
 
 
What is the purpose of this form?  You are being asked to sign this form so that 
may use and release your protected health 
information for research.  Participation in research is voluntary.  If you choose to participate in the research, you must sign this 
form so that your protected health information may be used for the research. 
 
Why do the researchers want my protected health information?  The researchers want to use your protected health information 
as part of the research protocol listed above and as described to you in the informed consent. 
 
What protected health information do the researchers want to use?  All medical information, including but not limited to 
information and/or records of any diagnosis or treatment of disease or condition, which may include sexually transmitted diseases 
(e.g., HIV, etc.) or communicable diseases, drug/alcohol dependency, etc.; all personal identifiers, including but not limited to your 
name, social security number, medical record number, date of birth, dates of service, etc.; any past, present, and future history, 
examinations, laboratory results, imaging studies and reports and treatments of whatever kind, including but not limited to 
drug/alcohol treatment, psychiatric/psychological treatment; financial/billing information, including but not limited to copies of 
your medical bills,  and any other information related to or collected for use in the research protocol, regardless of whether the 
information was collected for research or non-research (e.g., treatment) purposes. 
 
Who will disclose, use and/or receive my protected health information?  All Individuals/entities listed in the informed consent 
documents, including but not limited to, the physicians, nurses and staff and others performing services related to the research 
(whether at
 or elsewhere); other operating units of 
 
, as necessary for their operations; the IRB and its staff; the sponsor of 
the research and its employees and agents, including any CRO; and any outside regulatory agencies, such as the Food and Drug 
Administration, providing oversight or performing other legal and/or regulatory functions for which access to participant 
information is required. 
 
How will my protected health information be protected once it is given to others?  Your protected health information that is 
given to the study sponsor will remain private to the extent possible, even though the study sponsor is not required to follow the 
federal privacy laws. However, once your information is given to other organizations that are not required to follow federal privacy 
laws, we cannot assure that the information will remain protected. 
 
How long will this Authorization last?  Your authorization for the uses and disclosures described in this Authorization does not 
have an expiration date. 
 
Can I cancel this Authorization?  You may cancel this Authorization at any time by notifying the Principal Investigator, in 
writing, referencing the research protocol and IRB Protocol Number. If you cancel this Authorization, the study doctor and staff 
will not use any new health information for research. However, researchers may continue to use the protected health information 
that was provided before you cancelled your authorization. 
 
Can I see my protected health information?  You have a right to request to see your protected health information. However, to 
ensure the scientific integrity of the research, you will not be able to review the research information until after the research protocol 
has been completed. 
 
Signature of participant:  
 
 
 
 
 
 
 
 
Date:  
 
 
or participant's legally authorized representative:   
 
 
 
 
Date:  
 
 
Printed Name of participant’s representative:  
 
 
 
 
 
Relationship to the participant:  
 
 
 
 
 
 
 

SAP_002.pdf: 
CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
 
 
STATISTICAL ANALYSIS PLAN 
for 
DMID Protocol: 20-0013 
Study Title: 
A Multicenter Platform Trial of Putative 
Therapeutics for the Treatment of COVID-19 in 
Hospitalized Adults: ACTIV-5 
APPENDIX 7 BET-C: 
Danicopan/Standard of Care vs. Placebo/Standard of 
Care 
 
NCT04988035  
 
Version 1.0 
 
DATE: 24-JAN-2022 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL  
 
 


Statistical Analysis Plan - DMID Protocol: 20-0013  
Version 1.0 
Appendix 7 BET-C 
24JAN2022 
- 2 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 STUDY TITLE 
Protocol Number Code: 
DMID Protocol: 20-0013 
Development Phase: 
Phase 2 
Products: 
Danicopan + Standard of Care 
Placebo + Standard of Care 
Form/Route: 
Danicopan/Placebo: oral 
Remdesivir: IV 
Other standard of care: form and route will vary depending on 
type of standard of care administered 
Indication Studied: 
COVID-19 
Sponsor: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
Clinical Trial Initiation Date: 
July 21, 2021 
Clinical Trial Estimated 
Completion Date: 
TBD 
Date of the Analysis Plan: 
January 24, 2022 
Version Number: 
1.0 
This study was performed in compliance with Good Clinical Practice. 
Information contained in this publication is the property of Division of Microbiology and Infectious Diseases and is 
confidential. This information may not be disclosed to third parties without written authorization from Division of Microbiology 
and Infectious Diseases. This report may not be reproduced, stored in a retrieval system or transmitted in any form or by any 
means - electronic, mechanical, recording or otherwise - without the prior authorization from Division of Microbiology and 
Infectious Diseases. This document must be returned to Division of Microbiology and Infectious Diseases upon request. 
 


Statistical Analysis Plan - DMID Protocol: 20-0013  
Version 1.0 
Appendix 7 BET-C 
24JAN2022 
- 3 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
TABLE OF CONTENTS 
STUDY TITLE ................................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
PREFACE .....................................................................................................................8 
2. 
INTRODUCTION ........................................................................................................9 
2.1. 
Purpose of the Analyses ................................................................................................9 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................10 
3.1. 
Study Objectives .........................................................................................................10 
3.1.1. 
Primary Objectives .....................................................................................................10 
3.1.2. 
Secondary Objectives .................................................................................................10 
3.1.2.1. 
Key Secondary Objectives and Other Secondary and Exploratory 
Objective(s) .................................................................................................................10 
3.1.2.2. 
Stage Specific Objective(s) .........................................................................................10 
3.2. 
Endpoints ....................................................................................................................10 
3.2.1. 
Primary Endpoint ........................................................................................................10 
3.2.2. 
Secondary and Exploratory Endpoints .......................................................................10 
3.2.3. 
Stage Specific Exploratory Endpoint (s) ....................................................................10 
3.3. 
Study Definitions and Derived Variables ...................................................................11 
4. 
INVESTIGATIONAL PLAN .....................................................................................12 
4.1. 
Overall Study Design and Plan ...................................................................................12 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups ......................12 
4.3. 
Selection of Study Population ....................................................................................12 
4.4. 
Treatments ..................................................................................................................12 
4.4.1. 
Treatments Administered ............................................................................................12 
4.4.2. 
Identity of Investigational Product(s) .........................................................................12 
4.4.3. 
Method of Assigning Subjects to Treatment Groups (Randomization) .....................13 
4.4.4. 
Selection of Doses in the Study ..................................................................................13 
4.4.5. 
Selection and Timing of Dose for Each Subject .........................................................13 
4.4.6. 
Blinding ......................................................................................................................13 
4.4.7. 
Prior and Concomitant Therapy ..................................................................................13 
4.4.8. 
Treatment Compliance ................................................................................................13 


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4.5. 
Efficacy and Safety Variables ....................................................................................13 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................14 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................15 
6.1. 
General Principles .......................................................................................................15 
6.2. 
Timing of Analyses .....................................................................................................15 
6.3. 
Analysis Populations ..................................................................................................15 
6.4. 
Covariates and Subgroups ..........................................................................................15 
6.5. 
Missing Data ...............................................................................................................15 
6.6. 
Interim Analyses and Data Monitoring ......................................................................15 
6.7. 
Multicenter Studies .....................................................................................................15 
6.8. 
Multiple Comparisons/Multiplicity ............................................................................15 
7. 
STUDY SUBJECTS ...................................................................................................16 
7.1. 
Disposition of Subjects ...............................................................................................16 
7.2. 
Protocol Deviations ....................................................................................................16 
8. 
EFFICACY EVALUATION ......................................................................................17 
8.1. 
Primary Efficacy Analysis ..........................................................................................17 
8.2. 
Secondary Efficacy Analyses .....................................................................................17 
8.3. 
Exploratory Efficacy Analyses ...................................................................................17 
8.4. 
Stage Specific Exploratory Efficacy Analyses ...........................................................17 
8.4.1. 
SF-12 PCS and MCS Scores at Day 29 and Day 60 ...................................................17 
9. 
SAFETY EVALUATION ..........................................................................................18 
9.1. 
Demographic and Other Baseline Characteristics ......................................................18 
9.2. 
Measurements of Treatment Compliance ...................................................................18 
9.3. 
Adverse Events ...........................................................................................................18 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ....................18 
9.5. 
Pregnancies .................................................................................................................18 
9.6. 
Clinical Laboratory Evaluations .................................................................................18 
9.7. 
Vital Signs and Physical Evaluations .........................................................................18 
9.8. 
Concomitant Medications ...........................................................................................18 
9.9. 
Other Safety Measures ................................................................................................18 
10. 
PHARMACOKINETICS ...........................................................................................19 


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11. 
IMMUNOGENICITY ................................................................................................20 
12. 
OTHER ANALYSES .................................................................................................21 
13. 
REPORTING CONVENTIONS ................................................................................22 
14. 
TECHNICAL DETAILS ............................................................................................23 
15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ............................................................................................24 
16. 
REFERENCES ...........................................................................................................25 
17. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..............................................26 
APPENDICES ...............................................................................................................................27 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................28 
APPENDIX 2. GENERAL PROGRAMMING NOTES FOR SAP FIGURES .........................33 
 


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LIST OF ABBREVIATIONS 
ACTIV 
Accelerating COVID-19 Therapeutic Interventions and Vaccines 
ACTT 
Adaptive COVID-19 Treatment Trial 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BET 
Big Effect Trial 
BLOQ 
Below the Limit of Quantitation 
CI 
Confidence Interval 
Cm 
Centimeters 
CoV 
Coronavirus 
COVID-19 
Coronavirus Disease 2019 
CP 
Conditional Power 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
HLT 
High-Level Term 
DAIDS 
Division of AIDS 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data and Safety Monitoring Board 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic Case Report Form 
eGRF 
Estimated Glomerular Filtration Rate 
Hgb 
Hemoglobin 
INR 
International Normalized Ratio 
ITT 
Intent-to-Treat 
JAK 
Janus kinase 
Kg 
Kilograms 
KM 
Kaplan Meier 
LLOD 
Lower Limit of Detection 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
N 
Number (typically refers to subjects) 
NAAT 
Nucleic Acid Amplification Test 
NEWS 
National Early Warning Score 
NIAID 
National Institute of Allergy and Infectious Diseases 


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NIH 
National Institutes of Health 
OP 
Oropharyngeal  
OR 
Odds Ratio 
PAP 
Pulmonary Alveolar Proteinosis 
PBMC 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase Chain Reaction 
PK 
Pharmacokinetic 
PLT 
Platelet 
PT 
Preferred Term 
Q1 
First Quartile 
Q3 
Third Quartile 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS 
Severe Acute Respiratory Syndrome 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SD 
Standard Deviation 
SOC 
System Organ Class 
SpO2 
Blood Oxygen Saturation 
TEAE 
Treatment-Emergent Adverse Events 
TFL 
Tables, Figures, and Listings 
TNF 
Tumor Necrosis Factor 
ULOQ 
Upper Limit of Quantification 
US 
United States 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


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1. 
PREFACE 
Refer to the master SAP.  


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2. 
INTRODUCTION 
2.1. 
Purpose of the Analyses 
This Statistical Analysis Plan (SAP) encompasses all analyses for endpoints that are specific to the BET-C 
study only. Details for the BET-C futility analysis are also included. Details of the rest of the secondary and 
some exploratory endpoints are covered in the master SAP. Details regarding PK and virology exploratory 
endpoints will be covered in separate SAPs. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objectives 
Refer to Section 3.1. of master SAP for details regarding the primary objective. 
3.1.2. 
Secondary Objectives 
3.1.2.1. 
Key Secondary Objectives and Other Secondary and Exploratory Objective(s) 
Refer to Section 3.1.2 and Section 3.1.3 of the master SAP for a list of secondary and exploratory objectives 
for this study. 
3.1.2.2. 
Stage Specific Objective(s) 
1. To evaluate Patient Reported Outcomes.  
2. To evaluate danicopan pharmacokinetics (PK) and pharmacodynamics (PD) in selected subjects with 
COVID-19 at selected sites. 
Details regarding this exploratory PK endpoint will be covered in a separate SAP addendum. 
3.2. 
Endpoints 
3.2.1. 
Primary Endpoint 
Refer to Section 3.2.1 of the Master SAP for details regarding the primary endpoint. 
3.2.2. 
Secondary and Exploratory Endpoints 
Refer to Section 3.2.2 and Section 3.2.3 of the Master SAP for details regarding the secondary and 
exploratory endpoints. 
3.2.3. 
Stage Specific Exploratory Endpoint (s) 
1. SF-12 PCS and MCS scores at Day 29 and Day 60. 
2. Incidence of progression to renal failure requiring dialysis at Day 29. 
The SF-12 is a validated health-related quality of life (HR-QoL) instrument that is widely used across a broad 
spectrum of disease indications. Adapted from the 36-item SF survey that was designed to evaluate physical 
and mental health status, the SF-12 survey contains only 12 questions but covers the same 8 domains. There is 
a further stratification into 2 summary measures (Physical Component Summary (PCS) and Mental 
Component Summary (MCS)) as specified: 
i. 
PCS: 
1. General health (1 item) 
2. Physical functioning (2 items) 
3. Role physical (2 items) 
4. Body pain (1 item) 


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ii. 
MCS 
1. Vitality (1 item) 
2. Social functioning (1 item) 
3. Role emotional (2 items) 
4. Mental health (2 items) 
The PCS and MCS summary measures are scored using a norm-based method (i.e., mean = 5-, SD = 10)[1]. A 
PCS or MCS score of 50 indicates an average score with respect to a healthy population. Scores lower than 50 
reflect less than average health and scores greater than 50 reflect better than average health [2]. This scoring 
will be performed using the Qualitymetric software. Scores will be produced for each of the 8 domains along 
with overall scores for the physical and mental health components. The SF-12 assumes a recall of 1 week 
before responding to questions. The survey is anticipated to be completed in several minutes and can be 
completed by the subject or via an interviewer (in-person or over the phone). This form will not be monitored. 
If it is not completed by the subject, it will not be considered a protocol deviation. 
Details regarding the stage-specific PK endpoint will be covered in a separate SAP addendum. 
3.3. 
Study Definitions and Derived Variables  
Refer to the master SAP for the definition of study day, analysis visit windows, and laboratory sample 
collection study day windows. 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
See Section 4.1 of the master SAP. 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups 
See Section 4.2 of the master SAP. 
4.3. 
Selection of Study Population 
Approximately 200 (100 Danicopan + standard of care and 100 shared placebo) male and non-pregnant 
female adults ≥18 years of age or older with COVID-19 and who meet all eligibility criteria will be enrolled 
at up to 70 domestic sites and 5 international sites. The target population should reflect the community at 
large. The estimated time from screening (Day -1 or Day 1) to end of study for an individual subject is 
approximately 60 days.  
4.4. 
Treatments 
4.4.1. 
Treatments Administered  
All subjects will receive remdesivir as a 200 mg intravenous (IV) loading dose on Day 1, followed by a 100-
mg once-daily IV maintenance dose during hospitalization up to a maximum of 10 total doses (i.e., loading + 
maintenance doses received during study and pre-study if applicable). The duration of dosing may be adjusted 
by the site similar to what is described in the product label and based on a subject’s clinical course and 
ultimate disease severity. Any dose of remdesivir that is delayed may be given later that calendar day. Any 
dose of remdesivir that is missed (not given that calendar day) is not made up. The treatment course continues 
as described above even if the subject becomes PCR negative.  
In addition to receiving remdesivir, subjects in the BET-C trial will be randomized to receive danicopan or 
placebo as follows:  
• ≥70 years of age: 300 mg oral (or via nasogastric [NG] or gastrostomy [G] tube) loading dose on Day 
1, followed by 200 mg 4 times daily (QID) during hospitalization up to a maximum of 14 days.  
o At the end of the treatment course (discharge or 14 days, whichever comes first), treatment will be 
tapered as followed: 200 mg 3 times daily (TID) for 2 days, followed by 200 mg twice daily (BID) 
for 2 days, until complete cessation (total treatment duration up to 18 days or 4 days after 
discharge).  
• <70 years of age: 400 mg oral (or via NG or G tube) loading dose on Day 1, followed by 250 mg QID 
during hospitalization up to a maximum of 14 days.  
o At the end of the treatment course (discharge or 14 days, whichever comes first), treatment will be 
tapered as followed: 250 mg TID for 2 days, followed by 250 mg BID for 2 days, until complete 
cessation (total treatment duration up to 18 days or 4 days after discharge).  
4.4.2. 
Identity of Investigational Product(s) 
Refer to Section 6.1.1 of the Appendix B - BET-C protocol. 


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4.4.3. 
Method of Assigning Subjects to Treatment Groups (Randomization) 
See Section 4.4.3 of the master SAP. 
4.4.4. 
Selection of Doses in the Study 
The dose of remdesivir used in this stage will be the same dose shown to be efficacious in the ACTT-1 
clinical trial and is the dose approved by the US FDA. The duration of dosing may be adjusted by the site 
according to clinical severity. The maximum number of doses to be given during hospitalization is ten doses. 
This includes the loading dose and all maintenance doses given during the study and pre-study if applicable. 
For danicopan, the dosing strategy of 300 mg loading dose followed by 200 mg QID dose is proposed for age 
≥ 70 years old, and the 400 mg loading dose followed by 250 mg QID dose is proposed for age < 70 years old 
was chosen for this study based on the simulation results. Plasma PK exposures for these proposed doses are 
predicted to achieve ≥90% FD inhibition in the majority of subjects during the entire dose interval. 
Considering the overall safety profile of danicopan and the transient nature of liver enzymes elevation 
observed in the clinical program thus far, coupled with the laboratory monitoring schedule in this study, these 
doses provide the optimal benefit to risk balance. 
4.4.5. 
Selection and Timing of Dose for Each Subject 
Remdesivir will be administered as a 200 mg intravenous (IV) loading dose on Day 1, followed by a 100-mg 
once-daily IV maintenance dose during hospitalization up to a maximum of 10 total doses. 
For danicopan, 
• ≥70 years of age: 300 mg oral loading dose on Day 1, followed by 200 mg 4 times daily during 
hospitalization up to a maximum of 14 days.  
• <70 years of age: 400 mg oral loading dose on Day 1, followed by 250 mg 4 times daily during 
hospitalization up to a maximum of 14 days.  
4.4.6. 
Blinding 
See Section 4.4.6 of the master SAP. 
4.4.7. 
Prior and Concomitant Therapy  
Steroids and other concomitant therapies intended as specific treatment of COVID-19, as well as all biologics, 
will be assessed from 7 days prior to enrollment to Day 29. All other concomitant medications will be 
assessed from 7 days prior to enrollment to Day 15 or upon discharge, whichever comes first. 
4.4.8. 
Treatment Compliance 
Each dose of study product will be administered by a blinded member of the clinical research team who is 
qualified and licensed to administer the study product. Administration date and time, and whether any doses 
were slowed, halted or missed will be entered into the case report form (CRF). 
4.5. 
Efficacy and Safety Variables 
See Table 1 for schedule of study procedures. See Section 4.5 of the master SAP for additional details 
regarding efficacy and safety variables. 


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5. 
SAMPLE SIZE CONSIDERATIONS 
Refer to Section 5 of the master SAP. 


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6. 
GENERAL STATISTICAL CONSIDERATIONS 
6.1. 
General Principles 
Refer to Section 6.1 of the master SAP 
6.2. 
Timing of Analyses 
See Section 6.2.1 of the master SAP. 
6.3. 
Analysis Populations 
See Section 6.3 of the master SAP.     
6.4. 
Covariates and Subgroups 
See Section 6.4 of the master SAP. 
6.5. 
Missing Data 
See Section 6.5 of the master SAP. 
6.6. 
Interim Analyses and Data Monitoring 
Refer to Section 6.2.1 for details of the interim analyses for efficacy and futility. 
6.7. 
Multicenter Studies 
Refer to Section 6.7 of the master SAP. 
6.8. 
Multiple Comparisons/Multiplicity 
Refer to Section 6.8 of the master SAP.   


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7. 
STUDY SUBJECTS 
7.1. 
Disposition of Subjects 
Refer to Section 7.1 of the master SAP. 
7.2. 
Protocol Deviations 
Refer to Section 7.2 of the master SAP. 


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8. 
EFFICACY EVALUATION 
8.1. 
Primary Efficacy Analysis 
Refer to Section 8.1 of the master SAP for details regarding the primary analysis. Because of the background 
use of prophylactic antibiotics specific to this protocol, a supportive analysis will be performed by repeating 
the primary analysis to those subjects randomized to BET-C excluding any shared controls. 
8.2. 
Secondary Efficacy Analyses  
Refer to Section 8.1 of the master SAP. 
8.3. 
Exploratory Efficacy Analyses 
Refer to Section 8.3 of the master SAP for details regarding exploratory endpoints. 
8.4. 
Stage Specific Exploratory Efficacy Analyses 
8.4.1. 
SF-12 PCS and MCS Scores at Day 29 and Day 60 
Functional scores of health and well-being include the MCS and PCS scores from the SF-12 health survey as 
described in Section 3.2.3. Results from the SF-12v2 health survey will be scored using Qualitymetric 
software to obtain MCS and PCS scores. No imputation will be performed for missing data, analyses will be 
based on observed non-missing data. 
Summary statistics (mean, median, and quartiles) will be presented by treatment group (Table 2). P-value 
from Wilcoxon rank sum test will also be provided . 


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9. 
SAFETY EVALUATION 
9.1. 
Demographic and Other Baseline Characteristics 
Refer to Section 9.1 of the master SAP. 
9.2. 
Measurements of Treatment Compliance 
Refer to Section 9.2 of the master SAP. 
9.3. 
Adverse Events 
Refer to Section 9.3 of the master SAP regarding analysis of adverse events. 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events 
Refer to Section 9.4 of the master SAP.A summary of subjects who progressed to renal failure requiring 
dialysis at Day 29 is provided in Table 3. Renal failure events will be defined based on all Grade 4 renal 
failure adverse events. The number and proportion of subjects who progressed with 95% CI estimated using 
Blaker method are reported. A risk difference and 95% CI estimated using the Miettinen-Nurminen method is 
also provided. 
9.5. 
Pregnancies 
Refer to Section 9.5 of the master SAP. 
9.6. 
Clinical Laboratory Evaluations 
Refer to Section 9.6 of the master SAP. 
9.7. 
Vital Signs and Physical Evaluations 
Refer to Section 9.7 of the master SAP. 
9.8. 
Concomitant Medications 
Refer to Section 9.8 of the master SAP. 
9.9. 
Other Safety Measures 
No additional safety analyses are planned. 


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10. 
PHARMACOKINETICS 
Details for PK analysis will be provided in a separate SAP. 


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11. 
IMMUNOGENICITY 
Not Applicable. 


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12. 
OTHER ANALYSES 
Not Applicable.  


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13. 
REPORTING CONVENTIONS 
P-values ≥0.001 and ≤0.999 will be reported to 3 decimal places; p-values less than 0.0005 will be reported as 
“<0.001” and p-values greater than 0.9995 will be reported as “>0.999”. 
The mean, confidence intervals, median, IQR, and other statistics will be reported to 1 decimal place greater 
than the original data. The minimum and maximum will use the same number of decimal places as the 
original data. 
Proportions will be presented as 2 decimal places; values greater than zero but <0.01 will be presented as 
“<0.01”. Percentages will be reported to the nearest whole number; values greater than 0.5% but < 1% will be 
presented as “<1”; values greater than 99.5% but less than 100% will be reported as “>99”. 
For all other estimators, the NEJM statistical reporting guidelines will be followed: results will be presented 
with no more precision than is of scientific value and is meaningful. For example, measures of association, 
such as odds ratios, will be reported to two or three significant digits. Results derived from models will be 
limited to the appropriate number of significant digits. 
 


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


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15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES 
This is the first version of the BET-C SAP. There have been no changes in the planned analyses.  


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16. 
REFERENCES 
1. Jenkinson C, Layte R, Jenkinson D, Lawrence K, Petersen S, Paice C, et al. A shorter form health 
survey: can the SF-12 replicate results from the SF-36 in longitudinal studies? J Public Health Med. 
1997;19(2):179-86. 
2. Ware J, Jr., Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and 
preliminary tests of reliability and validity. Med Care. 1996;34(3):220-33. 


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17. 
LISTING OF TABLES, FIGURES, AND LISTINGS  
Table, figure, and listing shells are presented in Appendices 1, 2, and 3. 
 


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APPENDICES 
The tables and figures listed below are those that are specific to BET-C study. The rest of the 
tables will come from the master SAP. In all TFLs, Treatment A will be replaced by Danicopan 
+ SOC and Treatment B will be replaced by Placebo + SOC. 


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APPENDIX 1. TABLE MOCK-UPS 
LIST OF TABLES 
Table 1: 
Schedule of Study Procedures ....................................................................................29 
Table 2: 
Summary Statistics for SF-12 PCS and MCS Results on Day 29 and Day 60 
– mITT Population ......................................................................................................31 
Table 3: 
Incidence of Progression to Renal Failure Requiring Dialysis at Day 29– 
Safety Population ........................................................................................................32 
 


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9.5.1 Efficacy/Immunogenicity and Safety Measurements Assessed and Flow Chart 
Table 1: 
Schedule of Study Procedures 
 
Screen 
Baseline 
Study Intervention Period 
Follow-up Visits  
Day +/- Window 
−1 or 1 
11 
Daily until hospital discharge (up to Day 29) 
83 
±2 
152  
± 2 
223 
± 3 
292 
± 3 
603 
± 3 
ELIGIBILITY 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics & Medical History 
X 
 
 
 
 
 
 
 
Targeted physical exam 
X 
 
 
 
 
 
 
 
Review SARS-CoV-2 results 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Administration of investigational agent 
 
Danicopan or placebo (see dosing above)  
 
 
 
 
 
Administration of prophylactic antibiotics 
 
Prophylactic antibiotics (see Section 2.3.3 of the BET-C protocol) 
 
 
 
 
 
STUDY PROCEDURES 
 
 
 
 
 
 
 
 
Vital signs4 
 
X5 
 
 
X2 
 
X2 
 
Clinical data collection6 
 
X5 
Daily until discharge 
X 
X 
X 
X 
X7 
Adverse event evaluation 
 
X5 
Daily until discharge 
X 
X 
X 
X 
X 
Concomitant medication review8 
 
X5 
Day -7 until discharge or Day 15 
X 
X 
X 
X 
 
SF-12  
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
SAFETY LABORATORY 
 
 
 
 
 
 
 
 
Safety hematology, chemistry, and liver tests 
X9 
X5,10,11 
Day 3, 5, 8, 11 
(all ± 1 day) if hospitalized10,11 
 
X10 
 
X10 
 
Pregnancy test for females of childbearing potential 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH LABORATORY 12 
 
 
 
 
 
 
 
 
Blood draw for serum and plasma  
 
X 
Day 3, 5, 8, 11 (all ± 1 day) if hospitalized 
 
X 
 
X 
 
Blood for RNA 
 
X 
Day 3, 8 (all ± 1 day) if hospitalized 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
AT SELECTED SITES ONLY 
 
 
 
 
 
 
 
 
Danicopan pharmacokinetics and 
pharmacodynamics 13  
 
X 
Day 1: pre-dose prior to 1st and 2nd dose 
 
Day 3: pre-dose prior to 9th dose, 2hr, 4hr & 
6hr post-9th dose (Day 3 samples may be 
collected before and after a subsequent dose 
while hospitalized) 
 
X 
 
X 
 
Blood for PBMC14  
 
X 
Day 3, 8 (all ± 1 day) if hospitalized 
 
X 
 
X 
 
Notes: 
1 Day 1 is defined as the calendar day of randomization. 


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2 In-person visits are preferred but recognizing quarantine and other factors may limit the subject’s ability to return to the site for the visit. In this case, the visit may be performed by phone. 
• 
If still hospitalized at Days 15 and 29 or returns to the site for an in-person visit: assess adverse events, collect clinical data, vital signs, safety laboratory tests, and research laboratory 
samples (blood) as able.  
• 
If phone call only on Days 15 and 29 and all Day 22 and Day 60 visits: assess adverse events, clinical status (ordinal scale), readmission to a hospital, and mortality only. 
3 Day 8, 22 and Day 60 visits performed by phone if discharged from the site hospital. 
4 Vital signs include temperature, systolic blood pressure, heart rate, respiratory rate, O2 saturation and level of consciousness. In addition, height and weight are obtained only at baseline (height can 
be self-reported). Vital signs collected as part of standard care may be used. 
5 Baseline assessments should be performed prior to first drug administration. Laboratory tests performed as part of routine clinical care in the 24 hours prior to first dose will be accepted for the 
baseline safety laboratory tests. Baseline may be the same as the screening laboratory tests if obtained in the 24 hours prior to first dose. 
6 Refer to Section 8.1 of the protocol for details of clinical data to be collected including ordinal score, oxygen requirement, mechanical ventilator requirement, etc. 
7 Ordinal score only. 
8 Remdesivir, steroids and other therapies of COVID-19 will be assessed from 7 days prior to enrollment to enrollment. Then, all other concomitant medications (except those noted in 6.5.1) will be 
assessed from 7 days prior to enrollment to discharge or Day 15, whichever comes first. Antibiotics that will provide prophylaxis against meningococcal infections will be assessed until the end of the 
prescribed course. 
9 Screening laboratory tests include: ALT, AST, creatinine (and calculate an estimated glomerular filtration rate [eGFR] - the formula used is determined by the sites, but should be consistent 
throughout the study), and urine or serum pregnancy test for females of child-bearing potential. Laboratory tests performed as part of routine clinical care in the 48 hours prior to enrollment will be 
accepted for determination of eligibility. 
10 Safety laboratory tests include WBC count, differential, hemoglobin, platelet count, creatinine, total bilirubin, ALT, AST, INR, ferritin, fibrinogen, LDH, D-dimer, and C-reactive protein (CRP). Note: 
D-dimer and CRP values may predict severity and support assessment of outcomes and unlike other safety laboratory values, D-dimer and CRP should not be graded. 
11 Any laboratory tests performed as part of routine clinical care within the specified visit window can be used for safety laboratory testing. 
12 Blood draws for research labs may be omitted on any given study day if inappropriate for a subject’s clinical status per site investigator judgment. In some instances, it may not be possible to collect 
blood for research laboratory investigations due to logistical reasons such as weekends or holidays or lack of necessary supplies. This will not constitute a deviation from the protocol. 
13 A convenience sample of approximately 20 subjects included in this study will be involved in a PK/PD analysis to confirm the dosing regimen. Only selected sites will participate in this collection. 
14 Only collected at selected sites capable of collecting PBMC. 
 


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Table 2: 
Summary Statistics for SF-12 PCS and MCS Results on Day 29 and Day 60 – mITT 
Population 
Time Point Baseline Ordinal Score 
Danicopan + SOC 
(N=X) 
Placebo + SOC 
P-valuea 
n 
Mean 
Q1 
Median 
Q3 
n 
Mean 
Q1 
Median 
Q3 
Mental Component Summary 
Day 29 
Baseline Ordinal Score 5 
x 
xx.x 
xx 
xx 
xx 
x 
xx.x 
xx 
xx 
xx 
 
Baseline Ordinal Score 6 
x 
xx.x 
xx 
xx 
xx 
x 
xx.x 
xx 
xx 
xx 
 
Baseline Ordinal Score 7 
x 
xx.x 
xx 
xx 
xx 
x 
xx.x 
xx 
xx 
xx 
 
Any Baseline Ordinal Score  
x 
xx.x 
xx 
xx 
xx 
x 
xx.x 
xx 
xx 
xx 
x.xxx 
Day 60 
Baseline Ordinal Score 5 
x 
xx.x 
xx 
xx 
xx 
x 
xx.x 
xx 
xx 
xx 
 
Baseline Ordinal Score 6 
x 
xx.x 
xx 
xx 
xx 
x 
xx.x 
xx 
xx 
xx 
 
Baseline Ordinal Score 7 
x 
xx.x 
xx 
xx 
xx 
x 
xx.x 
xx 
xx 
xx 
 
Any Baseline Ordinal Score  
x 
xx.x 
xx 
xx 
xx 
x 
xx.x 
xx 
xx 
xx 
x.xxx 
Physical Component Summary 
Day 29 
Baseline Ordinal Score 5 
x 
xx.x 
xx 
xx 
xx 
x 
xx.x 
xx 
xx 
xx 
 
Baseline Ordinal Score 6 
x 
xx.x 
xx 
xx 
xx 
x 
xx.x 
xx 
xx 
xx 
 
Baseline Ordinal Score 7 
x 
xx.x 
xx 
xx 
xx 
x 
xx.x 
xx 
xx 
xx 
 
Any Baseline Ordinal Score  
x 
xx.x 
xx 
xx 
xx 
x 
xx.x 
xx 
xx 
xx 
x.xxx 
Day 60 
Baseline Ordinal Score 5 
x 
xx.x 
xx 
xx 
xx 
x 
xx.x 
xx 
xx 
xx 
 
Baseline Ordinal Score 6 
x 
xx.x 
xx 
xx 
xx 
x 
xx.x 
xx 
xx 
xx 
 
Baseline Ordinal Score 7 
x 
xx.x 
xx 
xx 
xx 
x 
xx.x 
xx 
xx 
xx 
 
Any Baseline Ordinal Score  
x 
xx.x 
xx 
xx 
xx 
x 
xx.x 
xx 
xx 
xx 
x.xxx 
N = Number of subjects in the mITT population.  
n = Number of subjects with non-missing SF-12 score data. 
a P-value calculated using Wilcoxon rank-sum test. 
 
 


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Table 3: 
Incidence of Progression to Renal Failure Requiring Dialysis at Day 29– Safety 
Population 
Actual Baseline Ordinal Score 
Treatment 
Number of Subjects Progressed to 
Renal Failurea 
Risk Difference 
n 
% 
95% CI 
Estimate 
95% CIb 
Baseline Ordinal Score 5 
Danicopan + SOC (N=X) 
x 
x 
x.x, x.x 
x 
x.x, x.x 
Placebo + SOC (N=X) 
x 
x 
x.x, x.x 
Baseline Ordinal Score 6 
Danicopan + SOC (N=X) 
x 
x 
x.x, x.x 
x 
x.x, x.x 
Placebo + SOC (N=X) 
x 
x 
x.x, x.x 
Baseline Ordinal Score 7 
Danicopan + SOC (N=X) 
x 
x 
x.x, x.x 
x 
x.x, x.x 
Placebo + SOC (N=X) 
x 
x 
x.x, x.x 
Any Baseline Ordinal Scorec 
Danicopan + SOC (N=X) 
x 
x 
x.x, x.x 
x 
 
Placebo + SOC (N=X) 
x 
x 
x.x, x.x 
x 
 
N=Number of subjects in safety population. n= Number of unique subjects that satisfies the row criteria.  
a Number of subjects who progressed to renal failure requiring dialysis at Day 29. Confidence intervals estimated using Blaker method. 
b 95% CI for risk differences calculated using the Miettinen-Nurminen method. 
c [X] additional subjects with an actual baseline ordinal score of 4 are included in the ‘Any Baseline Ordinal Score’ group. 


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APPENDIX 2. GENERAL PROGRAMMING NOTES FOR SAP FIGURES 
• Use the same color for a treatment on the different graphs (SAS standard colors): 
o Danicopan + SOC = Blue 
o Placebo + SOC = Red 
• For severity graphs (SAS standard colors): 
o 5 = green 
o 6 = blue 
o 7 = red 
o Death = black 
 

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APPENDIX C – ACTIV-5/BET-C: DANICOPAN/STANDARD CARE VS. 
PLACEBO/STANDARD CARE 
 
 


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TABLE OF CONTENTS  
Appendix C – ACTIV-5/BET-C: Danicopan/Standard Care vs. Placebo/Standard Care .............. 1 
TABLE OF CONTENTS ................................................................................................................ 2 
LIST OF TABLES .......................................................................................................................... 3 
LIST OF FIGURES ........................................................................................................................ 4 
1. 
PROTOCOL SUMMARY ...................................................................................................... 5 
1.1 
Synopsis .......................................................................................................................... 5 
1.2 
Schedule of Assessments (SOA) .................................................................................... 7 
2. 
INTRODUCTION .................................................................................................................. 9 
2.1 
Study Rationale ............................................................................................................... 9 
2.2 
Background ................................................................................................................... 10 
2.2.1 
Purpose of Study ................................................................................................... 10 
2.2.2 
Potential Therapeutic Agents ................................................................................ 10 
2.3 
Risk/Benefit Assessment .............................................................................................. 10 
2.3.1 
Known Overall Risks ............................................................................................ 10 
2.3.2 
Potential Risks of Remdesivir ............................................................................... 11 
2.3.3 
Potential Risks of Danicopan ................................................................................ 12 
2.3.4 
Known Potential Benefits ..................................................................................... 13 
3. 
OBJECTIVES AND ENDPOINTS ...................................................................................... 13 
4. 
STUDY DESIGN.................................................................................................................. 17 
4.1 
Overall Design .............................................................................................................. 17 
4.2 
Justification for Dose .................................................................................................... 17 
4.2.1 
Justification for Dose of Remdesivir .................................................................... 17 
4.2.2 
Justification for Dose of Danicopan ..................................................................... 17 
5. 
STUDY POPULATION ....................................................................................................... 20 
5.1 
Inclusion Criteria .......................................................................................................... 20 
5.2 
Exclusion Criteria ......................................................................................................... 21 
5.2.1 
Exclusion of Specific Populations ........................................................................ 22 
5.3 
Inclusion of Vulnerable Subjects .................................................................................. 22 
5.4 
Lifestyle Considerations ............................................................................................... 23 
5.5 
Screen Failures .............................................................................................................. 23 
5.6 
Strategies for Recruitment and Retention ..................................................................... 23 
6. 
STUDY PRODUCT.............................................................................................................. 24 
6.1 
Study Product(s) and Administration –Remdesivir, Danicopan, and Placebo ............. 24 
6.1.1 
Study Product Description .................................................................................... 24 
6.1.2 
Dosing and Administration ................................................................................... 24 
6.1.3 
Dose Escalation ..................................................................................................... 25 
6.1.4 
Dose Modifications ............................................................................................... 25 


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6.1.5 
Overdosage ........................................................................................................... 26 
6.2 
Preparation/Handling/Storage/Accountability .............................................................. 26 
6.2.1 
Acquisition and Accountability ............................................................................ 26 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................ 27 
6.2.3 
Product Storage and Stability................................................................................ 28 
6.2.4 
Preparation ............................................................................................................ 28 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................... 28 
6.4 
Study Intervention Compliance .................................................................................... 28 
6.5 
Concomitant Therapy.................................................................................................... 29 
6.5.1 
Permitted Concomitant Therapy and Procedures ................................................. 29 
6.5.2 
Prohibited Concomitant Therapy .......................................................................... 30 
6.5.3 
Rescue Medicine ................................................................................................... 30 
6.5.4 
Non-Research Standard of Care ............................................................................ 30 
7. 
STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................................... 30 
7.1 
Halting Criteria and Discontinuation of Study Intervention ......................................... 30 
7.1.1 
Individual Infusion Halting ................................................................................... 30 
7.1.2 
Study Halting ........................................................................................................ 31 
7.2 
Withdrawal from the Study ........................................................................................... 31 
7.3 
Readmission .................................................................................................................. 31 
7.4 
Lost to Follow-Up ......................................................................................................... 31 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 31 
8.1 
Screening and Efficacy Assessments ............................................................................ 31 
8.1.1 
Screening Procedures ............................................................................................ 31 
8.1.2 
Efficacy Assessments ............................................................................................ 33 
8.1.2.1 
Measures of Clinical Support, Limitations, and Infection Control ................... 33 
8.1.2.2 
Ordinal Scale ..................................................................................................... 33 
8.1.3 
Exploratory Assessments ...................................................................................... 34 
8.2 
Safety and Other Assessments ...................................................................................... 34 
8.3 
Adverse Events and Serious Adverse Events ............................................................... 35 
9. 
STATISTICAL CONSIDERATIONS.................................................................................. 35 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....... 35 
11. REFERENCES ..................................................................................................................... 35 
 
LIST OF TABLES 
Table 1. BET-C Schedule of Assessments ..................................................................................... 7 
Table 2. Summary of Adverse Reaction Rates in Subjects with Mild, Moderate, or Severe 
COVID-19 in ACTT-1 .................................................................................................................. 12 
Table 3. BET-C Study Objectives ................................................................................................ 13 
Table 4. 
 PK Exposure Summary Parameters for Danicopan ....................................... 20 
Table 5. Danicopan or placebo ..................................................................................................... 28 
 


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LIST OF FIGURES 
 
Figure 1. Simulated Serum Danicopan Concentrations on Days 1 and 4 (using a 400 mg loading 
dose and 250 mg QID maintenance dose for individuals 
 and a 300 
mg loading dose and 200 mg QID maintenance dose for individuals 
) ........................ 18 
 
 
 
 


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1. 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Rationale for Proposed Clinical Study 
The complement system is a part of the immune system that enhances the ability of antibodies 
and phagocytic cells to clear pathogens and damaged cells. The complement system has key 
roles in innate and adaptive immune responses, but when hyperactivated can lead to tissue injury. 
Factor D (FD) is one of nine serine proteases in the complement system. It is a highly specific 
enzyme with only one known substrate, factor B (FB), a rate-limiting step in the alternative 
pathway (AP) of complement.  
Preclinical evidence had suggested the role of complement activation in the pathogenesis of 
SARS-CoV-related acute respiratory distress syndrome (ARDS), together with evidence that 
modulation of the complement pathway may lead to favorable outcomes in the test setting of 
organ injury.(1-3) The pro-inflammatory milieu associated with endothelial injury resulting in 
the complement–netosis–coagulation interplay has been implicated in the pathogenesis of 
ARDS, acute kidney injury and stroke in patients with coronavirus-induced disease-2019 
(COVID-19).(4) Inhibition of complement activation by inhibition of FD may control the 
inflammatory processes which drives development of ARDS, thrombotic microangiopathy and 
organ failure in COVID-19.  
Danicopan (ALXN2040, previously ACH-0144471) is a small molecule, orally administered, FD 
inhibitor. It is hypothesized that treatment with danicopan may lead to improved clinical 
outcomes in patients hospitalized due to COVID-19. 
 
Study Design 
See the Master protocol document for a description of the study design. 
 
Study Objectives  
See Table 3 in Section 3.  
 
Population 
This trial will study danicopan in a hospitalized adult population (≥18 years old) with laboratory-
confirmed SARS-CoV-2 (COVID-19) infection. See Sections 5.1 and 5.2 for inclusion and 
exclusion criteria. 
 
Study Phase 
Phase 2 
 
Study Sites 
There will be up to 70 domestic sites and 5 international sites.  
 
Study Interventions 
Remdesivir (Velkury®) is standard therapy for hospitalized patients with COVID-19. Treating 
clinicians will have the option of providing remdesivir as part of standard care for appropriate 


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patients, or of using study-provided investigational-use remdesivir. Subjects who receive study 
provided remdesivir will receive a 200-mg intravenous (IV) loading dose on Day 1, followed by 
a 100-mg once-daily IV maintenance dose during hospitalization up to a maximum of 10 total 
doses (i.e., loading + maintenance doses received during study and pre-study if applicable). The 
duration of dosing may be adjusted by the site similar to what is described in the remdesivir 
package insert and based on a subject’s clinical course and ultimate disease severity.  
 
In addition to receiving remdesivir, subjects will be randomized to receive danicopan or placebo 
as follows:  
• ≥70 years of age: 300 mg oral (or via nasogastric [NG] or gastrostomy [G] tube) loading 
dose on Day 1, followed by 200 mg 4 times daily (QID) during hospitalization up to a 
maximum of 14 days.  
o At the end of the treatment course (discharge or 14 days, whichever comes first), 
treatment will be tapered as followed: 200 mg 3 times daily (TID) for 2 days, 
followed by 200 mg twice daily (BID) for 2 days, until complete cessation (total 
treatment duration up to 18 days or 4 days after discharge).  
• <70 years of age: 400 mg oral (or via NG or G tube) loading dose on Day 1, followed by 
250 mg QID during hospitalization up to a maximum of 14 days.  
o At the end of the treatment course (discharge or 14 days, whichever comes first), 
treatment will be tapered as followed: 250 mg TID for 2 days, followed by 
250 mg BID for 2 days, until complete cessation (total treatment duration up to 18 
days or 4 days after discharge).  
• It is anticipated that the majority of subjects will not have received a meningococcal 
vaccination within the 3 years prior to initiating treatment. If a meningococcal 
vaccination has not occurred within 3 years, or cannot be confirmed, subjects will receive 
antibiotics (listed in Section 2.3.3) for prophylaxis against meningococcal infections. 
Antibiotics will be initiated prior to the first dose of the blinded study drug (danicopan or 
placebo) and will be continued for 2 days after its last dose.  
 
Study Duration 
This stage is anticipated to enroll over 3 months, with an additional 1 month of follow-up, and 2 
months to lock the database.  
 
Participant Duration 
An individual subject will complete the study in about 60 days, from screening at Day -1 or 1 to 
follow-up on Day 60 ± 3 days.  
 
DSMB 
See Section 10.1.6.2 of the Master protocol document. 
 


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1.2 
Schedule of Assessments (SOA) 
Table 1. BET-C Schedule of Assessments 
 
Screen 
Baseline 
Study Intervention 
Period 
Follow-up Visits  
Day +/- Window 
−1 or 1 
11 
Daily until hospital 
discharge (up to 
Day 29) 
83 
±2 
152  
± 2 
223 
± 3 
292 
± 3 
603 
± 3 
ELIGIBILITY 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics & Medical 
History 
X 
 
 
 
 
 
 
 
Targeted physical exam 
X 
 
 
 
 
 
 
 
Review SARS-CoV-2 results 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Administration of 
investigational agent 
 
Danicopan or placebo  
(see dosing above)  
 
 
 
 
 
Administration of 
prophylactic antibiotics 
 
Prophylactic antibiotics  
(see Section 2.3.3) 
 
 
 
 
 
STUDY PROCEDURES 
 
 
 
 
 
 
 
 
Vital signs4 
 
X5 
 
 
X2 
 
X2 
 
Clinical data collection6 
 
X5 
Daily until discharge 
X 
X 
X 
X 
X7 
Adverse event evaluation 
 
X5 
Daily until discharge 
X 
X 
X 
X 
X 
Concomitant medication 
review8 
 
X5 
Day -7 until 
discharge or Day 15 
X 
X 
X 
X 
 
SF-12  
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
SAFETY LABORATORY 
 
 
 
 
 
 
 
 
Safety hematology, 
chemistry, and liver tests 
X9 
X5,10,11 
Day 3, 5, 8, 11 
(all ± 1 day) if 
hospitalized10,11 
 
X10 
 
X10 
 
Pregnancy test for females of 
childbearing potential 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH 
LABORATORY 12 
 
 
 
 
 
 
 
 
Blood draw for serum and 
plasma  
 
X 
Day 3, 5, 8, 11 (all ± 
1 day) if hospitalized 
 
X 
 
X 
 
Blood for RNA 
 
X 
Day 3, 8 (all ± 1 day) 
if hospitalized 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 


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AT SELECTED SITES ONLY 
 
 
 
 
 
 
 
 
Danicopan pharmacokinetics 
and pharmacodynamics 13  
 
X 
Day 1: pre-dose prior 
to 1st and 2nd dose 
 
Day 3: pre-dose prior 
to 9th dose, 2hr, 4hr 
& 6hr post-9th dose 
(Day 3 samples may 
be collected before 
and after a 
subsequent dose 
while hospitalized) 
 
X 
 
X 
 
Blood for PBMC14  
 
X 
Day 3, 8 (all ± 1 day) 
if hospitalized 
 
X 
 
X 
 
Notes: 
1 Day 1 is defined as the calendar day of randomization. 
2 In-person visits are preferred but recognizing quarantine and other factors may limit the subject’s ability to return to the site for the 
visit. In this case, the visit may be performed by phone. 
• 
If still hospitalized at Days 15 and 29 or returns to the site for an in-person visit: assess adverse events, collect clinical data, 
vital signs, safety laboratory tests, and research laboratory samples (blood) as able.  
• 
If phone call only on Days 15 and 29 and all Day 22 and Day 60 visits: assess adverse events, clinical status (ordinal scale), 
readmission to a hospital, and mortality only. 
3 Day 8, 22 and Day 60 visits performed by phone if discharged from the site hospital. 
4 Vital signs include temperature, systolic blood pressure, heart rate, respiratory rate, O2 saturation and level of consciousness. In 
addition, height and weight are obtained only at baseline (height can be self-reported). Vital signs collected as part of standard care may 
be used. 
5 Baseline assessments should be performed prior to first drug administration. Laboratory tests performed as part of routine clinical care 
in the 24 hours prior to first dose will be accepted for the baseline safety laboratory tests. Baseline may be the same as the screening 
laboratory tests if obtained in the 24 hours prior to first dose. 
6 Refer to Section 8.1 of the protocol for details of clinical data to be collected including ordinal score, oxygen requirement, mechanical 
ventilator requirement, etc. 
7 Ordinal score only. 
8 Remdesivir, steroids and other therapies of COVID-19 will be assessed from 7 days prior to enrollment to enrollment. Then, all other 
concomitant medications (except those noted in 6.5.1) will be assessed from 7 days prior to enrollment to discharge or Day 15, whichever 
comes first. Antibiotics that will provide prophylaxis against meningococcal infections will be assessed until the end of the prescribed 
course. 
9 Screening laboratory tests include: ALT, AST, creatinine (and calculate an estimated glomerular filtration rate [eGFR] - the formula 
used is determined by the sites, but should be consistent throughout the study), and urine or serum pregnancy test for females of child-
bearing potential. Laboratory tests performed as part of routine clinical care in the 48 hours prior to enrollment will be accepted for 
determination of eligibility. 
10 Safety laboratory tests include WBC count, differential, hemoglobin, platelet count, creatinine, total bilirubin, ALT, AST, INR, ferritin, 
fibrinogen, LDH, D-dimer, and C-reactive protein (CRP). Note: D-dimer and CRP values may predict severity and support assessment of 
outcomes and unlike other safety laboratory values, D-dimer and CRP should not be graded. 
11 Any laboratory tests performed as part of routine clinical care within the specified visit window can be used for safety laboratory 
testing. 
12 Blood draws for research labs may be omitted on any given study day if inappropriate for a subject’s clinical status per site 
investigator judgment. In some instances, it may not be possible to collect blood for research laboratory investigations due to logistical 
reasons such as weekends or holidays or lack of necessary supplies. This will not constitute a deviation from the protocol. 
13 A convenience sample of approximately 20 subjects included in this study will be involved in a PK/PD analysis to confirm the dosing 
regimen. Only selected sites will participate in this collection. 
14 Only collected at selected sites capable of collecting PBMC. 
 
 


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2. 
INTRODUCTION 
2.1 
Study Rationale 
The complement system is a part of the immune system that enhances the ability of antibodies 
and phagocytic cells to clear pathogens and damaged cells. It is made up of more than 30 plasma 
proteins that opsonize pathogens and induce a series of inflammatory responses to help fight 
infection. The complement system has key roles in innate and adaptive immune responses, but 
when hyperactivated can lead to tissue injury. Within the complement system there are 
3 pathways (classical, lectin, and alternative) that lead to cleavage of C5 and formation of the 
membrane attack complex, or terminal complement pathway. 
FD is one of nine serine proteases in the complement system. It is a highly specific enzyme with 
only one known substrate, FB, a rate-limiting step in the AP of complement. Of all the 
complement proteins, it is among the lowest abundance in serum with a concentration of 
approximately 2 µg/mL,(5) and is the rate-limiting step of AP activation.(6) It is a low molecular 
weight protein (24 kDa) that is primarily produced by adipocytes but can also be produced and 
secreted by monocytes/macrophages and astrocytes in humans. (6, 7) Due to its small size, it is 
freely filtered at the glomerulus, and then taken up by the proximal tubule cell where it is 
catabolized with an estimated fractional catabolic rate of 60% per hour. It is this rapid catabolism 
that is responsible for maintaining low circulating FD levels. As a result, renal dysfunction is 
associated with elevated FD levels, which may lead to increased AP activity and 
inflammation.(8, 9) The biochemical, physiological, and functional features of FD make it an 
attractive target for pharmacological inhibition as this may prove useful in the treatment of a 
wide spectrum of complement-mediated diseases. 
Prior to the COVID-19 pandemic, preclinical evidence had suggested the role of complement 
activation in the pathogenesis of SARS-CoV-related ARDS, together with evidence that 
modulation of the complement pathway may lead to favorable outcomes in the setting of organ 
injury.(1-3) Since the emergence of the COVID-19 pandemic, there has been increasing evidence 
suggesting the role of complement hyperactivation in organ injury associated with COVID-
19.(10, 11) The pro-inflammatory milieu associated with endothelial injury resulting in the 
complement–netosis–coagulation interplay has been implicated in the pathogenesis of ARDS, 
acute kidney injury and stroke in patients with COVID-19.(4) 
In a recent effort to explain the mechanism by which SARS-CoV-2 triggers complement-
mediated endothelial damage, Yu et al. used an in vitro system employing recombinantly 
synthesized COVID-19 proteins to determine if the spike proteins S1 and S2 or the N protein 
induced complement-mediated cytotoxicity.(12) The investigators demonstrated that SARS-
CoV-2 spike proteins bound heparan sulfate on the cell surface and triggered the alternate 
pathway of complement activation on cell surfaces, resulting in complement-mediated cell 
injury. Further, inhibition of the alternative pathway with an FD inhibitor reduced markers of 
complement activation on cell surfaces accompanied by a reduction in cell death. Interestingly, 
age-related macular degeneration, considered as a surrogate for alternative pathway 
dysregulation due to the high prevalence of genetic variants that affect factor H function, has 
been found to be a leading risk factor for intubation and death in COVID-19 patients.(13)  
 


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These data indicate a pivotal role for complement dysregulation in COVID-mediated organ 
failure. Inhibition of complement activation, specifically through the alternative pathway by 
inhibition of FD, may control the inflammatory processes which drives development of ARDS, 
thrombotic microangiopathy and organ failure in COVID-19. Danicopan (ALXN2040, 
previously ACH0144471) is a small molecule, orally administered, FD inhibitor. Danicopan is 
being developed for the treatment of complement-mediated diseases, such as paroxysmal 
nocturnal hemoglobinuria (PNH) and geographic atrophy (GA). It is hypothesized that treatment 
with danicopan will lead to improved clinical outcomes in patients hospitalized due to COVID-
19. As of 30 June 2019, a total of 266 subjects in completed trials have been exposed to 
danicopan, including trials in healthy volunteers as well as patients with renal impairment, 
hepatic impairment, and paroxysmal nocturnal hemoglobinuria.  
2.2 
Background 
2.2.1 
Purpose of Study 
See Section 1.1 of this Appendix. 
2.2.2 Potential Therapeutic Agents 
Remdesivir is a broad-spectrum nucleotide prodrug that inhibits RNA-dependent RNA 
polymerase. Remdesivir is licensed for the treatment of COVID-19 requiring hospitalization. In 
the ACTT-1 trial, remdesivir has been demonstrated to decrease the time to recovery from 15 to 
10 days (recovery rate ratio 1.29 (1.12 to 1.49); P<0.001).(14) Treating clinicians will be offered 
the ability to use study-provided investigational remdesivir or clinicians may choose to provide 
commercial remdesivir instead. In the case of use of commercial remdesivir, it will not be 
considered an investigational agent for the purposes of this trial.  
 
Danicopan is an oral small molecule inhibitor of FD being developed for complement-mediated 
diseases. It binds reversibly to FD with high affinity (KD◦=◦0.44◦nM) and demonstrates potent 
inhibition of AP activity under both in vitro and in vivo conditions. 
2.3 
Risk/Benefit Assessment 
2.3.1 
Known Overall Risks 
Potential risks of participating in this stage are those associated with having blood drawn, the IV 
catheterization, possible reactions to remdesivir and danicopan (as noted in Sections 2.3.2-2.3.3), 
and breach of confidentiality. 
 
Drawing blood may cause transient discomfort and fainting. Fainting is usually transient and 
managed by having the subject lie down and elevate his/her legs. Bruising at the blood collection 
sites may occur but can be prevented or lessened by applying pressure to the blood draw site for 
a few minutes after the blood is taken. IV catheterization may cause insertion site pain, phlebitis, 
hematoma formation, and infusate extravasation; less frequent but significant complications 
include bloodstream and local infections. The use of aseptic (sterile) technique will make 
infection at the site where blood will be drawn or at catheter site less likely. Rarely, severe 
allergic reactions (called anaphylaxis) can occur and may cause heart attacks and, if untreated, 
even death. 


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Risks to Privacy 
Subjects will be asked to provide personal health information (PHI). All attempts will be made to 
keep this PHI confidential within the limits of the law. However, there is a chance that 
unauthorized persons will see the subject’s PHI. All study records will be kept in a locked file 
cabinet or maintained in a locked room at the participating clinical site. Electronic files will be 
password protected. Only people who are involved in the conduct, oversight, monitoring, or 
auditing of this trial will be allowed access to the PHI that is collected. Any publication from this 
trial will not use information that will identify subjects. Organizations that may inspect and/or 
copy research records maintained at the participating site for quality assurance and data analysis 
include groups such as the IRB, NIAID and applicable regulatory agencies (e.g., FDA). For more 
information about confidentiality and privacy see Section 10.1.3 in Master protocol document. 
 
Risks of Genetic Testing 
Genetic findings can have emotional and psychological consequences as well as implications for 
health, employability, and insurability for the subject and family members. However, state and 
federal laws provide protections against genetic discrimination. Samples and the resulting data 
will be coded and kept private. Additionally, to protect confidentiality, results will be entered 
into a password-protected database restricted to the PI or appointed designees. Genetic 
information would only be divulged if a subject signs a waiver on an insurance application. 
Study analyses will not result in discoveries about identity or paternity. 
2.3.2 
Potential Risks of Remdesivir 
Remdesivir is an approved antiviral for the treatment of COVID-19 in hospitalized patients. 
Remdesivir may be obtained as part of standard care outside this clinical trial. For the BET-C 
study, investigational-use remdesivir is still considered a study product being used as part of an 
investigational trial and it will be tracked and monitored accordingly.  
 
Transaminase elevations have been observed in healthy volunteers who received remdesivir. The 
transaminase elevations were mild (Grade 1) to moderate (Grade 2) in severity and resolved 
upon discontinuation of remdesivir. Transaminase elevations have also been reported in patients 
with COVID-19 who received remdesivir.  
 
In ACTT-1, the collection of adverse event (AE) data was limited to severe (Grade 3) or 
potentially life-threatening (Grade 4) AEs, serious adverse events (SAEs), AEs leading to study 
drug discontinuation, and moderate (Grade 2) severity or higher hypersensitivity reactions. Rates 
of adverse reactions (≥ Grade 3), serious adverse reactions, and adverse reactions leading to 
treatment discontinuation are presented in Table 2. 
 


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Table 2. Summary of Adverse Reaction Rates in Subjects with Mild, Moderate, or Severe 
COVID-19 in ACTT-1 
Types of Adverse Reactions 
Remdesivir N=532 n (%) 
Placebo N=516 n (%) 
Adverse reactions, Grades ≥3 
41 (8%) 
46 (9%) 
Serious adverse reactions 
2 (0.4%)a 
3 (0.6%) 
Adverse reactions leading to 
treatment discontinuation 
11 (2%)b 
15 (3%) 
a. Seizure (n=1), infusion-related reaction (n=1).  
b. Seizure (n=1), infusion-related reaction (n=1), transaminases increased (n=3), ALT increased and AST 
increased (n=1), GFR decreased (n=2), acute kidney injury (n=3). 
 
There is the potential of the SARS-CoV-2 developing resistance to remdesivir, which could result 
in decreased efficacy. The clinical impact of the development of resistance is not clear at this time.  
 
Coadministration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not 
recommended based on cell culture data demonstrating an antagonistic effect of chloroquine on 
the intracellular metabolic activation and antiviral activity of remdesivir. 
 
See Package Insert for full discussion of clinical experience and risks. 
2.3.3 
Potential Risks of Danicopan 
Neisseria Meningitidis Infection 
Since a primary function of the complement system is to fight infections, pharmacologic 
inhibition of the complement system could theoretically result in an increased rate or severity of 
infections. Subjects receiving complement inhibitor therapy, such as C5 inhibitors, may have 
increased susceptibility to increased risk of bacterial infections, particularly Neisseria 
meningitidis.(15) Similarly, as suggested by individual case reports with complement system 
deficiencies, including FD, inhibition of the complement system may result in a lifetime 
increased risk of infection, notably with Neisseria meningitidis.(16, 17) However, this risk 
remains theoretical for FD inhibition as the classical pathway of complement is not inhibited by 
FD blockade and FD inhibition appears to have little impact on serum bactericidal activity in 
vaccinated or previously exposed patients.(18, 19)  
To reduce the risk, all subjects should either have been vaccinated against meningococcal 
infections within 3 years prior to receiving danicopan or should receive prophylactic antibiotics 
throughout treatment on this study. Antibiotics will be initiated prior to the first dose of the 
blinded study drug (danicopan or placebo) and will be continued for 2 days after the last dose of 
the investigational therapy. 
Antibiotics for prophylaxis administration could include one of the following: 
• Amoxicillin 250 mg po twice daily 
• Azithromycin 250 mg po or IV daily 
• Ciprofloxacin 500 mg po daily 
Patients receiving antibiotic regimens for other indications that include a Beta-lactam, 
Cephalosporin, Carbapenem, fluoroquinolone, or other antibiotic with coverage of N. 
meningitidis do not require additional antibiotic until that treatment is discontinued. 


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Hepatic Injury 
In healthy volunteers, elevations in alanine aminotransferase (ALT) levels have been observed in 
two subjects treated in the multiple ascending dose study (ACH471-002) with 500 mg twice 
daily and 800 mg twice daily doses for 14 days (Investigators Brochure). These ALT elevations 
were not associated with signs or symptoms of hepatic failure, occurred after completion of 
dosing, and were self-limited. 
Transient elevations in transaminases occurred in one subject from a Phase 2 PNH study in 
association with breakthrough hemolysis. These transient elevations were not associated with 
evidence of hepatic decompensation and resolved within a short time.  
Liver function tests are closely monitored in all clinical studies of danicopan to ensure early 
identification of any potential cases of drug-induced liver toxicity. Individual withholding 
criteria are also included ensuring prompt discontinuation of any patient with evidence of liver 
injury (see Section 6.1.4). 
2.3.4 
Known Potential Benefits 
Individual subjects with COVID-19 participating in this trial may or may not experience 
improved clinical outcomes. However, there is potential benefit to society from their 
participation in this study resulting from insights gained about the therapeutic agent under study 
as well as the natural history of the disease. While there may not be benefits for an individual 
subject, there may be benefits to society if a safe, efficacious therapeutic agent can be identified 
during this global COVID-19 outbreak.  
3. 
OBJECTIVES AND ENDPOINTS 
 
Table 3. BET-C Study Objectives 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
Primary 
 
To evaluate the clinical efficacy of danicopan 
relative to the control arm in adults 
hospitalized with COVID-19 according to 
clinical status (8-point ordinal scale) at Day 8. 
 
 
 
 Ordinal score at Day 8: 
1. Not hospitalized, no new or increased** 
limitations on activities; 
2. Not hospitalized, but new or increased 
limitation on activities and/or requiring new 
or increased home oxygen, CPAP or BiPAP; 
3. Hospitalized, not requiring new or 
increased supplemental oxygen - no longer 
requires ongoing medical care; 
4. Hospitalized, not requiring new or 
increased supplemental oxygen - requiring 
ongoing medical care (COVID-19 related or 
otherwise); 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
5. Hospitalized, requiring new or increased 
supplemental oxygen; 
6. Hospitalized, requiring new or increased 
non-invasive ventilation or high-flow oxygen 
devices; 
7. Hospitalized, on invasive mechanical 
ventilation or extracorporeal membrane 
oxygenation (ECMO); 
8. Death. 
Key Secondary 
 
1. To evaluate the clinical efficacy of 
danicopan as assessed by time to recovery 
compared to the control arm. 
 
 
Day of recovery is defined as the first day on 
which the subject satisfies 1 of the following 
3 categories from the ordinal scale (and does 
not return to a score of 4 or higher for the 
remainder of the study period): 
1. Not hospitalized, no new or increased 
limitations on activities; 
2. Not hospitalized, but new or increased 
limitation on activities and/or 
requiring new or increased home 
oxygen, CPAP, or BiPAP; 
3. Hospitalized, not requiring new or 
increased supplemental oxygen - no 
longer requires ongoing medical care. 
2. To evaluate the proportion of subjects alive 
and without respiratory failure through Day 
29. 
 
Subjects in ordinal scale 5 or 6 at baseline 
who did not meet either of the following two 
categories at any point through Day 29: 
7. Hospitalized, on invasive mechanical 
ventilation or ECMO; 
8. Death. 
Other Secondary 
 
1. To evaluate the clinical efficacy of 
danicopan as compared to the control arm as 
assessed by: 
• Clinical Severity 
o Ordinal scale: 
• Clinical status (8-point ordinal scale) 
at Days 15 and 29. 
• Time to an improvement of one 
category and two categories from 
 
 
 
• Clinical outcome assessed using ordinal 
scale daily while hospitalized and on Days 
15, 22, and 29. 
 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
Day 1 (baseline) using an ordinal 
scale. 
• Mean change in the ordinal scale 
from Day 1 to Days 3, 5, 8, 11, 15, 
22, and 29. 
o Oxygenation: 
• Supplemental oxygen use up to Day 
29. 
• Days of supplemental oxygen (if 
applicable) up to Day 29. 
o Non-invasive ventilation/high-flow 
oxygen: 
• Non-invasive ventilation/high-flow 
oxygen use up to Day 29. 
• Incidence and duration of new non-
invasive ventilation or high-flow 
oxygen use through Day 29. 
• Days of non-invasive ventilation/high-
flow oxygen (if applicable) up to Day 29. 
o Invasive mechanical ventilation/ 
ECMO: 
• Ventilator/ECMO use up to Day 29. 
• Incidence and duration of new 
mechanical ventilation or ECMO 
use through Day 29. 
• Days of invasive mechanical 
ventilation/ECMO (if applicable) up to 
Day 29. 
 
o Proportion of subjects alive and 
without respiratory failure at Day 29. 
Proportion of subjects who did not meet 
either of the following two categories on Day 
29: 
7. Hospitalized, on invasive mechanical 
ventilation or ECMO; 
8. Death. 
• Hospitalization: 
o Duration of hospitalization (days). 
o Duration of ICU stay  
 
• Days of hospitalization up to Day 29. 
• Days of ICU admission up to Day 29. 
• Mortality: 
o 14-day mortality. 
o 28-day mortality. 
o Time to death up to Day 29. 
o 60-day mortality. 
Date and cause of death (if applicable). 
 
• Markers of inflammation and 
coagulation. 
• C-reactive protein (CRP), ferritin, D-
dimer, fibrinogen, and LDH on Day 1; 
Days 3, 5, 8, and 11 (while hospitalized); 
and Days 15 and 29 (if attends in-person 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
visit or still hospitalized). 
2. To evaluate the safety of danicopan as 
compared to the control arm as assessed by: 
• Cumulative incidence of SAEs through 
Day 60. 
• Cumulative incidence of Grade 3 and 4 
clinical and/or laboratory AEs through 
Day 60. 
• Discontinuation or temporary 
suspension of study product 
administration (for any reason). 
• Changes in white blood cell (WBC) 
count with differential, hemoglobin, 
platelets, creatinine, total bilirubin, 
alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), and 
international normalized ratio (INR) 
over time (analysis of lab values in 
addition to AEs noted above).  
 
 
 
• SAEs. 
 
• Grade 3 or 4 AEs.  
 
• Episodes of early discontinuation or 
interruption of study product 
administration. 
 
• WBC with differential, hemoglobin, 
platelets, creatinine, total bilirubin, ALT, 
AST, and INR on Day 1; Days 3, 5, 8, and 
11 (while hospitalized); and Days 15 and 
29 (if attends in-person visit or still 
hospitalized). 
 
Exploratory  
 
1. To evaluate the impact of study 
interventions on markers of inflammation and 
immune response. 
• Proteomic analysis of plasma cytokines 
and markers of inflammation using a 
commercial multi-plex assay (such as O-
link inflammatory), or other assays. Other 
cytokines of interest may be tested 
individually. 
• Transcription, epigenetic, and molecular 
profiles of mRNA in peripheral blood 
mononuclear cells (PBMC). 
• Phenotypic and responsiveness markers in 
PBMC. 
2. To evaluate post-baseline usage of key 
concomitant COVID-19 treatments (e.g., 
steroids) in investigational therapeutic arms 
as compared to the control arm. 
• Use of concomitant COVID-19 treatments 
up to Day 29. 
• Incidence of progression to renal failure 
requiring dialysis at Day 29 
Stage-
specific 
objective/
endpoint 
3. To evaluate Patient 
Reported Outcomes. 
• SF-12 PCS and MCS scores at Day 29 
and Day 60 
4. To evaluate danicopan 
pharmacokinetics (PK) and 
At a limited number of preselected sites (and 
then only as able) - plasma and serum 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
pharmacodynamics (PD) in 
selected subjects with 
COVID-19 at selected sites. 
samples for PK and PD [APW (Alternate 
pathway Wieslab), Factor B, Ba, Bb, Factor 
D, C3, C4, C4d, C5, C5b9]: 
• Day 1: pre-dose prior to 1st and 2nd dose; 
• Day 3: pre-dose prior to 9th dose, 2hr, 4hr 
& 6hr post-9th dose (Day 3 samples may 
be collected before and after a subsequent 
dose while hospitalized) 
• Day 15 and Day 29 
** “New or increased” is relative to pre-COVID status 
4. 
STUDY DESIGN 
4.1 
Overall Design 
See Section 1.1 of the Master protocol document. 
4.2 
Justification for Dose 
4.2.1 
Justification for Dose of Remdesivir 
The dose of remdesivir used in this study will be the same dose shown to be efficacious in the 
ACTT-1 clinical trial,(14) and is the dose approved by the US FDA. The duration of dosing may 
be adjusted by the site according to clinical severity. The maximum number of doses to be given 
during hospitalization is ten doses. This includes the loading dose and all maintenance doses 
given during the study and pre-study if applicable.  
4.2.2 
Justification for Dose of Danicopan 
The current population PK model, developed using all the current available clinical PK data, 
indicates that 
.
 
 
Therefore, simulations have been 
conducted in 3 age groups, 
 years of age with their respective body 
weight distributions according to the Centers for Disease Control and Prevention database.  
 
In this study, the 300 mg loading dose followed by 200 mg QID dose is proposed for age 
, and the 400 mg loading dose followed by 250 mg QID dose is proposed for age 
. 
 
 
Considering the overall safety profile of danicopan and the transient nature of 
liver enzymes elevation observed in the clinical program thus far, coupled with the laboratory 
monitoring schedule in this study, these doses provide the optimal benefit to risk balance.  
 


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The
 
. The 
 
 as the population PK 
model uses extensive PK data from multiple clinical studies in subjects with a wide age range 
 under the assumption that the 
danicopan PK and PK-PD relationship are the same between healthy volunteers and subjects 
with COVID-19.  
 
A convenience sample of approximately 20 subjects included in this study will be involved in a 
PK/PD analysis to confirm the dosing regimen. It is anticipated that only a minority of study 
sites will be able to conduct the PK/PD sample collections. Subjects enrolled at sites and times 
when it is logistically feasible to collect the PK/PD samples will be selected for PK/PD 
collections.  
 
Justification for study drug taper: A taper is implemented at the end of dosing to minimize the 
potential risk of increase in complement and liver enzyme elevation following completion of 
treatment with danicopan.  
 
Figure 1. Simulated Serum Danicopan Concentrations on Days 1 and 4 (using a 400 mg 
loading dose and 250 mg QID maintenance dose for individuals 
 
 a 300 mg loading dose and 200 mg QID maintenance dose for 
individuals 
) 
 


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Table 4. 
 PK Exposure Summary Parameters for Danicopan 
Dose 
Age 
(yr) 
Parameter 
n 
Mean (SD) 
Median (range) 
CV 
Geometric 
mean 
Day 1 
300 mg x1 + 
200 mg QID 
 
 
 AUC (h*ng/mL) 
136 
11005 (2359) 
10725 (5571-18081) 
21 
10757 
 Cmax (ng/mL) 
136 
 613 (141) 
 588 (292-1020) 
23 
597 
Ctrough (ng/mL) 
136 
 348 (74) 
 346 (193-546) 
21 
341 
400 mg x1 + 
250 mg QID 
 
 
 AUC (h*ng/mL) 
234 
10445 (2380) 
10223 (4837-19498) 
23 
10180 
 Cmax (ng/mL) 
234 
 609 (152) 
 601 (313-1163) 
25 
590 
Ctrough (ng/mL) 
234 
 337 (90) 
 327 (149-677) 
27 
326 
 
 AUC (h*ng/mL) 
126 
12929 (2458) 
12848 (8225-20978) 
19 
12699 
 Cmax (ng/mL) 
126 
 723 (155) 
 726 (427-1163) 
21 
707 
Ctrough (ng/mL) 
126 
 423 (87) 
 419 (234-735) 
21 
414 
Day 4 
300 mg x1 + 
200 mg QID 
 
 
 AUC (h*ng/mL) 
136 
13961 (3797) 
13616 (6582-28083) 
27 
13472 
 Cmax (ng/mL) 
136 
 666 (171) 
 640 (301-1283) 
26 
644 
Ctrough (ng/mL) 
136 
 474 (156) 
 479 (192-1013) 
33 
449 
400 mg x1 + 
250 mg QID 
 
 
 AUC (h*ng/mL) 
234 
11464 (3110) 
10787 (4724-23420) 
27 
11067 
 Cmax (ng/mL) 
234 
 583 (144) 
 564 (264-1102) 
25 
566 
Ctrough (ng/mL) 
234 
 348 (130) 
 317 (118-794) 
37 
325 
 
 AUC (h*ng/mL) 
126 
15139 (3407) 
15039 (9234-27171) 
23 
14771 
 Cmax (ng/mL) 
126 
 741 (156) 
 749 (441-1234) 
21 
724 
Ctrough (ng/mL) 
126 
 492 (148) 
 470 (217-986) 
30 
471 
Abbreviations: AUC = area under the curve; Cmax = maximal serum drug concentration; Ctrough = minimal serum 
drug concentration; CV = coefficient of variation; QID = quarter in die (four times daily). Source: Alexion. 
5. 
STUDY POPULATION 
Approximately 200 (100 treatment and 100 shared placebo) male and non-pregnant female adults 
≥18 years of age or older with COVID-19 and who meet all eligibility criteria will be enrolled at 
up to 70 domestic sites and 5 international sites. The target population should reflect the 
community at large. The estimated time from screening (Day -1 or Day 1) to end of study for an 
individual subject is approximately 60 days.  
 
Subject inclusion and exclusion criteria must be confirmed by a clinician named on the 
delegation log. If there is any uncertainty, the site PI may consult the DMID Medical Officer on 
whether a potential subject is eligible for study enrollment; the site PI is ultimately responsible 
for making the final decision. There is no exclusion for receipt of SARS-CoV-2 vaccine. 
5.1 
Inclusion Criteria 
1.  Admitted to a hospital with symptoms suggestive of COVID-19 and requires ongoing 
medical care. 


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2.  Subject (or legally authorized representative) provides informed consent prior to 
initiation of any study procedures. 
3.  Subject (or legally authorized representative) understands and agrees to comply with 
planned study procedures. 
4. Male or non-pregnant female adult ≥18 years of age at time of enrollment. 
5.  Illness of any duration and has laboratory-confirmed SARS-CoV-2 infection as 
determined by PCR or other commercial or public health assay (e.g., Nucleic Acid 
Amplification Test [NAAT], antigen test) in any respiratory specimen or saliva ≤14 days 
prior to randomization. 
Note: if written documentation of the positive test result is not available at the time of enrollment 
(e.g., report came from other institution), the test should be repeated and the subject may be 
enrolled if positive. 
6.  Illness of any duration, and requiring, just prior to randomization, supplemental oxygen 
(any flow), mechanical ventilation or ECMO (ordinal scale category 5, 6, or 7).  
7. Women of childbearing potential and men must agree to either abstinence or use at least 
one acceptable method of contraception from the time of screening through 30 days after 
the last dose of danicopan for women and 90 days after the last dose for men. 
Note: Acceptable methods include barrier contraceptives (condoms or diaphragm) with 
spermicide, intrauterine devices (IUDs), hormonal contraceptives, oral contraceptive pills, and 
surgical sterilization.  
8. Agrees not to participate in another blinded clinical trial (both pharmacologic and other 
types of interventions) for the treatment of COVID-19 through Day 29 (see Section 5.4 
for more information about concurrent trial participation).  
5.2 
Exclusion Criteria 
1. ALT or AST >5 times the upper limit of normal. 
2. Subjects with a low glomerular filtration rate (eGFR), specifically: 
a. Subjects with an eGFR 15-30 mL/min are excluded unless in the opinion of the PI, 
the potential benefit of participation outweighs the potential risk of study 
participation. 
b. All subjects with an eGFR <15 mL/min (including hemodialysis and hemofiltration) 
are excluded. 
3. Pregnancy or breast feeding  
4. Anticipated discharge from the hospital or transfer to another hospital which is not a 
study site within 72 hours of enrollment. 
5. Allergy to any study medication. 
6. Received five or more doses of remdesivir prior to screening.  
7. Treatment with a complement inhibitor in the prior 8 weeks.* 
8. Has active uncontrolled opportunistic infection, or uncontrolled cirrhosis.* 
9. History of infection with N. meningitidis.* 


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10. Known history of hypersensitivity to danicopan or its excipients.* 
11. Has a medical condition that could, in the judgment of the investigator, limit the 
interpretation and generalizability of trial results.  
12. Positive test for influenza virus during the current illness (influenza testing is not required 
by protocol). 
13. History of liver cirrhosis.* 
14.  Previous participation in an ACTIV-5/BET trial. 
15. Refuses to refrain from breastfeeding from the time of screening through 30 days after 
the last dose of danicopan.* 
16. Refuses to receive prophylactic antibiotics against meningococcal infections if the subject 
has not been vaccinated in the 3 years prior to Study Day 1.* 
* Stage-specific criteria. 
5.2.1 
Exclusion of Specific Populations 
Children and adolescents will not be included in this trial. Remdesivir has only been used in a 
small number of pediatric patients. Initial information about the epidemiology of COVID-19 
indicates that the overwhelming burden of severe disease occurs among older adults, especially 
those with comorbidities. Given significant gaps in knowledge in this population, and a low 
incidence of severe morbidity/mortality in children, the risk/benefits do not warrant inclusion of 
this population into this trial at this time.  
 
Remdesivir and danicopan have not been studied in pregnant women. Because the effects on the 
fetus and the pregnant woman are not fully known, pregnant women will not be eligible for the 
trial.  
 
It is not known whether remdesivir or danicopan is secreted in human milk. Because the effects 
of remdesivir and danicopan on the breastfeeding infant is not known, women who are breast 
feeding will not be eligible for the trial. 
5.3 
Inclusion of Vulnerable Subjects 
Certain human subjects are categorized as vulnerable populations and require special treatment 
with respect to safeguards of their well-being. For this clinical trial, examples include cognitively 
impaired or mentally disabled persons and intubated individuals who are sedated. When it is 
determined that a potential research subject is cognitively impaired, federal and institutional 
regulations permit researchers to obtain consent from a legally authorized representative (LAR). 
The study team will obtain consent from these vulnerable subjects using an IRB-approved 
protocol-specific process for consent using a LAR. 
 
For subjects for whom a LAR gave consent, during the course of the study, if the subject regains 
the capacity to consent, informed consent must be obtained from the subject and the subject 
offered the ability to leave the study if desired. 


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5.4 
Lifestyle Considerations 
During this study, subjects are asked to: 
• Refrain from drinking alcohol through Day 15.  
• Women should avoid becoming pregnant during the study from the time of screening to 
30 days after the last dose of danicopan.  
• Men should use an effective means of contraception for 90 days after the last dose of 
danicopan. 
• Subject’s participation in other trials for COVID-19 or SARS-CoV-2 infection are 
restricted/permitted as follows:  
o Blinded trials of interventions of antiviral or immunomodulatory agents for 
treatment of COVID-19 are prohibited through Day 29. 
o Co-enrollment in non-blinded (open-label) interventional studies that evaluate 
how to apply a standard of care intervention or strategy for patients with COVID-
19 (e.g., comparing dose, duration or schedule of VTE prophylaxis regimens; ICU 
strategies such as proning) is permitted.  
o Co-enrollment in natural history studies of COVID-19 and/or studies of SARS-
CoV-2 diagnostics is permitted.  
o Participation in both ACTIV-5/BET and these studies can only occur if the 
recommended blood collection volumes are not exceeded. 
o If a subject is co-enrolled in a prohibited study noted above, this should be 
reported as a protocol deviation, but the subject should not be withdrawn from 
this trial to participate in the other study. Full follow-up should occur per 
protocol.  
5.5 
Screen Failures 
Following consent, after the screening evaluations have been completed, the investigator or 
designee is to review the inclusion/exclusion criteria and determine the subject’s eligibility for 
the study stage. If there is any uncertainty, the PI should make the decision on whether a 
potential subject is eligible for study enrollment.  
 
Only basic demographic information and the reason(s) for ineligibility will be collected on 
screen failures. Subjects who are found to be ineligible will be told the reason(s) for ineligibility. 
 
Individuals who do not meet the criteria for participation in this study (screen failure) because of 
an abnormal laboratory finding may be rescreened once. 
5.6 
Strategies for Recruitment and Retention 
See Section 5.4 of the Master protocol document. 
 
 


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6. 
STUDY PRODUCT 
6.1 
Study Product(s) and Administration –Remdesivir, Danicopan, and 
Placebo 
6.1.1 
Study Product Description  
Remdesivir Component: 
Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular 
delivery of a modified adenine nucleoside analog GS-441524. In addition to the active 
ingredient, the solution and lyophilized formulations of remdesivir contains the following 
inactive ingredients: water for injection (solution only), betadex sulfobutyl ether sodium, and 
hydrochloric acid and/or sodium hydroxide. 
 
Danicopan Component: 
The danicopan investigational drug product is a film-coated, immediate release tablet in 
strengths of 50 mg and 100 mg, intended for oral administration. The tablet contains the drug 
substance, lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulphate, 
magnesium stearate, colloidal silicon dioxide and hypromellose acetate succinate. The tablet 
coating components are polyvinyl alcohol, titanium dioxide, macrogol/polyethylene glycol and 
talc.  
 
Danicopan matching placebo: The supplied matching placebo of danicopan is identical in 
physical appearance to the active oral formulation and contains the same inactive ingredients. 
The placebo does not contain any danicopan drug substance. 
6.1.2 
Dosing and Administration 
Treating clinicians will be offered the ability to use study-provided investigational remdesivir, or 
they may choose to use their institutional-provided commercial remdesivir instead. In the case of 
use of commercial remdesivir, it will not be considered an investigational agent for the purposes 
of this trial. Subjects receiving investigational remdesivir will receive 200 mg IV loading dose 
on Day 1, followed by a 100 mg once-daily IV maintenance dose for the duration of the 
hospitalization up to a 10-day total course. If subjects already received the loading dose prior to 
study enrollment, then start at 100 mg/day on Day 1. Any doses of remdesivir given within 1 
week of enrollment will be counted, so that the total duration of remdesivir (i.e. pre-enrollment + 
on this trial) is up to 10 days (i.e., a maximum of 10 total infusions). Any doses of remdesivir 
administered prior to study enrollment should be documented on the electronic case report form 
(eCRF) as a concomitant medication given prior to Day 1. The duration of dosing may be 
adjusted by the site similar to what is described in the package insert and based on a subject’s 
clinical course and ultimate disease severity.  
 
Any dose of remdesivir that is delayed may be given later that calendar day. Any dose of 
remdesivir that is missed (not given that calendar day) is not made up. The treatment course 
continues as described above even if the subject becomes PCR negative.  
 


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 Subjects in the BET-C trial will be randomized to receive danicopan or placebo as follows:  
• Subjects ≥70 years of age: subjects will receive 300 mg oral (PO or via NG or G tube) 
loading dose followed by 200 mg QID dose as maintenance dose for the duration of the 
hospitalization up to a 14-day total course.  
o At the end of the treatment course (discharge or 14 days, whichever comes first), 
treatment will be tapered as follows: 200 mg TID for 2 days, followed by 200 mg 
BID for 2 days, until complete cessation (total treatment duration up to 18 days or 
4 days after discharge).  
• Subjects <70 years of age: subjects will receive 400 mg (PO or via NG or G tube) loading 
dose followed by 250 mg QID dose as maintenance dose for the duration of the 
hospitalization up to a 14-day total course.  
o At the end of the treatment course (discharge or 14 days, whichever comes first), 
treatment will be tapered as follows: 250 mg TID for 2 days, followed by 250 mg 
BID for 2 days, until complete cessation (total treatment duration up to 18 days or 
4 days after discharge).  
 
It is anticipated that the majority of subjects will not have received meningococcal vaccination 
within the 3 years prior to initiating treatment. If vaccination has not occurred, or cannot be 
confirmed, subjects will receive appropriate antibiotics for prophylaxis against meningococcal 
infections. Appropriate antibiotics will be initiated prior to the first dose of the blinded study 
drug (danicopan or placebo) and will be continued for 2 days after the last dose.  
 
If the dose of danicopan is delayed, it should be given as soon as practical, unless the next dose 
is due within 3 hours, in which case the missed dose should be skipped. If a dose is skipped, this 
will be documented as a protocol deviation.  
 
Danicopan and its placebo may be administered via NG or G tube to subjects who are unable to 
swallow the study drug orally. Further details will be provided in the pharmacy manual. 
6.1.3 
Dose Escalation 
Not Applicable 
6.1.4 
Dose Modifications 
Remdesivir component: 
The infusion should be held and not given if the subject is found to have any of the following 
laboratory values: 
 
• eGFR decreases to <15 mL/min 
o Remdesivir infusion will resume when the eGFR increases to ≥15 mL/min and the 
potential benefit of giving remdesivir outweighs the potential risk.  
o If renal function worsens during the study to the point that they require hemodialysis 
or hemofiltration, remdesivir will be discontinued. 
• ALT and/or AST increases to >10 times upper limits of normal (ULN); resume 
remdesivir infusions when ALT and AST ≤5 times ULN. 
 


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Danicopan component:  
The dose of danicopan or matching placebo should be held and not given if the subject is found to 
have:  
• ALT and/or AST increases to >5 times ULN 
o Danicopan/placebo will be held and not be restarted until the ALT and AST 
return to ≤5 times ULN. 
6.1.5 
Overdosage 
There is no known antidote for remdesivir. In the case of overdose, the subject should receive 
supportive therapy based on the subject´s signs and symptoms. 
 
There is no known antidote for danicopan. In case of overdose, elevations in aminotransferase 
and other liver function tests may occur. General supportive measures based on the subject’s 
signs and symptoms are recommended. It is not known if danicopan can be removed by dialysis.  
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Acquisition and Accountability 
Investigational products (IP) will be shipped to the site either directly from participating 
companies, from the Sponsor, or from other regional or local drug repositories. All other supplies 
should be provided by the site. Multiple lots of each IP may be supplied. 
 
Study products received at the sites will be open-label and not kit specific, unless specified in the 
stage-specific Manual of Procedures (MOP). Drug preparation will be performed by the 
participating site’s research pharmacist on the same day of administration to the subject. See the 
MOP for detailed information on the preparation, labeling, storage, and administration of 
remdesivir, danicopan, and placebo.  
 
Accountability 
The site PI is responsible for study product distribution and disposition and has ultimate 
responsibility for study product accountability. The site PI may delegate to the participating 
site’s research pharmacist responsibility for study product accountability. The participating site’s 
research pharmacist will be responsible for maintaining complete records and documentation of 
study product receipt, accountability, dispensation, storage conditions, and final disposition of 
the study product(s). Time of study drug administration to the subject will be recorded on the 
appropriate case report form (CRF). All study product(s), whether administered or not, must be 
documented on the appropriate study product accountability record or dispensing log. The 
Sponsor’s monitoring staff will verify the participating site’s study product accountability 
records and dispensing logs per the site monitoring plan. Refer to the protocol-specific MOP for 
details on storing study medications.  
 
Destruction 
After the study treatment period has ended or, as appropriate over the course of the study, after 
study product accountability has been performed, used active and placebo vials can be destroyed 


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on-site following applicable site procedures with a second staff member observing and verifying 
the destruction.  
 
Unused vials at the end of the study should be saved until instructions are received from the 
Sponsor. 
 
Complexities of COVID-19 impact on institutions and policies for safety and mitigation of 
exposure require alternate procedures. Study product dispensed to subjects for dosing after 
discharge will not be returned to the site. Sites will advise subjects on study product dispensation 
for study product not used.  
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
Remdesivir 
Remdesivir may be supplied in two formulations: 
• The concentrated solution of remdesivir is supplied as a single dose in a Type 1 clear 
glass vial containing 100 mg/20 mL (5 mg/mL) of remdesivir per vial for dilution into 
0.9% sodium chloride infusion bag. It is a sterile, preservative-free, clear, colorless to 
yellow, aqueous-based concentrated solution that is to be diluted into 0.9% sodium 
chloride infusion bag prior to administration by intravenous infusion. In addition to the 
active ingredient, the solution formulation of remdesivir contains the following inactive 
ingredients: water for injection, betadex sulfobutyl ether sodium, hydrochloric acid, 
and/or sodium hydroxide. For more information, refer to the MOP. 
 
• The lyophilized formulation of remdesivir is a sterile, preservative-free, white to off-
white to yellow powder containing 100 mg of remdesivir to be reconstituted with 19 mL 
of sterile water for injection and diluted into IV infusion fluids prior to IV infusion. 
Following reconstitution, each vial contains a 5 mg/mL remdesivir concentrated solution 
with sufficient volume to allow withdrawal of 20 mL (100 mg of remdesivir). It is 
supplied in a single-use, Type 1 clear glass vial. In addition to the active ingredient, the 
lyophilized formulation of remdesivir contains the following inactive ingredients: water 
for injection, betadex sulfobutyl ether sodium, hydrochloric acid, and/or sodium 
hydroxide. For more information, refer to the MOP. 
 
Remdesivir will be labeled according to manufacturer specifications. 
 
Danicopan or placebo 
Danicopan is provided as specified in Table 5. 
 
The supplied matching placebo of danicopan is identical in physical appearance to the active oral 
formulation and contains the same inactive ingredients. 
 
Each of the study products will be labeled according to manufacturer specifications and include 
the statement “Caution: New Drug Limited by Federal Law to Investigational Use.” 
 


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Table 5. Danicopan or placebo  
Compound Name 
Danicopan (ALXN2040)  
Placebo 
Type  
Drug 
Placebo 
Dose Formulation 
Tablet 
Tablet 
Unit Dose Strengths 
50 mg; 100 mg 
50 mg; 100 mg 
 
6.2.3 
Product Storage and Stability 
Refer to the MOP for instructions regarding the stability and storage of remdesivir, danicopan, 
and placebo. 
6.2.4 
Preparation 
Refer to the MOP for details about preparation and handling of remdesivir, danicopan, and 
placebo.  
 
Remdesivir and danicopan do not meet the criteria for a hazardous compound as defined by 
NIOSH and ASHP hazard classification systems. The study products may be prepared in a clean 
room but do not need to be prepared or handled in a fume hood. 
 
Measures that minimize drug contact with the body should always be considered during 
handling, preparation, and disposal procedures as indicated in the MOP.  
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Randomization will be a two-step process. Subjects will first be randomized to one of the stages 
to which they are eligible (e.g., danicopan or other BET interventions) with equal allocation. 
Then subjects are randomized to the active or placebo version of that intervention with allocation 
k:1, where k is the number of eligible stages the study site is currently randomizing. All eligible 
subjects will receive remdesivir. Subjects randomized to BET-C in the first stage will be 
randomized to receive either danicopan or placebo in the second stage. Randomization will be 
stratified by: 
• Site 
• Severity of illness at enrollment: baseline ordinal score 5 versus ordinal score 6 or 7 
 
The randomization procedure will be described in the MOP. 
6.4 
Study Intervention Compliance 
Each dose of study product will be administered by a blinded member of the clinical research 
team who is qualified and licensed to administer the study product. Administration and date, and 
time, will be entered into the CRF. 


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6.5 
Concomitant Therapy 
6.5.1 
Permitted Concomitant Therapy and Procedures 
For subjects that are eligible for the study, other therapy received prior to enrollment with any 
other experimental treatment or off-label use of marketed medications that are intended as 
specific treatment for COVID-19 or the SARS-CoV-2 infection (i.e., post-exposure prophylaxis 
[PEP]) are permitted but must be discontinued on enrollment. There is no waiting period 
between discontinuation of these treatments and administration of study products. However, 
these prior treatments and their end date should be documented on the concomitant medication 
form in the electronic data capture (EDC) system.  
 
It is anticipated that the majority of subjects will not have received meningococcal vaccination 
within the 3 years prior to initiating treatment. If vaccination has not occurred, or cannot be 
confirmed, subjects will receive appropriate antibiotics for prophylaxis against meningococcal 
infections. Appropriate antibiotics will be initiated prior to the first dose of the blinded study 
drug (danicopan or placebo) and will be continued for 2 days after the last dose of the danicopan 
or placebo. Appropriate prophylaxis may be provided through antibiotics that the study subject 
might be receiving for another indication such as bacterial pneumonia. Suggested regimens are 
described in Section 2.3.3. 
Concomitant medications will be assessed from 7 days prior to enrollment to Day 15 or upon 
discharge, whichever comes first. All prescription medications should be recorded during this 
time period with the exceptions listed in the bullets below. All medications, except biologics, 
convalescent plasma and corticosteroids, can be recorded once regardless of the number of times 
it was given during the time period. For example, vasopressors should be recorded when first 
dose given (as the start date) and the last dose given (as the end date) during the period of 
assessment. 
Sites do not need to record any of the following categories of medications as concomitant 
medications: 
o All topical medications: ointments, creams, and lotions; 
o All intranasal medications: nasal decongestants, nasal allergy medications, nasal steroids, 
and nasal saline drops/sprays;  
o All ophthalmic medications: ophthalmic allergy medication, ophthalmic medications for 
infection, and ophthalmic medications for eye dryness (e.g., saline eye drops); 
o Antiseptic mouth wash, lozenges; 
o Cough medication: mucolytics, cough suppressants, and expectorates; 
o GI medications: H2 blockers, proton pump inhibitors, GI stimulants, prokinetics, 
laxatives, stool softeners, antacids, anti-diarrheal and anti-nausea medications; 
o Insulin and medications for diabetic control; 
o Symptomatic care medications: antipyretics, antihistamines, decongestants, and NSAIDs;  
o Vitamins, minerals or herbal supplements, dietary supplements, iron/ferrous sulfate, 
magnesium, calcium, electrolyte replacement; 
o Albumin infusions; 


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o Melatonin; 
o Nicotine patch, lozenge, gum, or nasal spray, or other product to treat tobacco 
dependence; 
o Dyes: iodine-based dye, barium sulfate, and diatrizoate sodium. 
 
See the MOP for more information about recording concomitant medications. 
6.5.2 
Prohibited Concomitant Therapy 
Receipt of any exclusionary treatments or medications prior to screening will be assessed at 
screening to determine eligibility as described in the exclusion criteria.  
 
The following medications are prohibited during this study: 
o Other immunosuppressants which, in the judgment of the investigator, pose risk of 
immunosuppression in combination with danicopan that is larger than the risk of COVID-
19. 
o Chloroquine or hydroxychloroquine use for the treatment of COVID-19 
 
A recent study found that chloroquine antagonizes remdesivir in a dose dependent manner as 
evidenced by an increase in the median effective dose (EC50) for remdesivir with increasing 
chloroquine concentration. Another in vitro study found that chloroquine induces a dose 
dependent inhibition of the formation of the active nucleoside triphosphate metabolite of 
remdesivir. Thus, chloroquine or hydroxychloroquine use for the treatment of COVID-19 is 
prohibited during the study. 
 
Concomitant use of any other experimental treatment or off-label use of marketed medications 
intended as specific treatment for COVID-19 or SARS-CoV-2 infection, and not specified in 
local written guidelines or the NIH COVID-19 Treatment Guidelines, are prohibited.  
6.5.3 
Rescue Medicine 
Not Applicable 
6.5.4 
Non-Research Standard of Care 
Not Applicable 
7. 
STUDY INTERVENTION DISCONTINUATION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Halting Criteria and Discontinuation of Study Intervention 
7.1.1 
Individual Infusion Halting 
See Section 6.1.4 for information about dosing modifications due to laboratory abnormalities. 
 
For an individual subject, an individual infusion must be stopped if they have a suspected drug-
related event of hypersensitivity (Grade 2 or higher) during the infusion. While there are no 


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criteria for grading “hypersensitivity” in the Division of AIDS (DAIDS) Table for Grading the 
Severity of Adverse Events,(20) sites should use Acute Allergic Reaction from that toxicity 
table. Subjects who have an IV infusion stopped for a safety related issues will not continue with 
dosing.  
 
The treatment of any given subject may be stopped for SAEs, clinically significant AEs, severe 
laboratory abnormalities, or any other medical conditions that indicate to the site Investigator 
that continued dosing is not in the best interest of the patient. 
 
In addition, a subject in this clinical study may discontinue study drug at their request for any 
reason. Every effort should be made to encourage subjects to remain in the study for the duration 
of their planned outcome assessments. Subjects should be educated on the continued scientific 
importance of their data, even if they discontinue study drug.  
 
Unless the subject withdraws consent, those who discontinue study drug early will remain in the 
study. The reason for subject discontinuation of study drug should be documented in the case 
report form. 
7.1.2 
Study Halting 
Given the potential severity of COVID-19, there are no pre-specified study stopping rules. 
Instead there will be close oversight by the protocol team and frequent DSMB reviews of the 
safety data.  
7.2 
Withdrawal from the Study 
See Section 7.2 of the Master protocol document. 
7.3 
Readmission 
See Section 7.3 of the Master protocol document. 
7.4 
Lost to Follow-Up 
See Section 7.4 of the Master protocol document. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Screening and Efficacy Assessments 
8.1.1 
Screening Procedures 
Screening procedures may be done from Day -1 to Day 1 (Day 1 is the calendar day of 
randomization). However, in many cases all the screening assessments can be done in less than 
24 hours. If that is the case, Day 1 pre-study product administration baseline assessments, 
specimen collection and the initial study product administration can occur on the same calendar 
day as the screening procedures.  
 
After the informed consent, the following assessments are performed to determine eligibility: 
• 
Confirm the positive SARS-CoV-2 test result (per inclusion criteria).  


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• 
Take a focused medical history, including the following information:  
• Day of onset of COVID-19 signs and symptoms. 
• Prior enrollment in ACTIV-5/BET. 
• History of chronic medical conditions, including chronic oxygen requirement and/or 
use of CPAP or BiPAP at home, prior to onset of COVID-19.  
• History of medication allergies. 
• Medications and therapies for this current COVID-19 illness and history of any 
medication listed in the exclusion criteria. Site should identify if the patient received 
any steroids in the 7 days prior to randomization.  
• Ask if the patient is participating in another clinical trial or plans to enroll in another 
clinical trial in the next 30 days. 
 
• Women of childbearing potential must agree to either abstinence or use at least one 
acceptable method of contraception from the time of screening through 30 days after the last 
dose of study IP.* 
• Men must agree to either abstinence or use of contraception from the time of screening 
through 90 days after the last dose study IP.*  
*Note: Acceptable methods include barrier contraceptives (condoms or diaphragm) with spermicide, 
intrauterine devices (IUDs), hormonal contraceptives, oral contraceptive pills, and surgical sterilization. 
• 
Women must agree not to breastfeed for 30 days after last dose of IP.  
• 
Targeted physical examination (targeted exam details in MOP).  
• 
Height and weight (height can be self-reported). 
• 
Assess need for supplemental oxygen, mechanical ventilation, or ECMO. 
• 
Blood for screening laboratory evaluations, if not done as part of routine clinical care in the 
preceding 48 hours, should be collected to evaluate the following parameters: 
 ALT 
 AST 
 Serum creatinine (and calculate eGFR)  
• Any automated calculation by the clinical laboratory or published formula for this 
calculation is acceptable. The site should select a formula to be used for all 
subjects enrolled at the site for the duration of the study. 
• 
Urine or serum pregnancy test (in women of childbearing potential).  
 
Clinical screening laboratory evaluations will be performed locally by the site laboratory. A 
screening lab (i.e., from the hematology and chemistry laboratory panels) may be repeated once 
if, in the opinion of the investigator, the laboratory abnormality is due to an intercurrent transient 
condition or it is an aberrant laboratory value. The overall eligibility of the subject to participate 
in the study will be assessed once all screening values are available. If performed just prior to 
randomization, data obtained from screening can also be a baseline assessment of severity and 
efficacy.  
 


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Study subjects who qualify will be randomized in the interactive response technology (IRT) 
system, and all others will be registered as screen failures only in the EDC system. The ordinal 
scale should be done at the time of randomization; the site will need this data to randomize the 
subject. Clinical laboratory tests performed as part of routine clinical care in the 48 hours prior to 
enrollment will be accepted for determination of eligibility.  
8.1.2 
Efficacy Assessments 
For all baseline assessments and follow-up visits, refer to the Schedule of Assessments (SOA) 
for procedures to be completed, and details below for each assessment. 
 
Laboratory tests performed as part of routine clinical care in the 24 hours prior to first dose will 
be accepted for the baseline laboratory tests. Baseline may be the same as the screening 
laboratory tests if obtained in the 24 hours prior to first dose. 
8.1.2.1 
Measures of Clinical Support, Limitations, and Infection Control 
The subject’s clinical status will be captured on each study day while hospitalized up until and 
including Day 29. Once subjects are discharged from the hospital, they will have a study visit on 
Days 8, 15, 22, 29, and 60 visits (only the ordinal score and SF-12 will be obtained on Day 60) 
as an outpatient. The Day 8, Day 22 and Day 60 visits do not have laboratory tests or collection 
of samples and may be conducted by phone. Day 15 and Day 29 visits are preferred to be in 
person in order to collect safety laboratory testing, stored samples, and virologic assessments but 
may be performed by phone. Clinical status is largely measured by the ordinal score. The ordinal 
scale can also be evaluated over the phone if the discharged subject is unable to return for in-
person visits on Day 15 and 29.  
 
The following measures are recorded for the ordinal scale. See MOP for more detailed description 
of ventilatory devices in each category: 
• Hospitalization. 
• Oxygen requirement. 
• Non-invasive mechanical ventilation (via mask) requirement. 
• High-flow oxygen requirement. 
• Invasive mechanical ventilation (via endotracheal tube or tracheostomy tube) 
requirement. 
• ECMO requirement. 
• Ongoing medical care preventing hospital discharge (COVID-19 related or other medical 
conditions). 
• Limitations of physical activity (self-assessed and reported as new or increased 
limitations as compared to status prior to the onset of COVID-19). 
• Isolated for infection control purposes. 
8.1.2.2 
Ordinal Scale 
The ordinal scale is the primary measure of clinical outcome per the Master protocol document 
(Section 8.1.1.1) 


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8.1.3 
Exploratory Assessments 
See Section 8.1.2 of the Master protocol document. Additional exploratory assessments include: 
• Plasma cytokines or other inflammatory markers on Days 1, 3, 8, 15, and 29 (if attends 
in-person visit or still hospitalized). 
• Blood RNA transcriptome analysis on Days 1, 3, 8, 15, and 29 (if attends in-person visit 
or still hospitalized). 
• PBMC assessment for phenotype and functional reactivity on Days 1, 3, 8, 15, and 29 (if 
attends in-person visit or still hospitalized; collected only at sites capable of collecting 
and processing PBMC).  
• Plasma samples for PK: 
o Day 1: pre-dose prior to 1st and 2nd dose; 
o Day 3: pre-dose prior to 9th dose, 2hr, 4hr & 6hr post-9th dose (Day 3 samples 
may be collected before and after a subsequent dose while hospitalized) 
• Patient-reported outcomes: 
o Short-Form (SF)-12: The SF-12 is a validated health-related quality of life 
(HR-QoL) instrument that is widely used across a broad spectrum of disease 
indications. Adapted from the 36-item SF survey that was designed to evaluate 
physical and mental health status, the SF-12 survey contains only 12 questions but 
covers the same 8 domains. There is a further stratification into 2 summary 
measures (Physical Component Summary [PCS] and Mental Component 
Summary [MCS]) as specified: 
 PCS: 
• General health (1 item) 
• Physical functioning (2 items) 
• Role physical (2 items) 
• Body pain (1 item) 
 MCS 
• Vitality (1 item) 
• Social functioning (1 item) 
• Role emotional (2 items) 
• Mental health (2 items) 
The PCS and MCS summary measures are scored using a norm-based method 
(i.e., mean = 5-, SD = 10).(21) A PCS or MCS score of 50 indicates an average 
score with respect to a healthy population. Scores lower than 50 reflect less than 
average health and scores greater than 50 reflect better than average health.(22) 
The SF-12 assumes a recall of 1 week before responding to questions. The survey 
is anticipated to be completed in several minutes and can be completed by the 
subject or via an interviewer (in-person or over the phone). This form will not be 
monitored. If it is not completed by the subject, it will not be considered a 
protocol deviation. 
8.2 
Safety and Other Assessments 
Safety procedures and assessments are described in Section 8.2 of the Master protocol document. 
The total volume of blood collected over the course of this study for safety and research 


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evaluations (including samples for secondary research) is approximately 500 mL, with a 
maximum daily volume of approximately 75.5 mL. At select sites, approximately 18 mL will be 
collected at 6 collection times for PK and PD evaluation in approximately 20 subjects who will 
be included in the PK/PD analysis, for an estimated additional total blood volume of 108 mL.  
8.3 
Adverse Events and Serious Adverse Events 
AE reporting will occur as described in Section 8.3 of the Master protocol document. 
9. 
STATISTICAL CONSIDERATIONS 
See Section 9 of Master protocol document. 
 
Because of the background use of prophylactic antibiotics specific to this protocol, an additional 
supportive analysis will be conducted: the primary analysis will be repeated limited to those 
subjects randomized to BET-C. 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
All supporting documentation and operational considerations are applicable to the entire 
platform trial and are not unique to the individual stages. These are therefore covered in the 
Master protocol document (Section 10). 
11. 
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